Research & Development Projects July 1, 2001 – June 30, 2004

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Research & Development Projects July 1, 2001 – June 30, 2004

RESEARCH PROJECTS JULY 1, 2008 – JUNE 30, 2009

Project Title: Activity of mecillinam vs E. coli PI: George Zhanel; Funding Source(s): Leo; Total Funding Amount: $50,000; Duration: 2008-2009

Project Title: Activity of NXL-104 on bacterial isolates from Canadian Hospitals (as part of the CANWARD 2009 Study). PI: George Zhanel and Daryl Hoban; Co-PI: Philippe Lagacé-Wiens; Project Description: Evaluate susceptibility of clinical bacterial isolates from Canadian hosptals. Funding Source(s): Pharmaceutical (Novexel); Total Funding Amount: $28,700USD; Duration: 2008-2009

Project Title: Activity of NXL-104 in Combination with Cephem and ß-Lactam Antibiotics Against Genetically Characterized AmpC, ESBL and Reduced Susceptibility to Carbapenem Isolates of E. coli Obtained from Canadian Hospitals PI: Dr. G.G. Zhanel; Co-PI: Dr. D.J. Hoban; Project Description: To assess the activity of NXL-104 in combination with various cephalosporins and ß-lactam antibiotics against genetically characterized E. coli with derepressed AmpC, various ESBL genotypes and isolates with reduced susceptibility to carbapenems obtained from Canadian hospitals. Funding Source(s): Novexel S.A. Total Funding Amount: $19,500; Duration: 6 months (Mar-Sep 2009)

Project Title: Activity of NXL-104 on ESBL, AmpC producing and reduced-susceptibility to carbapenem E. coli and Klebsiella pneumoniae. PI: Philippe Lagacé-Wiens; Co-PI: George Zhanel; Project Description: Evaluate susceptibility of multi-drug resistant Enterobacteriaeceae to a novel -lactamase inhibitor. Funding Source(s): Pharmaceutical (Novexel) Total Funding Amount: $19,500USD; Duration: 2008-2009

Project Title: Agronomic practices to limit the survival in soil of potential human pathogens from livestock manure PI: Krause, Denis, Ivan Oresnik, and Mario Tenuta; Project Description: As above; Funding Source(s): Manitoba Association of Agricultural Societies/ARDI; Total Funding Amount: $70,953; Duration: 2007 – 2010

Project Title: Algorithms and Software for Personalized Genomics PI: Inanc Birol; Co-PI: Steven Jones, Cenk Sahinalp; Project Description: The goal of this proposal is to develop analysis tools for exploring the structural variation of DNA from sequencing data of cancer patient samples. Funding Source(s): BCIC; Total Funding Amount: $292,760 CAD; Duration: 2009 – 2014

Project Title: Alteration of APOBEC3G virion incorporation pathway leads to HIV-1 inactivation in the presence of Vif: Development of a novel anti-HIV strategy PI: Xiaojian Yao; Project Description: APOBEC3G (A3G), a deoxycytidine deaminase, is a powerful host antiviral factor that is recently found to be able to restrict HIV-1 infection. It has been shown that this host protein is able to target into HIV-1 particles and acts to mutate viral DNA as well as to inhibit HIV-1 reverse transcription soon after virus invades into cells. However, although this host protein holds potent antiviral potentials, its action is counteracted by a HIV-1 Vif protein. Mechanistic studies have revealed that HIV-1 Vif is capable of interacting with A3G, and consequently induces its degradation and prevents A3G to be incorporated into viral particles. Due to the fact that host A3G exerts a potent anti-HIV activity which was blocked by HIV-1 Vif, this cellular/viral protein interaction is of considerable interest, as it provides a compelling target for novel therapeutic strategies for treating HIV-1 infection. Successful disruption of the Vif-blockage on A3G’s action is predicted to rescue A3G expression, its virion packaging, and therefore stimulate its natural antiviral activity. In this study, we hypothesize that, if A3G virion incorporation could break though the Vif’s blockage, the antiviral molecule will be efficiently delivered into viral particles and consequently restrict HIV infection and dissemination. To test this hypothesis, we generated an R88-A3G fusion protein by fusing A3G with a virus targeting signal polypeptide derived from HIV-1 Vpr protein, and tested its anti-HIV effect. Interestingly, we demonstrate that R88-A3G fusion protein, but not for the wild type A3G, drastically disrupt HIV-1 infection in the presence of Vif. Moreover, our results revealed that the presence of R88-A3G significantly inhibited virus-associated reverse transcriptase activity. All of these results have demonstrated a novel anti-HIV strategy. To continue the investigation of the feasibility to develop this potent anti-HIV strategy, our research group, in collaboration with other three laboratories in University of Manitoba and The National Microbiology Laboratory, will further characterize and optimize the efficacy of this anti-HIV strategy to block HIV infection and transmission in different CD4+ T cells including healthy and HIV-1 infected primary PBMCs. In addition, the molecular mechanisms underlying this anti-HIV action will be extensively studied. Overall, this study presents a novel strategy of using host antiviral factor to efficiently combat HIV-1 infection. We believe that the successful characterization and optimization of this system may lead to the development of new prevention and therapeutic strategy against HIV-1 infection. Funding Source(s): CIHR HIV prevention operating grant (HPR85525). Total Funding Amount: $ 378,690; Duration: 11/2007 – 11/2010

Project Title: The Antibiotic Resistance Pipeline PI: Dr. Gerry Wright; Co-PI: Michael Mulvey, George Zhanel; Funding Source(s): Institutes for Health Research, Institute of Infection and Immunity; Total Funding Amount: $100,000; Duration: 2008-2009

Project Title: Antiretroviral Therapy Delivery in Two Long-Standing Research Cohorts in Nairobi PI: Lawrence Gelmon; Collaborators: J. Kimani, S. Barasa, C. Wachihi; Project Description: The purpose of this project is to provide antiretroviral delivery and care to the research subjects in the long-standing Pumwani and Majengo research cohorts in Nairobi Kenya. These women, their children and partners have been the subjects of research for over twenty years, and this project provides the opportunity for the delivery of antiretroviral care to those members of the cohorts who require it. Besides providing antiretroviral care to several hundred members of the research cohort and their families, the project assesses the provision of basic HIV/AIDS treatment as well as promotion of prevention programmes, including peer support, voluntary counseling, testing and risk reduction counseling. Funding Source(s): United States Government – PEPFAR program; Total Funding Amount: US$ 105,000 per year; Duration: until March 29, 2010

Project Title: ART treatment in South Africa PI: Chester Morris; Co-PI: Salome Charalambous; Funding Source(s): CDC; Total Funding Amount: $25,000,000 Duration: 2008-2009

Project Title: Assessment of the functional mechanisms driving immune quiescence and infection resilience observed in HIV resistant sex workers. PI:Keith Fowke; Co-Investigators: Xiao-jian Yao, Andrew Mouland; Project Description: We have identified a group of commercial sex workers from Nairobi, Kenya who, despite their intense exposure to HIV, remain uninfected. We have determined that although they are not infected with HIV, their immune system can see HIV infected cells and destroy them. The goal of our research has been to determine the immune, genetic and molecular environment required for this resistance phenotype to be established. We recently determined from studying the CD4+ T cell (which is the main coordinating cell of the immune system and target of HIV infection) that in HIV resistant women these cells are characterized by have a very low amount of activated cells. We have termed this quiet immune response, Immune Quiescence. These cells also express low amounts of factors that are important in establishing HIV infection. This proposal will study the mechanisms responsible for the Immune Quiescence including what causes this state and determine the molecular mechanism that lead to few cells being infected with HIV. Through these studies we will gain insight into how the very important cellular and molecular environment can be shaped to establish an immune environment that is protective against HIV infection, which is the ultimate goal of HIV therapy and vaccine research. Funding Source(s): CIHR; Total Funding Amount: $332,046. Duration: April 2008-March 2011

Project Title: Assessment of a targeted treatment for hepatocellular carcinoma: Phase 1: Toxicology. PI: M.L.H. Gruwel; Co-PI: E. McKenzie; Project Description: As above; Funding Source(s): Industry; Total Funding Amount: $33,969; Duration: 2008-2009

Project Title: Attacking HIV Protease Cleavage Sites with Immunization – Explore the rapid mutation rate of HIV PI: Dr. Ma Luo; Co-PI: Dr. T. Blake Ball, Dr. Gary Kobinger, Dr. Paul Sandstrom; Project Description: Use of a cocktail of peptides overlapping 12 protease cleavage sites as immunogens and deliver the peptides using two different approaches; Funding Source(s): CIHR CVC Catalyst Grant: Vaccines of the 21st Century; Total Funding Amount: $100,000; Duration: 2009-2010 Project Title: Autophagy proteins as molecular targets for cancer treatment PI: M. Bally, K. Gelmon, S. Gorski, J. Lum, R. Young; Co-PI: Steven Jones, et al; Project Description: The overall objective of this proposal is to enhance the translation of these promising autophagyrelated discoveries and therapeutic strategies to treatments beneficial for patients with late stage and recurrent/treatment resistant cancers. Funding Source(s): CIHR; Total Funding Amount: $2,500,000 CAD; Duration: 2010 – 2014

Project Title: The behavioural, social, and cultural factors affecting the epidemiology of sexually transmitted infections (STIs) and bloodborne pathogens (BPs) in high-risk populations in Canada: Determing risk space in Canada’s vulnerable populations. PI: John Wylie; Co-PI: Ann Jolly; Collaborators: Carole Beaudoin, Magdy Dawood, Paul Van Caeseele Project Description: As above; Funding Source(s): CIHR; Total Funding Amount: $538,390; Duration: 2007- 2012.

Project Title: Bioinformatic approaches for the interpretation of cancer genomes PI: Steven Jones; Collaborators: A. Brooks-Wilson, P. Hoodless, I. Tai; Project Description: To apply genomic and bioinformatic technologies to the study of human cancer. Funding Source(s): MSFHR; Total Funding Amount: $500,000 CAD; Duration: 2008 – 2013

Project Title: Bioinformatics Platform for Genome Data Analysis at the BC Cancer Agency PI: Steven Jones, Inanc Birol; Project Description: This application for a Genome Data Analysis Center outlines data analysis pipelines and approaches to be established at the Genome Sciences Centre, Vancouver, Canada (GSC), to interrogate cancer genomes and transcriptomes; Funding Source(s): NIH/NCI; Total Funding Amount: $9,134,551 US; Duration: 2009 – 2014

Project Title: Bioinformatics Training for Health Research PI: Steven Jones, Fiona Brinkman; Project Description: The explosion of genetic information, such as the sequencing of the human genome, has created a demand for highly skilled scientists who have a combination of computational and biological training; Funding Source(s): CIHR; Total Funding Amount: $1,950,000 CAD Duration: 2009 – 2015

Project Title: Biology of Cancer: Insights from Genomic Analyses of Lymphoid Neoplasms PI: J. Connors, R. Gascoyne, D. Horsman, M. Marra; Co-PI: S. Jones; Project Description: We propose to apply our Illumina sequencing and bioinformatics pipelines to genome-wide analysis of lymphomas, with the objectives of analyzing entire transcriptomes, including microRNAs, and discovering mutated genes, novel transcript structures, and candidate small molecule inhibitors of proteins we will identify. Funding Source(s): NCIC; Total Funding Amount: $6,284,994 CAD; Duration: 2008 – 2013

Project Title: Blastomycosis: Various Epidemiological and Clinical Studies. Principle Investigator: John M. Embil Projects Descriptions: a) The Appearance of Blastomycosis of the Lungs on Computed Axial Tomographic Scans with Co- Principle Investigators: Michael Meyers and Collaborators: Suzanne Ronald. Project Description: This is one of the ongoing projects concerning the epidemiology, clinical presentations and optimal treatment strategies of blastomycosis in the Manitoba/western Ontario region. In this project, a review of computed axial tomographic scans of the chest is being undertaken to determine patterns observed in pulmonary blastomycosis. Funding Source(s): Unfunded; Duration: 2 years b) Case-Control Genetic Analysis Study of Risk Factors for Acquisition of Endemic Blastomycosis; Co-PI: Stephen Chanock (genetic studies); Lyle Wiebe and Bill Limerick (epidemiologic studies); Collaborators: Kerry Macdonald, Pete Sarsfield, Maxym Choptiany (epidemiologic studies); Project Description: The objectives of this case-control study are to establish the following: a) using a standardized questionnaire, establish behavioural and environmental risk factors for the acquisition of endemic B. dermatitidis infections; b) using a molecular genetics analysis, determine whether differences exist between cases and control for the acquisition of endemic B. dermatitidis disease; and c) if genetic variation exists between cases, a comparison will be undertaken to determine whether there are specific host genetic factors which predispose to invasive versus localized disease; Total Funding Amount: Unfunded; Duration: 5 years c) Risk Factors for Acquisition of endemic Blastomycosis; Co-PI: Choptiany M, Wiebe L, Limerick B, Sarsfield P, Cheang M, Light B, Hammond G, MacDonald K, Trepman E, Pappas P. Project Description: Case controlled study to determine risk factors for acquisition of endemic blastomycosis

Project Title: “Building Capacity to Respond to HIV/AIDS in China” PI: James Blanchard; Collaborators: John O’Neil, Stephen Moses, Ellen Judd (Anthropology), Nancy Yu (Community Health Sciences. Project Description: A Tier 2 agreement from CIDA to build the capacity of the West China School of Public Health at Sichuan University to design training programs for improving HIV prevention, care and support in China. Funding Source(s): CIDA; Total Funding Amount: $998,000; Duration: 2007-2013.

Project Title: Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS). Collaborators: Matthew Gilmour; Project Description: Molecular characterization of multi-drug resistant Salmonella enterica serovar Heidelberg strains isolated from agricultural and clinical samples; plasmid gene characterization; comparative microarray genomics. This project has policy implications on the use of antibiotics in the agricultural sector. Duration: 2005-present

Project Title: Canadian Nosocomial Surveillance Program Studies PI: Various: Co-Investigators J Embil, J Embree, M Mulvey et al Project descriptions: 1) Vancomycin Resistant Enterococci Suveillance in CHEC/CNISP Health Care Facilities: An ongoing surveillance since 1998 of the incidence and changing trends of vancomycin resistance among Enterococci in Canadian sentininel hospitals. MRSA Suveillance in CHEC/CNISP Health Care Facilities: 2) An ongoing surveillance since 1995 of the incidence, changing trends and associated risk factors of MRSA in Canadian sentininel hospitals. Duration: Ongoing; Funding: Health Canada

Project Title: Cancer transcriptome characterization using massively parallel DNA sequencing PI: Marco Marra; Collaborators: Steven Jones, A. Delaney, M. Hirst, R. Holt, R. Moore, R. Morin, R. Roscoe, YJ Zhao; Project Description: Our objective is to establish and operate a high throughput Genome Characterization Centre (GCC) that specializes in sequencing libraries, prepared from mRNAs and microRNAs purified from cancer cells and tissues. Funding Source(s): NIH; Total Funding Amount: $28,879,340 US; Duration: 2009 – 2014

Project Title: Can-Ward 2009 study PI: George Zhanel; Co-PI: Daryl Hoban; Project Description: Nineteen labs in Canada are recruited to collect, identify and ship to the reference centre (HSC, Microbiology) pathogens associated with infections in hospitalized patients in Canada. At the reference site assessment is performed of antimicrobial resistance rates in Canada as well as molecular characterization of resistance in pathogens. Funding Source(s): Wyeth $50,000; Oryx $5,000; Pfizer $100,000; Johnson and Johnson $150,000; Merck $50,000; Astelles $35,000; Abbott $10,000; Novexel $25,000; Targanta $8,000; Cerexa $35,000 Duration: ongoing

Project Title: Characterization of the role of the polymerase basic 1 protein (PB1) in virulence of the 1918 pandemic virus PI: Darwyn Kobasa; Project Description: It has been demonstrated that the PB1 acts as virulence determinant in both the mouse and ferret models of infection. My laboratory has established a minigenome reporter system to evaluate the contribution of the polymerase complex proteins to efficiency of transcription of the viral and messenger RNA produced during infection. We will further validate our findings with live viruses generated by reverse genetics in the mouse model. Funding Source(s): Public Health Agency of Canada;Total Funding Amount: $25,000; Duration: 2008-2009

Project Title: Chemical Pre-clinical development of a nasal adenovirus-based vaccine against Ebola virus. PI:Dr. Gary Kobinger; Project Description: As above; Funding Source(s): Biological, Radiological, and Nuclear (CBRNE) Research and Technology Initiative. Total Funding Amount: $1,168,000 Can; Duration: 2007-2010 Project Title: Chromatin marks in normal and malignant stem cells PI: P. Lansdorp; Co-PI: Steven Jones, M. Hirst, K. Humphries, L. Lefebvre, M. Lorincz; Project Description: This proposal is focused on deciphering the molecular chromatin-based mechanisms that enable normal stem cells to divide and produce daughter cells with functional properties that are identical to the parental cell. Funding Source(s): CIHR; Total Funding Amount: $2,497,744 CAD; Duration: 2008 – 2013

Project Title: CIHR Team in Genomic, Imaging and Modeling Approaches to Advance Population-Based Colorectal Cancer Screening PI: A. Coldman, M. Elwood, C. MacAulay, S. Peacock, I. Tai, H. Zeng; Collaborators: Steven J.M. Jones (BC), Marco Marra; Project Description: Developing multi-dimensional tools to improve detection rates for colorectal cancer. Funding Source(s): CIHR; Total Funding Amount: $2,384,996 CDN; Duration: 2007 – 2013

Project Title: A combined pharmacogenomic: Chemical library screening approach to identify novel drug combinations that will enhance platinum-containing chemotherapy when used to treat ovarian cancer PI: Marcel Bally; Co-PI: Steven Jones, D. Huntsman, Yuzhuo Wang; Funding Source(s): NCIC; Total Funding Amount: $450,741 CAD; Duration: 2009 – 2012

Project Title: Comparison and basis of efficacy in commercial conventional vaccines against the H5N1 influenza virus. Co-PI: Dr. Gary Kobinger; Project Description: As above; Funding Source(s): Canadian Institute of Health Research; Total Funding Amount: $1,500,000 Can.Duration: 2008-2011

Project Title: Comparison of proteomics network changes in TSE pathology using cell-free in situ protein expression array generated from full-length cDNA libraries PI: Leluo Guan; Co-PI: Stephanie Booth; Project Description: Transmissible Spongiform Encephalopathies (TSE) are fatal neurodegenerative diseases which occur in humans and various animal species. It is known that abnormal prions cause plaques to form on the neurons preventing them from functioning properly. However, it is not yet clear whether other proteins are affected by the alteration of prion protein in whole protein network of central nervous system. In this study, we aimed to identify protein-protein interactions that may have involved in TSE disease progression using NAPPA (nucleic acid programmable protein array) technology. Funding Source(s): Alberta Ingenuity Fund Prion Initiative; Total Funding Amount: $200,000; Duration: 2008-2011

Project Title: Comparison of the in vitro activities of ceftaroline and ceftobiprole using clinical isolates of gram- positive and gram-negative bacteria associated with patients with complicated skin and skin structure infections and community-acquired pneumonia PI: Karlowsky JA; Co-PI: Hoban DJ, Zhanel GG; Project Description: Comparison of the in vitro activities of ceftaroline and ceftobiprole using clinical isolates of gram-positive and gram-negative bacteria associated with patients with complicated skin and skin structure infections and community-acquired pneumonia; Funding Source(s): Cerexa, Inc; Total Funding Amount: $93,600; Duration: 2008-2009

Project Title: Comparative genomics of Ruminococcus albus PI: Denis Krause; Project Description: As above; Funding Source(s): NSERC Discovery; Total Funding Amount: $155,000; Duration: 2005-2010

Project Title: A comprehensive catalog of human Dnasel hypersensitive sites PI: John Stammatoyannopolous; Co-PI: Steven J.M. Jones (BC), Marco Marra; Project Description: Accurate maps of Dnasel hypersensitive sites across the human genome will be a major milestone in the delineation of human cis-regulatory DNA. This project component will focus on sequencing of Dnasel 2-hit fragment libraries using the Solexa technology. Funding Source(s): NIH; Total Funding Amount: $443,304 US; Duration: 2007 – 2011

Project Title: Comprehensive Studies of HIV Resistance in Highly-Exposed Uninfected Women. PI: Frank Plulmmer; Collaborators: Keith Fowke; Rafick-Pi P Sekaly; Rupert Kaul; Joshua Kimani; Kenneth Rosenthal; Terry Blake Ball; Ma Luo; Benson Estambale; Walter Jaoko and Yan Li. Project Description: The solution to the HIV/AIDS pandemic, the greatest health issue facing humankind, is the development of effective vaccines. Almost all vaccines were derived out of an understanding, no matter how primitive, of what results in protective immunity. Development of HIV vaccines has suffered from a lack of understanding of the correlates and causal pathways of immunity to HIV. We seek to understand the mechanisms of natural protection against HIV in women who are highly exposed to HIV yet escape infection. A subset of women in a highly HIV exposed Kenyan sex worker (SW) cohort studied since 1985 remain uninfected despite many hundreds of exposures. These women have systemic and mucosal cellular immunologic responses to HIV (both CD4 and cytotoxic T cell [CTL] responses) and mucosal CTL and neutralizing IgA antibody to HIV. While this type of data has been clear for some time in this and other groups of highly exposed, HIV uninfected individuals, an understanding of why these responses develop is limited. A partial answer may lie in genetic correlates of HIV resistance. HLA alleles correlate with protection against HIV infection, as do polymorphisms in immune response genes and HIV co-receptor molecules. Although resistance to HIV infection certainly segregates as a familial trait in genetic studies, it is unclear how these genetic associations correlate with putative protective immune responses. A key reason for slowness in the advance of knowledge on the targets of protective immune response to HIV and the reasons for their development is the small scale – both in terms of numbers of individuals studied and the parameters examined - of previous studies. Our Specific Objective is to undertake an exhaustive analysis of immunologic and genetic factors mediating HIV-1 resistance with the goal of a more complete understanding what constitutes protective immunity against HIV infection. Goal 1: To characterize correlates of protective immune responses to HIV in the systemic and mucosal compartments of resistant and susceptible women by: 1.1 Determine the functional phenotype/specificity of HIV specific CD4 and CD8 T cells, 1.2 Characterise the frequency, specificity, neutralisation capacity and ability to inhibit transcytosis of HIV specific IgA and IgG, 1.3 Determine if resistant women exhibit differential responsiveness to innate stimulation, or altered innate receptor expression such that are more likely to develop protective immune responses to HIV, Goal 2: To identify genetic and innate factors associated with resistance in resistant women and their families by: 2.1 Conducting a non-biased genome wide SNP screen to map genes associated with resistance in both the SW and Kindred cohorts, 2.2 Determine if associations exist between resistance and polymorphisms in previously identified genes important in susceptibility to HIV-1, 2.3 Determine by gene expression analysis if there are genes differentially expressed in resistant women and their families, 2.4 By a mass spectrometry approach identify known and unknown innate factors in serum or mucosa differentially expressed in resistant and susceptible women Goal 3: To determine how genotypes/phenotypes identified above will determine immune responsiveness to a model antigenic challenge of a live, attenuated mucosal vaccinogen. 3.1 The nature and specificity of immune responsiveness to the challenge vaccinogen will be determined by a combination of assays utilised above (gene expression analysis, proteomics, and T cell analysis of function and specificity), Goal 4: To determine if genotypes/phenotypes associated with resistance, or with a favourable response to the model vaccinogen protect against HIV infection in a prospective study of HIV serocoversion in sexworker and non-sexworker cohorts. 4.1 The presence of innate, genetic, or the development of HIV specific cellular immune responses correlate with a reduced likelihood of HIVs seroconversions in initially HIV uninfected individuals at significant risk for HIV infection. Funding Source(s): Bill and Melinda Gates Foundation / CIHR Grand Challenge in Global Health program; Total Funding Amount: $6,632,459 USD (Gates) and $2,072,644 CAD (CIHR); Duration: July 2005-Aug 2010

Project Title: CRTI-06-0218RD PI: Gary Kobinger; Collaborators: Amine Kamen, James E. Strong, Darwyn Kobasa, Maria Croyle, Heinz Feldmann; Project Description: Pre-clinical development of a nasal adenovirus-based vaccine against Ebola virus. Funding Source(s): Chemical, Biological, Radiological, and Nuclear (CBRNE) Research and Technology Initiative (CRTI); Total Funding Amount: $1,219,595; Duration: Ongoing Project Title: 3D-nanoBioMedical Imaging Node (3D-nBMIN). PI: Mai S. Co-PI: Klonisch T. et al. Funding Source(s): CFI; Total Funding Amount: $3,200,000; Duration: 1 year

Project Title: Decontamination Nanofibre project PI: Michelle Alfa and Wen Zhong; Project Description: as above; Funding Source(s): University of Manitoba Total Funding Amount: $1,072.50; Duration: 2008-2009

Project Title: Deep sequencing of a profound mammalian hibernator PI: T. Marr, R. McCombie; Co-PI: Steven Jones, Inanc Birol; Project Description: This project seeks to develop modern molecular research tools for a new animal model that thrives under several sources of stress that are lethal to humans, or that lead to chronic diseases such as type II diabetes or cardiovascular disease. Funding Source(s): NIH; Total Funding Amount: $1,878,617 US; Duration: 2009 – 2012

Project Title: Dendritic Cell Analysis in Hepatitis C Infected Patients. PI: Dr. Sylvia Van den Hurk; Co-PI: Skinner S (Co-investigator), Sanche S (Co-investigator), Wilson J (Co- investigator). Project Description: Evaluation of Hepatitis C virus (HCV): HCV is the etiological agent of non-A, non-B hepatitis. An estimated 170 million people are infected with HCV. We demonstrated the potential for dendritic cell therapy against HCV in a mouse model. To further evaluate the potential of approach, we plan to characterize the dendritic cells from chronic HCV patients in comparison to healthy individuals, and to optimize the functional properties of these dendritic cells by treatment with immunomodulatory compounds. Funding Source(s): Unfunded; Duration: 2009-2012

Project Title: The Determinants of Tuberculosis Transmission in the Canadian-born Population of the Prairie Provinces. PI: R. Long; Co-PI: P. Orr, V. Hoeppner, S. Abonyi, D. Kunimoto, M. King, R. Menzies Project Description: This study looks at the agent, host and environmental determinants of TB transmission among Canadian-born individuals in Manitoba, Saskatchewan and Alberta. Funding Source(s): CIHR Research Grant Total Funding Amount: $902,410 awarded January 2006; Duration: 5 years

Project Title: Developing public health prevention programs: a collaboration between Colombia and Canada to address the spread of HIV and STI PI: John Wylie; Co-PI: Barbara McMillan, Carlos Rojas; Project Description: Relevance Review: The pilot studies described here build towards or provide a future research base for three of the thematic areas within this program call: 1) Global Health: This proposal has a global health focus given the international collaboration involved and our focus on diseases of global concern; 2) Analyzing the impacts of the social and built environments on health: Our proposed research, set within the context of an international collaboration, provides opportunities for developing and adapting public health programs to different socio-cultural and political contexts; 3) Understanding and promoting equity in health: Our proposed research focuses on vulnerable populations and the development of public health programs that specifically cater to the needs of those populations. Overview: This catalyst grant proposal is based on a collaboration between Canada and Colombia. Our research program focuses on population and public health issues related to HIV and related pathogens. Colombia is in a particularly vulnerable position with respect to HIV, and our collaboration provides an opportunity for Canada to continue to develop its capacity to engage in research that addresses global health problems. However, the potential for reciprocal benefits to Canadians also exists. New initiatives in Colombia, aimed at reducing social inequity, provide unique opportunities for comparative studies and observation of natural policy experiments that have the potential to inform researchers and policy makers in other countries, including Canada. The pilot studies described in this proposal will build our collaboration and research base in Colombia so that future comparative studies of similar scope can be mounted simultaneously in both Canadian and Colombia populations. 1. Demonstrate the feasibility of providing HIV point-of-care (POC) testing to sex workers in Medellin: Here we intend to demonstrate the feasibility of providing HIV testing services to commercial sex workers in an urban field setting. This work is novel as published studies to date have only described the use and acceptability of HIV POC testing in outpatient or mobile clinics. By improving access to HIV testing we will be responding to calls for increased use of HIV POC to increase the number of persons who are aware of their HIV status. Our hypothesis is that peer-driven recruitment can be used to create client- centred public health prevention programs where the unique concerns and needs of stigmatized populations are accommodated. 2. Demonstrate the feasibility of working collaboratively with rural aboriginal communities for provision of HIV POC testing: This pilot study focuses on aboriginal populations and examines the feasibility of using HIV POC tests in small rural communities. In addition to frequently representing a disproportionately large percentage of HIV cases, many aboriginals live in geographically isolated communities, creating problems for access to health care. In these settings HIV POC testing on-site in a community, could improve testing uptake such that communities can better understand the prevalence of HIV in their local populations and plan appropriate prevention and treatment responses with that knowledge. However, small communities pose unique challenges with respect to the use of HIV POC and this pilot study is meant to begin to examine those issues. Our hypothesis is that collaborative work with a community will provide a means for them to effectively assist in the design and implementation of public health initiatives appropriate for small community conditions. 3. Conduct evaluations of knowledge translation/education activities currently underway for youth in Canada and Colombia: This pilot study has an education focus and is meant to continue building our relationship with street youth in Winnipeg and begin establishing similar types of relationships with street youth in Medellin. It consists of an evaluation of an educational tool developed for street youth in Winnipeg and subsequent planning meetings and activities in Colombia to initiate an exchange of methods and approaches for youth education with a focus on disenfranchised youth. Our hypothesis is that comparative evaluation and review of education initiatives in different countries will assist in the creation of programs amenable to transfer between countries. Funding Source(s): CIHR; Total Funding Amount: $47,429; Duration: 2008-2009

Project Title: Developing a strategy of forage and grassland management in Manitoba through an examination of multi-functionality of forages, including net greenhouse gas emissions and nutrient utilization in forage-based beef cattle production systems. PI: Ominski, K. H., Wittenberg, K. M., and Krause, D. O. Project Description: This multidisciplinary project evaluates how forages can be best integrated into beef cattle production systems in Manitoba, particularly when animals experience hypothermia during over-wintering. The parameters of interest are pathogen shedding, nutrient accumulation in manure and soil, metabolic adaptation to hypothermia, green house gas emissions, and animal productivity. Funding Source(s): Canadian Cattlemen’s Association, Manitoba Rural Adaptation Council Total Funding Amount: $561,000 Budget for microbial and adaptation studies is approximately $50,000 per year. Duration: 2008-2011

Project Title: Development of Canadian diagnostic capability for Rift Valley fever virus PI: Hana Weingartl; Co-PI: William Wilson, Ute Stroeher, Robbin Lindsay, Markus Czub, Stuart Nicol; Project Description: Development of diagnostic tests (including reagents) and control samples for RVFV in cattle, sheep and goats, basic pathogenesis and immune response studies; Funding Source(s): CRTI-06-0138RD; Total Funding Amount: $1,215,000; Duration: 2008-2013

Project Title: Development of Efficient Algorithms and Technologies for Structural Variation Detection by Single Molecule Sequencing PI: I. Birol, C. Sahinalp; Co-PI: Steven Jones; Project Description: The group of researchers will develop a mapping algorithm for single DNA sequencing technologies and analysis methods to detect structural variations in resequencing experiments. Funding Source(s): Genome BC; Total Funding Amount: $68,000 CAD; Duration: 2008 2011

Project Title: Development of high-throughput comparative genomic methods for studying the molecular epidemiology of infectious diseases PI: Dr. Eduardo Taboada, Host and Pathogen Determinants program, LFZ, PHAC. Collaborators: Dr. Victor P. J. Gannon, LFZ, Host and Pathogen Determinants program. Dr. Yongxiang Zhang, LFZ, Host and Pathogen Determinants program. Dr. Andrew Kropinski, LFZ, Host and Pathogen Determinants program lead. Dr. Clifford Clark, NLM, Enteric Diseases program. Dr. Cathy Carrillo, BMH, Campylobacter Laboratory. External participants Dr. Brenda Allan, Vaccine and Infectious Diseases Organization, University of Saskatchewan. Dr. Hugh Townsend, Vaccine and Infectious Diseases Organization, University of Saskatchewan. Project Description: Microarray-based comparative genomic hybridization (MCGH) has uncovered significant intraspecies genomic heterogeneity in C. jejuni and E. coli O157:H7. This project involves the development, testing, and validation of a series of assays for C. jejuni and E. coli based on determining the presence and absence of these heterogenous genes. A 40 gene multiplex PCR has already been developed and tested as part of this project, and current research is focussed on further developments of the method. A second assay in development uses microsphere suspension microarrays (Luminex beads), a platform that can carry out a 20-gene assay for 96 samples in less than one hour and that has the capability to test as many as 100 genes in a single assay. The data will be analyzed in a molecular epidemiological framework aimed at finding clonal relationships between human clinical isolates and isolates from environmental/animal reservoirs for the determination of likely sources of contamination or transmission (i.e. source attribution/tracking) and finding clonal relationships between clinical isolates in order to identify prevalent pathogenic; Funding Source(s): Health Canada Genomics/Biotechnology funding; Total Funding Amount: $817,000; Duration: 2008-2011.

Project Title: Development of live replicating viruses as vaccines and therapies for Viral Hemorrhagic fever viruses PI: SM Jones; Co-PI: Ute Stroher; Collaborators: Tom Geisbert, USAMRIID, Fort Detrick, USA; Mike Bray, Biodefense Clinical Research Branch Office of Clinical Research, NIH, Bethesda, USA; Project Description: Same as above; Funding Source(s): CRTI; Total Funding Amount: $4.8 M , $2.01M direct remainder in kind; Duration: 5 years

Project Title: Development of Low Volume Stool Collector Device for Elderly Incontinent Patients with Clostridium difficile Associated Disease PI: Michelle Alfa; Co-PI: Greg Hammond; Project Description: as above; Funding Source(s): DSM Operating Grant Total Funding Amount: $12,000; Duration: 2008-2009.

Project Title: Development of Efficient Algorithms and Technologies for Structural Variation Detection by Single Molecule Sequencing PI: I. Birol, C. Sahinalp; Co-PI: Steven Jones; Project Description: The group of researchers will develop a mapping algorithm for single DNA sequencing technologies and analysis methods to detect structural variations in resequencing experiments. Funding Source(s): Genome BC; Total Funding Amount: $68,000 CAD; Duration: 2008 2011

Project Title: Development of Efficient Algorithms and Technologies for Structural Variation Detection by Single Molecule Sequencing PI: I. Birol, C. Sahinalp; Co-PI: Steven Jones; Project Description: The group of researchers will develop a mapping algorithm for single DNA sequencing technologies and analysis methods to detect structural variations in resequencing experiments. Funding Source(s): Genome BC; Total Funding Amount: $68,000 CAD; Duration: 2008 2011

Project Title: Development of recombinant Ebola and Marburg virus vaccines PI: Steven Jones; Co-PI: H. Feldmann; Project Desciption: We will use two alternative vaccine vectors, VSV and Adenovirus, to deliver the two major immunogenic proteins of ZEBV and MBGV, the glycoprotein (GP) and nucleoprotein (NP), either singly or in combination. Both the VSV and Adenovirus systems have proven utility as vaccine vectors, both have certain their strengths and difficulties. We have already established that both recombinant VSV and recombinant Adenovirus expressing ZEBV glycoprotein can protect mice from challenge with mouse-adapted ZEBV. We will compare these different vaccine constructs thoroughly using optimized, standardized and validated immune function assays and animal protection experiments. Using this approach we will be able to compare the efficacy of each vector system directly with the other and hence determine which vaccine should be developed as a commercial licensed human vaccine. The choice will be based on technical considerations, particularly the efficacy, economic considerations with respect to manufacturing costs and CRBN priority guidelines. Funding Source: CRBN Research and Technolgy Initiative (CRTI); Canada; Total Funding Amount: CAD $ 2,175,000 (over 3 years); Duration: 08/2006 – 07/2009 Project Title: Diabetic feet projects - An ongoing program of study of the infectious and other complications of diabetic feet. PI: John Embil a) Dietary Habits and Nutritional Status of Patients with Diabetic Foot Ulcers; Co-PI: Courtney Ross; Project Description: Masters Thesis; Funding Source(s): Unfunded; Duration: Two years b) The epidemiology, health care utilization, and cost of inpatient and outpatient care by patients with diabetes and lower extremity complications. Duration and Funding: 2001-ongoing; 2001- 2002 Health Science Centre - $24,985; 2002-onward Eli Lillie - $50,000 x 1 year then $25,000/year c) Lower Extremity Complications of Type 2 Diabetes in First Nations in Manitoba; Co-PI: Heather Dean, Elizabeth Sellers; Project Description: This is a burden of illness study where the objectives are to: establish the prevalence of lower extremity complications of diabetes in children with type 2 diabetes presenting to the Pediatric Diabetes Clinic at the Children’s Hospital; characterize the lower extremity complications in terms of neuropathy, ulcers, paronychia; perform a baseline regional physical examination including vascular assessment and neurosensory examination; perform a retrospective chart review of subject’s chart to determine frequency and magnitude of previous lower extremity complications, and local surgical interventions; establish patient demographics and risk factors, such as: community of residence, age, gender, smoking, status of footwear, access to running water in home, school attendance; and determine current medical care: medications, past medical history, measures of longterm glycemic control, age of diagnosis. Funding Source(s): Unfunded; Duration: 2 years d) Mental Health Status of Persons with Diabetes and Foot Ulcers; Co-PI: Jatinder Sareen; Project Description: Case control study of persons who have diabetes with and without foot ulcers and their caregivers. The rationale is to determine whether the diabetic foot ulcer and care thereof, leads to significant mental health concerns.

Project Title: Dissecting Gene Regulatory Network in Cardiac Cushion Development PI: Aly Karsen; Co-PI: Steven J.M. Jones (BC), Pamela Hoodless, Marco Marra; Project Description: The purpose of this project is to investigate what genes are required to be present for the heart to develop proper valves and walls. We will also investigate how one particular gene controls the presence of numerous other genes in the same location. Funding Source(s): Heart & Stroke Foundation; Total Funding Amount: $376,416 CDN; Duration: 2007 – 2010

Project Title: Educational grant PDF PI: George Zhanel; Funding Source(s): Wyeth; Total Funding Amount: $25,000; Duration: 2008-2009

Project Title: Educational grant summer students PI: George Zhanel; Funding Source(s): Wyeth; Total Funding Amount: $25,000; Duration:2008-2009

Project Title: Efficacy and Safety of Drotrecogin Alfa (Activated) in Adult Patients with Septic Shock PI: Bruce Light; Co-PI: A. Kumar, D. Funk, D. Easton, D. Bell, B. Paunovic; Funding Source(s): Eli Lilly; Total Funding Amount: $72,429.50; Duration: 2009-2010

Project Title: The effect of the CD4 pathogenicity island on HIV susceptibility and disease progression PI: Keith Fowke; Co-PI: Ma Luo, Xiao-Jian Yao; Project Description: As humans we all share the same set of gene, however, we all possess slightly different versions of those gene and that is what makes us all unique as individuals. These genetic differences, called polymorphisms, also have been shown to be associated with differing susceptibility to disease, such as HIV. Our lab has previously demonstrated a link between increased susceptibility to HIV infection and a particular version of the gene that encodes the main host protein that HIV uses to enter into a cell, called CD4. Recent studies from our lab have shown that the genes that surround CD4 could also be linked to altered HIV susceptibility. We have termed this group of genes the CD4 pathogenicity island and this proposal seeks to explore the genetic linkages between these genes and also determine at a molecular level how they affect susceptibility to HIV infection. These studies could lead to be better understanding of the molecular events necessary to HIV to infect a cell which would provide a foundation for further anti-HIV drug development.; Funding Source(s): CIHR; Total Funding Amount: $663,050; Duration: 2008-2013 Project Title: Effects of Novel Wheat Bran and Extracts to Improve Cholesterol Metabolism, Diabetes Control and Gut Health Using Animal Models PI: Taylor, Carla, Harold Aukema, Scott Harding, Peter Jones, and Harry Sapirstein; Co-PI: Denis O. Krause; Project Description: As above; Funding Source(s): Agriculture and Agri-Food Canada; Total Funding Amount: $297,271; Duration: 2008 – 2012

Project Title: Enhance Karnataka: integrated HIV/AIDS prevention and care in India PI: Stephen Moses; Co-PI: James Blanchard, Vandana Gurnani, Reynold Washington; Collaborators: EngenderHealth, PSI, St. John’s Medical College, Swasti, Karnataka Health Promotion Trust; Project Description: This project expands the University of Manitoba’s work in India through additional HIV prevention work in Karnataka, as well as through development of a large HIV/AIDS-related care and support program in Karnataka and in the neighbouring state of Andhra Pradesh. The project’s overall goal is to develop a comprehensive program that provides HIV/AIDS prevention, care, support and treatment to vulnerable and affected populations in 12 high prevalence districts in Karnataka and in five coastal districts in Andhra Pradesh. To achieve this goal, four components will be implemented: HIV prevention among high-risk groups in rural areas; HIV prevention for vulnerable general populations in rural areas; community-based care, support and treatment; and capacity building and systems strengthening. This project will complement the University’s existing prevention programs in India, will significantly expand its work in the care and support field, and most importantly, will provide needed care and support programs and services to the most vulnerable HIV positive individuals. The University of Manitoba is the principal recipient of the grant and is responsible for overall management and design of the project. EngenderHealth, Population Services International, St. John’s Medical College and Swasti will provide technical and capacity building support. The Karnataka Health Promotion Trust (KHPT) will be responsible for overall coordination, management, contracting, monitoring and evaluation of programs and services. For field level implementation, KHPT will work with a group of institutions and NGOs that are already part of its network of implementing partners. Funding Source(s): United States Agency for International Development; Total Funding Amount: USD $22 million; Duration: October 1, 2006 – September 30, 2011

Project Title: Enhancing the Sustainability of Grassland Systems Receiving Hog Manure on Coarse-Textured Soil; the fate of zoonotic pathogens in the environment PI: Tenuta, M., Ominski, K., Flaten, D.; Co-PI: Denis Krause; Project Description: As above; Funding Source(s): Manitoba Livestock Manure Management Initiative; Total Funding Amount: $276,810; Duration: 2007-2010

Project Title: Epidemiology of STI and BBP in an inmate population PI: C Beaudoin, J Wylie; Co-PI: M Dawood, T Larsen, M Sloane, P VanCaeseele, M Wood; Funding Source(s): CIHR Total Funding Amount: $105,304; Duration: 2007-2009

Project Title: Establishing a Novel Proteomics Approach to Assess Effects of Influenza Infection on Lung Cells PI: Kevin Coombs; Funding Source(s): The Manitoba Institute for Child Health (MICH); Small Grant; Total Funding Amount: $ 4,500; Duration: Nov. 2008 to Apr. 2009

Project Title: Etiology of Inflammatory Bowel Disease: Gene & Environment Interactions PI: Barkema, H. W., Krause, D. O. Project Description: This is a large network grant that will develop a population cohort (approximately 700) and then assesses the impacts of genetic predisposition, environmental variables, and microbial causes of IBD. It is divided into Tier I (microbial surveillance of biopsy tissue), and Tier II (tissue culture and animal model studies with adherent invasive E. coli and Mycobacterium paratuberculosis). In both Tiers of the study various individuals are responsible for recruitment, clinical assessment, epidemiology, endoscopy, immunology, and microbiology. Funding Source(s): Alberta Heritage Foundation for Medical Research; Total Funding Amount: $5 million; Duration: 2008-2013

Project Title: Evaluation of AADs Co-PI: George Zhanel; Funding Source(s): CIHR; Total Funding Amount: $150,000; Duration:2008-2009

Project Title: Evaluation of Adenovirus-vectored and conventional inactivated vaccines in cynomolgus macaques. PI: Gary Kobinger; Co-PI: Darwyn Kobasa; Collaborators: Veronika von Messling, Jim Strong Project Description: Development and testing of adenovirus based vaccines for influenza virus and comparison with a conventional inactivated vaccine in a macaque model of lethal infection with the 1918 pandemic influenza virus. Funding Source(s): PHAC, CIHR Duration: 2008 and is ongoing

Project Title: Evaluation of charcoals in an Escherichia coli K88 infectious diseases model, Pancosma PI: Krause, D. O., and Nyachoti, C. M. Project Description: Pancosma, a Swiss biopharmaceutical company approached me because they were interested in evaluating chemically modified charcoals as a therapeutic against enterotoxigenic E. coli in pigs. Their interest was prompted by the fact that Dr. Nyachoti and I bring strong combined/collaborative research in microbiology and production research. Duration: 2008-2010

Project Title: Evaluation of determinants of variable pathogenicity of the swine H1N1 pandemic viruses in a mouse model PI: Darwyn Kobasa; Collaborators: Steven Theriault, Yan Li, Gary Kobinger; Project Description: We have determined that highly related swine H1N1 pandemic viruses can cause variable pathogenesis in a mouse model of infection. Using reverse genetics and molecular virology approaches we will map the viral determinants of pathogenicity. Funding Source(s): Public Health Agency of Canada;Total Funding Amount: $25,000; Duration: 2008-2009

Project Title: Evaluation of the OSOM Trichomonas Rapid Test versus culture and wet preparation examination for the detection of Trichomonas vaginalis PI: Karlowsky JA; Project Description: Evaluation of the OSOM Trichomonas Rapid Test versus culture and wet preparation examination for the detection of Trichomonas vaginalis; Funding Source(s): Diagnostic Services of Manitoba (DSM); Total Funding Amount: DSM internal funding; Duration: 2008

Project Title: Evaluation of protective immunity after mucosal vaccination against Ebola virus Co-PI: Dr. Gary Kobinger; Project Description: As above; Funding Source(s): National Institute of Health (NIAID for Biodefense). Total Funding Amount: $2,666,797 USD; Duration: 2008-2013

Project Title: An Evaluation of Spondylodiscitis in Manitoba PI: Embil, JM; Co-PI: Reynolds J, Sutherland S, Kreck J. Project Description: Radiographic and microbiologic description of spondylodisciti in Manitoba. Funding Source(s): Unfunded; Duration: 2008-2009

Project Title: Evaluation of a water soluble yeast culture as an antimicrobial agent in weaned piglets using the Escherichia coli K88 disease challenge model PI: Nyachoti, Charles, and Denis Krause; Project Description: As above; Funding Source(s): Diamond V Mills, Inc Total Funding Amount: $31,350; Duration: 2007 – 2009

Project Title: Expansion of molecular typing to support food traceback investigations and active surveillance systems PI: Celine Nadon; Co-PI: Matthew Gilmour; Project Description: Capacity for molecular subtyping is necessary for enhancing real-time surveillance for enteric bacterial diseases in Canada. Recent trends like the E.coli outbreaks in spinach and lettuce demonstrate the increasing importance of illnesses caused by foodborne pathogens that are not included in current surveillance programs. These recent outbreaks have also highlighted a decreasing utility for current subtyping methods for some bacterial pathogens. Additionally, the burden of illness of some enteric bacterial pathogens (e.g. Salmonella) has been so large that not all cases are characterized by appropriate methods in real-time, limiting any linkages that may be made with food products. Specific activities include: optimization, validation and implementation of new methods to characterize important foodborne bacterial pathogens. Special focus will be given to “next-generation” methods (e.g. multi-locus, variable number of tandem repeats analysis) for molecular characterization of certain pathogens for which current methods have limited utility, including prevalent serotypes of Salmonella (e.g., Enteritidis, Typhimurium, Heidelberg). Additionally, research will be conducted on the development of methods for foodborne pathogens not currently captured by laboratory surveillance (non-O157 VTEC). New methods will be applied in parallel to existing PulseNet standardized methods to verify correlation at points along the food safety continuum (farm environment, animal, food production and processing, human illness). Funding Source(s): Memorandum to Cabinet: Food Safety and Consumer Action Plan; Total Funding Amount: $1,212,000; Duration: 2008-2013 Project Title: Frequency of Comorbidity in Multiple Sclerosis PI: Ruth Ann Marrie; Co-PI: Lawrence Elliott, Nancy Yu, Jamie Blanchard; Project Description: As above; Funding Source(s): Multiple Sclerosis Society of Canada; Total Funding Amount: $111,288; Duration: 2008-2011

Project Title: Functional Host Genomics of Virus-Infected Cells PI: Kevin M. Coombs; Collaborators: Andrew Halayko (Physiology); Oleg Krokhin (Medicine); Darwyn Kobasa (Medical Microbiology); Sam Kung (Immunology); John Wilkins (Medicine); Project Description: The development of interfering RNA (RNAi; siRNA; shRNA) strategies has allowed functional screening of the importance of various genes by knocking down (or out) the gene of interest and then examining subsequent effects. Microarray technologies have identified large numbers of host genes that are affected during viral infections and we have been undertaking proteomic analyses (detailed in earlier projects) to identify and measure similar effects on host proteins after various human cells are infected with either reovirus or influenza virus. For this project, we are taking advantage of our access to a unique (in Canada) shRNA Library that targets each gene in the entire human genomic repertoire. Populations of cells are transduced with each shRNA, then infected with each virus. Cells that survive are recovered and analyzed to identify host genes that are dispensable to the host but required by the virus for efficient replication. This is expected to provide not only a wealth of basic information about virus-host interactions, but may also contribute to anti-viral strategies. Funding Source(s): Dean of Medicine Strategic Fund (for the Libraries); CIHR (for reovirus research); Total Funding Amount: Dean of Medicine: $425,000; CIHR: $717,535; Duration: Dean of Medicine: 2006-07; CIHR: 2008-13

Project Title: Genetic, serological and microbial factors related to patterns of ileal inflammation PI: Silverberg, M. S., Krause, D. O. et al; Project Description: This project is an example of a unique collaboration between an academic physician (Silverberg) and a scientist (Krause). Dr. Silverberg is an academic gastroenterologist at Mt. Sinai Hospital at the University of Toronto, but also has a PhD in human genetics with an interest in inflammatory bowel disease. This project will evaluate human genetic, immunological, microbiological, and clinical aspects of pouchitis, a disease that often develops in individuals who have had a pouch resection of the caecum as a result of surgical removal of diseased tissue in inflammatory bowel disease patients. One of the interesting aspects of this disease is that it develops within 18 to 36 months of the resection and is considered a good human model of inflammatory bowel disease. Mt. Sinai Hospital has the largest pouch resection clinic in Canada and Dr. Silverberg obtains the biopsy tissues as part of his clinical duties and does genetic studies. Biopsy tissue is then sent to Manitoba where microbiological analysis is done. Funding Source(s): Crohn’s and Colitis Foundation of Canada; Total Funding Amount: $449,816 A total of $56,000 is set aside for the microbiological analysis in years two and three of the project in my laboratory. Duration: 2008 – 2011

Project Title: Genomic Analysis of ‘Novel’ Chronic Bacterial Pathogens in Cystic Fibrosis Patients PI: Dr. Cindi Corbett; Collaborators: Dr. Morag Graham, Dr. Gary Van Domselaar, Dr. Michael Surette, Dr. Jody Berry, Dr. Francis Plummer, Ms. Kathryn Bernard. Project Description: Cystic Fibrosis (CF) is the most common fatal genetic disorder affecting young Canadians. It is estimated that approximately 3,400 Canadians are currently living with CF. Most CF patients succumb to respiratory failure, due to chronic lung infections established in early childhood. The majority of CF patients are colonized with Pseudomonas aeruginosa, however respiratory infections in CF are polymicrobial in nature.The role of host oropharyngeal flora bacteria, namely the Streptococcus milleri group (SMG), in the pathogenesis of CF has been investigated and clinical studies have recently revealed that SMG levels are contributing to acute respiratory exacerbations in some CF patients. Currently there are no reliable diagnostic assays or tools to assess the level of pathogenic SMG isolates within a chronic CF lung infection. We hypothesize that an assessment of the bacterial genomes of each SMG species and their corresponding B-cell immunomes will enable us to rationally develop targets for diagnostic and potentially therapeutic assays, as well as pave the way to functional genomic studies. These studies will have far reaching implications, as these bacteria are also responsible for chronic bronchiectasis and invasive infections Funding Source(s): Federal Intramural Genomics R&D Initiative; Total Funding Amount: 258,000; Duration: 2008- 2010

Project Title: Genomics-Enhanced Forecasting Tools to Secure Canada’s Near-Term Lignocellulosic Feedstock Supply for Bioenergy using the Mountain Pine Beetle-Pinus spp. System PI: J. Bohlmann, J. Cooke; Co-PI: Steven Jones, C. Breuil, D. Coltman, N. Erbilgin, M. Evenden, et al; Collaborators: U. Hacke, N. Isabel, S. Kelly, M. Lewis, E. Plettner, K. Raffa, M. Reid, S. Richards, C. Tittiger Project Description: Develop new genomic resources and functionally characterize defence genes for lodgepole pine and jack pine. Use physiological genomics of pines to assess the impact of drought, a critical environmental factor, on pine–MPB–fungus interaction; Funding Source(s): Genome Canada; Total Funding Amount: $8,625,412 CAD; Duration: 2009 – 2012

Project Title: Genomics of Shiga toxin-producing Escherichia coli PI: Matthew W. Gilmour; Co-PI: Brian Coombes (MacMaster University); Collaborators: Gary Van Domselaar (Manitoba), Morag Graham (Manitoba); Project Description: as above; Funding Source(s): Genomics Research and Development Initiative; Total Funding Amount: $700K; Duration: 2008-2011

Project Title: Genomics of Shiga toxin-producing Escherichia coli PI: Matthew W. Gilmour; Co-PI: Brian Coombes (MacMaster University); Collaborators: Gary Van Domselaar (Manitoba), Morag Graham (Manitoba); Project Description: as above; Funding Source(s): Genomics Research and Development Initiative; Total Funding Amount: $700K; Duration: 2008-2011

Project Title: Harnessing mobile phone usage for HIV and horizontal health systems improvement: PMTCT. PI: Joshua Kimani Co investigators: Lisa Avery, Larry Gelmon, Richard Lester Funding source: IDRC/CIDA African Health Systems Initiatives. 350 000 Canadian, 2009- 2012

Project Title: Healthcare and medical textile research laboratory PI: Wen Zhong; Project Description: Infrastructure is requested for supporting research and development in medical/ healthcare textiles. Funding Source(s): CFI_LOF_N; Total Funding Amount: $100,000; Duration: 2008- 2009

Project Title: Health Research Enhancing Existing Capacity in Applied Health Services and Policy Research in Western Canada. PI: Sheps S, Backman A, Barer M, Casebeer A, Doupe M, Kelly K, Lix L, Marchildon G, Martens PJ Co-PI: Andrusiek D, Berg S, Black C, D'Arcy C, DeCoster C, Dionne F, Dobson R, Elliott L, Forget E, Ghali W, Grunau G, Hadjistavropoulos H, Hemmelgarn B, Horsburgh M, Jette N, Lepnurm R, Macdonald S, Marshall D, Menon D, Moffatt M, Morgan S, Noseworthy, T, Poole B, Roos, LL, Roos N, Thorne S, Voaklander D, White D. Project Description: As above; Funding Source(s): CIHR Strategic Training Initiative in Health Research; Total Funding Amount: $1,790,000; Duration: 2009 – 2015

Project Title: Healthcare and medical textile research laboratory PI: Wen Zhong; Project Description: Infrastructure for supporting research and development in medical/ healthcare textiles. Funding Source(s): CFI_LOF_N; Total Funding Amount: $200,000; Duration: 2009-2010

Project Title: HIV prevention among mobile sex workers and men at risk in Karnataka and Maharashtra. PI: James Blanchard; Co-PI: Stephen Moses, John O’Neil, B.M. Ramesh, Sushena Reza Paul, Shiva Halli, Reynold Washington; Project Description: HIV prevention programs in India have been largely urban-focused and geographically static. As a result, there are important prevention gaps in high-risk rural areas. This project’s goal is to reduce the impact of the HIV/AIDS epidemic among vulnerable populations in six districts of India with high HIV prevalence by providing preventive programs and services to female sex workers and high risk men. Prevention programs will include support for sex worker organizations to mobilize their community members and to provide peer education on HIV and STI risk reduction. High quality STI services for female sex workers will be developed and supported through the project. For the many mobile sex workers in this geographic area, the project will support sex worker organizations to promote social cohesion among sex workers at the origin and destination points of migration, and to develop systems for efficiently linking migrant sex workers to programs and services when they change locations. The project will provide risk reduction and STI services to high risk men, including men who have sex with men and male clients of female sex workers. The project areas will be three neighbouring districts in northern Karnataka and three in southern Maharashtra. Along with the major cities of Mumbai and Pune, the urban areas of the 3 southern Maharashtra districts have long been a primary destination point for migrant sex workers from the rural areas of the bordering districts in Karnataka. There is therefore an important connection between commercial sexual networks in these districts and those in northern Karnataka, which facilitates HIV transmission along these migration corridors. Perhaps more importantly, the mobile FSWs of this region are difficult to reach with sustained prevention programs and health services, thus increasing their risk and vulnerability to HIV. This difficulty is accentuated by the fact that a large proportion of mobile FSWs come from village settings, where programs and services seldom reach. This project will focus on this geographic area, with a special emphasis on ensuring the continuity of comprehensive prevention programs and services for mobile FSWs in this migration corridor. The project has four main objectives: to reduce the transmission of HIV and STIs in the context of female sex work in Bijapur, Bagalkot and Belgaum Districts of Karnataka; to reduce the transmission of HIV and STIs in the context of female sex work in Sangli, Sholapur and Satara districts of Maharashtra; to reduce the migration-related vulnerability of migrant rural female sex workers from northern Karnataka at both the migration source and destination locations; and to reduce the transmission of HIV and STIs among high risk men who have sex with men (MSM) in the six “Corridor” districts.; Funding Source(s): Bill & Melinda Gates Foundation; Total Funding Amount: $6,756,000 Duration: Four years

Project Title: Host genomics of hepatitis C antiviral treatment response Co-Leaders: Dr. Morag Graham and Dr. Anton Andonov; Project Team: Michael Coulthart, Meenu Sharma, Gary Van Domselaar, Shaun Tyler, and Carla Osiowy; External Collaborators: Kelly Kaita (Univ. of MB), Stephen Wong (Univ. of MB), Magdy Dawood (Cadham PHL), Leonard C. Schalkwyk (Univ. of London); Project Description: We are in a new era in the field of genetics, in which the complete DNA sequence of the human genome is available for analysis. DNA sequences are the blueprint or recipe for building a particular organism and individual differences in DNA sequence are the genetic basis of human variability. Techniques have been developed to rapidly identify variable DNA sequences (genes) and are being applied in genetic association studies aimed at identifying which DNA variations underlie a particular disease predisposition, drug response or clinical outcome. One form of genetic analysis focuses upon the alternative spellings, called single nucleotide polymorphisms (SNPs), which normally occur in the sequence of the ~3-billion DNA letters that make up a person’s genome. SNPs resemble single-letter variations in the spellings of a word. A small fraction of these differences may alter the function of a gene, often only slightly. Combining the effect of many slightly altered genes may significantly increase susceptibility to infection, but identifying such a complex set of genetics differences is challenging. Finding susceptibility-causing variants or variants associated with variable therapy responses is one of the highest priorities of current biomedical research. A significant proportion of patients infected with Hepatitis C virus (HCV) fail to respond to the best antiviral therapy currently available. Hence, we propose to apply genetic techniques to compare patients that differ in therapeutic outcome for the purpose of identifying which genetically variable regions may be related to patient responses during antiviral treatment of HCV infections. The planned research uses state-of-the-art genomics technology called GeneChip® microarrays that simultaneously probe millions of sequence variants from an individual. The cost of this type of genetic work is usually prohibitively expensive. However, the cost can be reduced by applying DNA “pooling” techniques to sample populations and such association testing by DNA pooling is an effective initial screening method for nominating host regions potentially involved in disease. This investigation will be the first to look at a clinically relevant problem (HCV) in a Manitoba population and will provide substantial information for future, more comprehensive studies. It also will augment pre-existing expertise at the National Microbiology Laboratory (NML) for microarray research and data analysis, enabling scientists to develop similar whole-genome projects in the future to study other processes involved in susceptibility to infectious disease and drug responses. Funding Source(s): Federal Intramural Genomics Fund Total Funding Amount: $118,300.00 per year; Duration: 2008-2010

Project Title: A Human Study on The Genetic, Environmental and Microbial Interactions that Cause IBD. The Michael J. Howorth IBD GEM Project PI: Croitoru, K., Denis O. Krause, et al ; Project Description: As above; Funding Source(s): Crohn's and Colitis Foundation of Canada ;Total Funding Amount: $5,500,000; Duration: 2007 – 2013

Project Title: Identification of Genetic Factors Related to Response of Antiviral Treatment of Chronic Hepatitis C Virus (HCV) Infection by Genomewide Single Nucleotide Polymorphism Association Studies PI: Dr. Morag Graham; Co-PI: Drs. M. Coulthart, A. Andonov, C. Osioway and M. Sharma; Funding Source(s): Genomics Research and Development; Total Funding Amount: $355,000; Duration: 2008-2011

Project Title: Identification of MiRNA Driven Regulatory Circuits Involved in Prion-Induced Neurodegeneration PI: Stephanie Booth; Collaborators: Leluo Guan, Stephen Moore, Luis Schang Project Description: Prion diseases, or transmissible spongiform encephalopathies, are fatal neurodegenerative disorders of humans and animals. An abundance of evidence links the development of disease with the conformational conversion of PrPC, a normal cellular protein, into PrPSc, a structural isoform that is infectious. In contrast, very little is known about the pathways triggered by these agents that lead to the damage, and ultimate death of neurons. A number of studies have identified global gene expression changes in prion-infected brain; these have revealed multiple genes and signaling pathways that may be involved in pathogenesis. It is extremely important to determine which of these genes and pathways have a ‘cause’, rather than ‘effect’, role in the disease. The development of micro-dissection techniques to isolate and study the genetic content of individual cells allows us to specifically target degenerating neurons. Especially important is the identification of key regulators activated by exposure to prions that may be potential targets for therapeutics. These include transcription factors and regulatory protein kinases. The recent identification of a novel class of small non-coding RNAs, the microRNAs (miRNAs), has revealed an important new layer of gene regulation. MiRNAs potentially control the expression of one third of the human genome and can have a broad influence over diverse genetic pathways. It is therefore not surprising that mounting evidence suggests that the misexpression of miRNAs is an important factor in disease processes such as cancer, Alzheimers disease and polyglutamine neurodegenerative disorders. The aim of the proposed study will be to identify specific miRNAs, and associated gene regulatory circuits, that control neuronal survival and apoptosis during prion diseases. We will also test the utility of a novel system to deliver small RNAs to the brain to investigate miRNA function in vivo and to explore the use of miRNAs as novel therapies for prion diseases. Funding Source(s): PrioNet Canada; Total Funding Amount: $491,000; Duration: 2008-2011

Project Title: Identification of Molecular Biomarkers in Bovine Urine PI: David Knox; Study description: The use of PrPd as a pre-clinical, or general marker for surveillance is limited, due to the fact that it is present in extremely small amounts in accessible tissues, or in body fluids such as cerebrospinal fluid, blood and urine. Specific detection of these small amounts of the PrPd conformer is further exacerbated by the presence of a large excess of endogenous PrP. Thus the identification of alternative biomarkers applicable to the development of diagnostic tests or intervention therapies is needed. Urine, due to its ease of collection and comparatively less complex protein profile, is perhaps the ideal fluid for surveillance provided a sufficiently sensitive and specific alternative biomarker for prion infection can be identified. The objectives of this proposal are 1) characterize changes in the the urinary protein profile caused by TSE disease in a variety of model systems, including cattle. 2) identify proteins excreted in urine that will act as biomarkers in the surveillance and diagnosis of TSE diseases. 3) identify the biological processes affected by TSE disease that are responsible for the changed urinary protein profile. The accomplisment of these project objectives will advance efforts aimed at enhancing the surveillance and control of TSE diseases and further our understanding of TSE pathobiology. Funding Source: Alberta Prion Research Institute Total Funding Amount: $197,000 Duration: 2008-2009

Project Title: The identification of mutation specific inhibitors through whole genome re-sequencing of breast cancer cell-lines PI: Steven J.M. Jones (BC); Co-PI: Jianghong An; Project Description: To use next generation sequencing technology to derive the complete genomic sequence of five breast cancer cell lines. Funding Source(s): NCIC Total Funding Amount: $605,066 CDN; Duration: 2007 - 2012

Project Title: Immune Control of Viral Infections: Letting Nature Direct Vaccine Design PI: Keith R. Fowke; Project Description: understanding the role of the immune response in preventing or controlling viral infections. Funding Source(s): MHRC: Manitoba Research Chair Salary Award Program; Total Funding Amount: $500,000; Duration: 09/2008-/08/2013

Project Title: Immunogenetic & immunoregulatory basis for mucosal immune responses to HIV-1 in highly exposed uninfected Kenyan women PI: Frank Plummer; Collaborators: Keith Fowke; Study description: Expand our studies of resistance to further characterize mucosal immune mechanisms potentially mediating HIV-1 resistance with the goal of understanding the correlates of protection against HIV. Duration: July 2004 – June 2009; Funding: NIH; $1,900,725 USD

Project Title: The Immunogenetic Program of First Nations and Susceptibility to Mycobacterium tuberculosis isolates. PI: P. Orr; Co-PI: L. Larcombe; Project Description: This study looks at cytokine polymorphisms in the immune response of Dene and Cree populations to infectious agents. The virulence of Manitoba TB fingerprints in an animal model is also explored. Funding Source(s): National Sanitarium Association Research Grant; Total Funding Amount: $442,200 awarded February 2006; Duration: over 3 years

Project Title: “An impact assessment of targeted intervention for prevention of HIV in India” PI: Dr. James Blanchard; Project Description: The primary objectives of the project are to elucidate HIV transmission dynamics in India; examine whether targeted interventions have been implemented as intended in India; and to evaluate the extent to which targeted interventions have contributed to reduced HIV transmission in India. Funding Source(s): World Bank; Total Funding Amount: $159,000 USD; Duration: March 12, 2009 – February 26, 2010

Project Title: Improved management of dry cows and transition cows PI: Plaizier, J.C. (Kees), Krause, D. O., and Connor, L. M. Project Description: This project examines the nutritional, reproductive, microbial, and metabolic responses in transition dairy cows. Funding Source(s): Westgen Endowment Fund ($20,0000 ; Manitoba Association of Agricultural Societies/ARDI ($68,750); Duration: 2008 - 2011

Project Title: Improving diagnosis and treatment of sub-acute ruminal acidosis and butter fat depression in dairy cows PI: Plaizier, J.C., and Denis O. Krause; Project Description: as above; Funding Source(s): Manitoba Rural Adaptation Council; Total Funding Amount: $40,000; Duration: 2007 - 2009

Project Title: Individual, social and environmental barriers to HIV risk reduction among men who have sex with men and transgendered populations in India PI: Dr. James F. Blanchard; Co-PI: Ms. Monika Doshi, Drs. Robert Lorway, Stephen Moses, John O’Neil, BM Ramesh, Sushena Reza-Paul; Project Description: The overall goal of this project is to create knowledge about the environmental, social and individual factors that inhibit the adoption of safer sexual and health-seeking behaviours by MSM and Hijras in urban settings of India. The specific aims of the project are to: 1) describe patterns of social and sexual networking of MSM-H in different urban settings. 2) compare and contrast how local social environmental and structural factors influence stigma and discrimination experienced by MSM-T in these settings. 3) assess and analyze how psychosocial factors influence sexual risk taking and health seeking behavior. Funding Source(s): CIHR; Total Funding Amount: $109,670; Duration: September 1, 2007 – August 31, 2009

Project Title: Influenza nonhumanprimates and mouse studies Principle Investigator: Heinz Feldmann: Co-PI: Hideki Ebihara; Project Description: The proposed research will study the biology and pathogenesis of pandemic and highly pathogenic avian influenza viruses in vitro and in vivo. The goal of the studies is a better understanding of the pathogenic mechanisms for the development of new countermeasures. Funding Source: NIAID, NIH (ARRA Funds); Total Funding: US $ 1,500,000 (over 2 years) Duration: 10/2009 – 09/2011

Project Title: Informal social supports, caregiving and HIV/AIDS: A community-based study PI: C. Pindera, J. Mignone; Co-PI: L. Elliott, C. Harvey, Akan M, Smith C.; Project Description: The study uses qualitative research methods to determine how the issues impacting on social support networks, formal and informal caregiving contribute to the health and social outcomes of people living with and affected by HIV/AIDS. Funding Source(s): CIHR; Total Funding Amount: $224,248; Duration: 2007-2009.

Project Title: INSL3 in the human thyroid gland. PI: Hoang-Vu C; Co-PI: Klonisch T. Funding Source(s): DFG, German Research Council Total Funding Amount: Euro 145,000; Duration: 2008-2010

Project Title: Integrated Epigenetic Maps of Human Embryonic and Adult Cells PI: J. Costello, M. Marra; Co-PI: Steven Jones, M. Hirst, R. Roscoe; Project Description: We propose to work cooperatively with other Mapping Centers and the Data Coordination Center (EDACC) funded by this Roadmap mechanism to comprehensively map epigenomes of select human cells with significant relevance to complex human disease. Funding Source(s): NIH; Total Funding Amount: $11,655,600 US; Duration: 2008 – 2013 Project Title: International Infectious Disease and Global Health Training Program: Four Continents, One Shared Experience PI: K. Fowke; Co-PIs F. Plummer, J. Wylie, S. Moses, J. Blanchard, L. Elliott, M Becker; Project Description: Project Description: The objective of this research project is to support advanced trainees (PhD students, postdoctoral fellows and clinical fellows) from all four of CIHR’s pillars of research (basic, clinical, epidemiology and social sciences).The Program includes four major research centres (Nairobi, Medellin, Bangalore, Manitoba).with 3 major research foci (HIV, emerging infections and global health) and 4 themes (Aboriginal health, ethics, knowledge translation and professional development). Funding Source(s): Canadian Institutes of Health Research; Total Funding Amount: $325,000 per year; Duration: 2009-2015

Project Title: In vivo evaluation of conventional and experimental Avian influenza A (H5N1) virus vaccines PI: Dr. Gary Kobinger; Project Description: As above; Funding Source(s): Canadian Institute of Health Research Total Funding Amount: $147,400 Can; Duration: 2007-2009

Project Title: Investigation of molecular mechanisms underlying the action of HIV-1 integrase during viral nuclear import and replication PI: Xiaojian Yao; Collaborators: Dr. Andrew Mouland, McGill University; Project Description: The capacity to infect non-dividing cells productively is one of the hallmarks that distinguishes HIV-1 from oncoretroviruses. This feature is particularly important for the establishment of HIV-1 replication and pathogenesis in exposed hosts, since infection of postmitotic cells including macrophages, mucosal dendritic cells as well as quiescent T cells may be essential not only for viral replication and dissemination, but also for the establishment of persistent viral reservoirs. Mechanistically, the ability of HIV-1 to infect non-dividing cells relies on an active nuclear import of viral preintegration complex (PIC) by using cellular nuclear import machinery. Interestingly, accumulated evidence also suggests that such mitosis-independent nuclear import of HIV-1 PIC is an essential step not only for a successful viral infection in non-dividing cells, but also in dividing cells. Therefore, the active viral PIC nuclear import is one of the key steps towards to a successful viral infection. However, it is still not fully understood how HIV-1 recruits cellular nuclear import pathway(s) to ensure its PIC nuclear import and subsequent integration into host genome. The integrase (IN) of HIV-1 is a critical enzymatic protein that catalyzes integration of viral cDNA into host chromosome. In addition, this viral protein has been shown to be a karyophilic protein and plays an important role during HIV-1 PIC nuclear import. Interestingly, in contrast to MAp17 and Vpr that are only required for efficient HIV-1 nuclear import in non-dividing cells, IN was shown to be necessary for this viral replication step in both dividing and non-dividing cells. It suggests that IN may utilize different nuclear transport pathways from that of MAp17 and Vpr during HIV-1 active nuclear import. We have focused our studies to elucidate the molecular mechanism(s) involved in IN’s action during viral nuclear import, and our data indicates that the tri-lysine regions located in the C-terminal domain of HIV-1 IN contributes to HIV-1 nuclear import. Moreover, we have recently demonstrated that HIV-1 IN, but not MAp17, interacts with cellular nuclear transport receptors importin  and importin 7. Interestingly, our data further shows that the C-terminal domain of IN is essential for IN interacting with these two cellular factors. Based on these observations we hypothesize that, unlike other HIV-1 karyophilic proteins such as MAp17, HIV-1 IN may utilize unique cellular nuclear transport machineries for efficient HIV-1 PIC nuclear import. By targeting different cellular factors with HIV-1 IN and other viral factors, these may synergize to ensure efficient HIV-1 PIC nuclear import even in non-dividing cells. In our following studies, we will also expand our analyses to explore the molecular basis underlying these viral/cellular interactions. In addition, we would like to establish a live cell BRET assay to investigate the interaction between HIV-1 IN, and imp/imp7 in a real time manner. This may help to generate a potential cell-based system for screening anti-HIV peptides, and compounds that specifically target this viral/cellular interaction. By using different approaches, we hope to acquire a better understanding of HIV-1 IN actions during the early stage of virus replication, and at the same time open opportunities for new therapeutic strategies against HIV-1 infection. Funding Source(s): CIHR; Total Funding Amount: $322,842; Duration: 10/2006 - 09/2009

Project Title: “Large Animal Biosecurity Laboratory” PI: Krause, D. O; Funding Source(s): Gut Microbiome Laboratory, Canadian Innovation Foundation, Leading Opportunities Fund; Total Funding Amount: $832,534; Duration: 2009 Project Title: Legionella pneumophila serogroup 1 sequence-based type (SBT) distribution in Canada. PIs: Aleisha Reimer and Kathryn Bernard; Collaborators: S. Schindle, S. Au; Project Description: NML strains of L. pneumophila, primarily serogroup 1 but also other serogroups, were typed using a SBT approach used for global surveillance by the European working group for Legionella Infections [EWGLI] and collated with respect to geographic location, patient demographics and if considered as sporadic, or outbreak case; Funding Source(s): in house funding;Total Funding Amount: ~$28-30k; Duration: 2008-2009

Project Title: Macrolide-resistant S. pneumoniae Co-PI: George Zhanel; Funding Source(s): MICH; Total Funding Amount: $40,000; Duration: 2008-2009

Project Title: The Manitoba Multiple Sclerosis Epidemiology Study: Comorbidity And Complications In Multiple Sclerosis PI: Ruth Ann Marrie; Co-PI: Lawrence Elliott, Nancy Yu, Jamie Blanchard; Project Description: as above; Funding Source(s): MHRC; Total Funding Amount: $99,000; Duration: 2008-2010

Project Title: Manitoba Multiple Sclerosis Epidemiology Study: An Update Study PI: Ruth Ann Marrie; Co-PI: Lawrence Elliott, Nancy Yu, Jamie Blanchard; Project Description: as above; Funding Source(s): Health Sciences Centre Foundation; Total Funding Amount: $35,000; Duration: 2008-2009

Project Title: Mapping key populations for HIV prevention in Sri Lanka PI: Stephen Moses; Co-PI: Robert Lorway, BM Ramesh, Shajy Isac and Faran Emmanuel; Project Description: The overall goal of the project is to provide accurate information on the size and characteristics of vulnerable key populations in Colombo and 4-5 other key urban areas of Sri Lanka. Funding Source(s): World Bank; Total Funding Amount: $46,200 USD; Duration: April 13, 2009 – November 30, 2009

Project Title: Mechanisms of HOX protein mediated transformation PI: Jay Hess; Co-PI: Steven Jones, Gordon Robertson, Ali Shilatifard; Project Description: Using bioinformatics tools, we will identify and characterize regulatory elements responsive to HOXA9 in hematopoietic cells. Funding Source(s): NIH; Total Funding Amount: $90,000 US; Duration: 2006-2011

Project Title: Michael Smith Prize in Health Research PI: Dr. F.A. Plummer; Funding Source(s): CIHR; Total Funding Amount: $100,000 CAD Duration: July 1, 2007 – June 30, 2012

Project Title: Microbial Forensics PI: Dr. Cindi Corbett; Collaborators: Dr. Steven Jones, Dr. Morag Graham, Dr. Gary Van Domselaar, Dr. Betty Golsteyn-Thomas, Dr. Michael Surette, Dr. John Austin, Dr. Wangxue Chen, Dr. Kingsley Amoako, Mr. Douglas Bader, Mr. Chad Stratilo; Project Description: The federal government must be able to rapidly assess and establish a thorough criminal case to bring perpetrators of a bio-crime to justice. The case must stand up to legal scrutiny and meet international standards due to the nature and global importance of successful prosecution. Funding Source(s): CRTI ; Total Funding Amount: 2.7 million; Duration: 2007-2011

Project Title: MicroRNAs and Infectious Disease: A Novel Regulatory Mechanism in Host-Pathogen Interaction PI: Stephanie Booth; Co-PI: Jingxin Cao, Timothy Booth; Collaborators: Quaid Morris, Manjunath Swamy Project Description: The innate immune system is the cell’s first line of defence against invading organisms. Many viruses have evolved elegant strategies to overcome this innate immune response and successfully replicate in host cells. These strategies involve blocking the host response pathways at either the protein or gene expression levels. Recently a new mechanism of gene regulation has been discovered: specific small nucleic acid molecules, or miRNAs, that can bind to genes to prevent their expression. These miRNAs are emerging as pivotal regulators of many biological processes and although the study of miRNAs and their function is in its infancy preliminary data suggests that they also play key roles in modulating the immune response to viral infections. In this proposal we will bring together a number of PHAC scientists to investigate the role of miRNAs in the host response to viral infections in an attempt to more fully understand the complexity of host-pathogen interactions. This will provide a tremendous opportunity to provide explanations of such enigmas as viral tropism, and the mechanisms by which viruses bypass host defenses, and also enable identification of important gene and miRNA targets for therapeutics. Funding Source(s): Biotechnology Initiative for Government Laboratories; Genomics and Proteomics; Total Funding Amount: $842,564; Duration: 2008-2011

Project Title: Molecular Characterization of Chlamydia trachomatis Virulence Factors PI: Grant McClarty; Project Description: Members of the genus Chlamydia are obligate intracellular bacteria that are ubiquitous pathogens of mammals. Hundreds of millions of people globally are afflicted by Chlamydia trachomatis infections. C. trachomatis urogenital infections are the leading cause of bacterial sexually transmitted diseases (STDs) in both industrialized and developing nations. C. trachomatis STDs are considered a risk factor in facilitating the transmission of HIV and the progression of papilloma virus-caused neoplasia. C. trachomatis ocular infections cause trachoma, a disease that afflicts >400 million people and remains the world's leading cause of preventable blindness. Because of its public health importance, C. trachomatis infections are the focus of intense public health control programs that have largely focused on diagnosis and antimicrobial treatment. Despite aggressive antimicrobial control measures over the past decade, the prevalence of C. trachomatis STDs has surprisingly increased. These findings argue that the most effective way to control, or eradicate, C. trachomatis STDs is through development of a vaccine. Despite a broad range of host species, disease manifestations, and tissue tropisms of these organisms in nature, the genome sequences of chlamydiae are remarkably similar. C. trachomatis strains that cause distinct diseases in humans, including trachoma and sexually transmitted infections, as well as the more distantly related mouse pathogen Chlamydia muridarum, exhibit near genomic synteny. Comparative genomics suggests that genes necessary for the intracellular survival of chlamydiae are conserved, while genetic shift is limited to host- and tissue-specific virulence genes. Diversity in infection tropism and disease potential correlates with genes located in a hypervariable portion of the chlamydial genome termed the plasticity zone. Our previous functional genomics studies have determined that the chlamydial plasticity zone is a hot spot for recombination in the relatively stable Chlamydia genomes and that the tryptophan synthase and cytotoxin loci are important virulence determinants. The mouse model has been particularly useful in elucidating the basis of chlamydial immunity and has firmly established the critical role of CD4+ type 1 T cells. in vitro and in vivo studies indicate that IFN- is a critical cytokine for controlling chlamydial infection, and this has been demonstrated in both mice and humans. We have shown that there is a dramatic difference in the susceptibility of different chlamydial strains to IFN- effector mechanisms in different host species, tissues, and cells in culture. Multiple observations suggest that this is due to differences in the antichlamydial effector mechanisms induced by IFN- in various hosts and the presence of chlamydial strain-specific virulence genes. A better understanding of chlamydial virulence factors and host defense mechanisms are needed to guide vaccine development. The genetic basis for virulence, the diversity of disease expression and tissue tropism remain major unanswered question in Chlamydia biology that will be addressed in this proposal. The specific hypothesis to be addressed is: Variation in the tryptophan synthase and cytotoxin loci in circulating chlamydial strains modulate virulence; the genotype that ultimately establishes infection in a given individual is determined by host mediated immune and environmental selection. The following specific aims will guide our research: 1. To collect swabs for testing for chlamydia positivity by PCR and culture. Urethral swabs will be collected from men in Kisumu, Kenya and cervical swabs will be collected from females in Nairobi, Kenya. 2. To PCR amplify and sequence the MOMP, tryptophan synthase, and cytotoxin loci from all chlamydial DNA positive clinical samples. 3. To characterize the in vitro growth characteristics of the clinical chlamydial isolates in various cell lines under different culture conditions, mimicking the in vivo environment. 4. To clone, express, purify, and characterize, in vitro and in vivo, the different tryptophan synthase and cytotoxin genotypes identified in the clinical isolates. The experimental approaches required draw on our expertise in the area of host-pathogen interaction at the cellular and molecular level. The knowledge generated from these experiments will provide a better understanding of chlamydial persistence and disease pathogenesis, could possibly be used to improve treatment strategies and may be applied to vaccine development. Funding Source(s):CIHR; Total Funding Amount:$127,000/yr; Duration:2006-2011

Project Title: Molecular epidemiology of human papillomavirus in cervical cancer in Manitoba PI: Magdy Dawood; Co-PI: Alberto Severini, Robert Lotocki, Erich Kliewer, Alain Demers, Brenna Shearer, Esther Ravinsky, Patricia Baker, Cathy Ludwick; Project Description: We want to study the historical trends in the molecular epidemiology of HPV in cervical cancer cases in Manitoba, in order to define: a) the rate of variation, if any, of the frequency of HPV types causing cancer in Manitoba and b) the relative prevalence of the vaccine vs. non-vaccine types. This will allow for the estimation of the probability of a long term type shift or type replacement after the vaccine is introduced and the proportion of vaccine-preventable cancers in Manitoba, and thus inform the evaluation of the HPV vaccine program. To study the genetics of the most frequent HPV types in cancer (HPV 16, 18 and possibly HPV 31 and 45) and to estimate their diversity and rate of mutation. In addition to the scientific interest of such an unprecedented study, the data obtained will provide an estimate of the rate of genetic changes in HPV after the introduction of vaccine, and an estimate of the likelihood of the insurgence of vaccine escape mutants. Funding Source(s): Manitoba Health and Healthy Living;Total Funding Amount: $222,830; Duration: 2008-2010

Project Title: Molecular mechanisms of a CD4 gene polymorphism associated with HIV disease progression PI: Keith Fowke Project Description: We have performed genetic studies among African cohorts that described a new genetic risk factor that is associated with greater susceptibility to HIV infection and a more rapid course of HIV disease once infected. A novel polymorphism in the gene encoding the primary receptor for HIV, the CD4 molecule, is described. Models and functional studies suggest that significant changes in the three dimensional structure of CD4 could result leading to altered CD4 function. The premise of this study is that the CD4 genetic polymorphism encodes a CD4 molecule with altered tertiary structure. We hypothesize that this alteration either a) increases binding to gp120 thus affect the efficiency of HIV infection or b) alters the normal functions of the CD4 molecule. Either of these scenarios results in higher viral loads leading to increased HIV transmission and rapid disease progression. Funding Source(s): Canadian Foundation for AIDS Research 2006-2008); CIHR (2006- 2009); Total Funding Amount: $94,318 (CIHR); $29,000 (CFAR); Duration: Sept 2006-Aug 2009

Project Title: Monitoring of Antiretroviral Therapy in South India PI: Marissa Becker; Co-PI: Stephen Moses, James Blanchard, Reynold Washington; Project Description: As above; Funding Source(s): Manitoba Medical Services Foundation; Total Funding Amount: $22,500; Duration: January 1, 2009- Dec 31, 2009

Project Title: Monoclonal antibody Laboratory for PrionNet PI: Dr. Niel Cashman, University of B.C. Co-PI: Jody Berry Project Description: Development of an antibody laboratory to support the Prionnet project. Funding Source(s): NCE – PrionNet; Total Funding Amount: $54,000 per annum; Duration: 2006-2011

Project Title: Mother-Child HIV Transmission and Pediatric AIDS in Nairobi Kenya CO-PIs: Drs L Gelmon, J Kimani, J Embree, F Plummer, B Ball Project Description: This is a long standing cohort study conducted with the University of Nairobi in Nairobi, Kenya. The goal is to determine epidemiologic, immunologic, and virologic factors that enhance or protect against maternal transmission of HIV from an infected mother to her child. Maternal-infants pairs were enrolled into the cohort from January 1986 through August 2000 and followed prospectively. Both HIV seropositive and seronegative mother-infant pairs were enrolled. Infants born to seropositive mothers were followed to determine whether they acquired HIV from their mother perinatally or through breast milk or whether they escaped infection. Until recently, antiretroviral agents for the prevention of perinatal HIV transmission or for the treatment of HIV/AIDS were not available or accessible. This situation is being rectified and the study is being modified to address the issues related to the implementation of preventive and therapeutic interventions in this setting. Duration: 1986 and ongoing; Funding: Previously EEC, CHRF, NIH, IDRC, NHRDP, MRC, and CIHR grants; PEPFAR

Project Title: The Mountain Pine Beetle Epidemic PI: Joerg Bohlmann, Janice Cooke; Co-PI: Steven J.M. Jones (BC), Rob Holt, Marco Marra; Project Description: Using genomics of the interacting bark beetles, fungal pathogens, and host pine trees to improve forest ecological risk models. Funding Source(s): Genome BC; Total Funding Amount: $4,063,524 CDN; Duration: 2008 – 2009

Project Title: (Multi-center) Protocol CBX1812-201, A Phase II, Randomized, Double-Mask, Double-Dummy Study Comparing the Efficacy and Safety of Peramivir Administered Intravenously Once Daily versus Oseltamivir Administered Orally Twice Daily in Adults with Acute Serious or Potentially Life-Threatening Influenza. Co-PI: Stuart Skinner; Project Description: As above; Funding Source(s): Biocryst Pharmaceuticals, Inc. Total Funding Amount: to be determined; Duration: 2008 onwards.

Project Title: A Multi-centred, Retrospective Review of Imported Pediatric Malaria at Three Canadian Pediatric Hospitals PI: Maryanne Crockett; Co-PI: Sergio Fanella; Collaborators: David Goldfarb, Shalini Desai Project Description: This is a retrospective review of 18 years of experience with imported pediatric malaria at the Winnipeg Children’s Hospital, the Children’s Hospital of Eastern Ontario, and the Hospital for Sick Children. Funding Source(s): N/A; Duration: 2008-9

Project Title: National anaerobe study Co-PI: George Zhanel; Funding Source(s): Merck; Total Funding Amount: $100,000; Duration: 2008-2009

Project Title: National situation analysis of male circumcision in South Africa PI: Chester Morris; Co-PI: Chiweni Chimbwete; Collaborators: National Department of Health South Africa Funding Source(s): USAID; Total Funding Amount: $300,000; Duration: 2008-2009

Project Title: Natural and Experimental Models of Evolution of Influenza A Viruses. Collaborators: Brown, Babiuk L., Von Messling, Zhou, Mubareke, Weingartl; Project Description: Understanding genetic basis for host range among influenza A in swine, ferrets, guinea pigs, and mice. Funding Source(s): CIHR grant 183963; Total Funding Amount: 95,000$ (Weingartl); Duration: 2008-2010

Project Title: A naturally occurring hepatitis B surface antigen variant, T123A, reduces HBsAg diagnostic detection PI: Dr. Carla Osiowy; Co-PI: Magdy Dawood (Cadham Provincial Health Laboratory, MB); Project Description: Mutations within the antigenic determinant of the hepatitis B virus surface antigen (HBsAg) have been shown to be involved in immune escape, including a possible lack of protection following vaccination and the loss of diagnostic detection. Several Canadian HBV strains having discrepant HBsAg diagnostic testing results by the Abbott AxSym platform were found to have in common a mutation at amino acid 123 within the surface antigen coding region. This amino acid falls within the putative “first loop” of the antigenic determinant to which monoclonal antibodies used for immunoassay detection are often prepared. The HBsAg coding region from one strain was cloned to allow mammalian expression of the mutant HBsAg protein (A123). The wild type protein (T123) was also expressed following site-directed mutagenesis of the mutant clone. Both proteins have been expressed, quantified, diluted and tested on various HBsAg immunoassay platforms (Abbott AxSym, Abbott Architect, Siemens Centaur, Ortho Vitros, Bio-Rad MONOLisa, International Immunodiagnostics), to determine the sensitivity of detection of the mutant and wild type forms. Funding Source(s): Public Health Agency of Canada Total Funding Amount: n/a

Project Title: Neurocognitive Studies in HIV Patients PI: Ned Sacktor (primary investigator; Co-PI: Allan Ronald; Collaborators: Elly Katabira; Funding Source(s): NIH Total Funding Amount: $300,000; Duration: 2007-2009

Project Title: NKT cell and DC interaction in chlamydial lung infection PI: Xi Yang; Funding Source(s): CIHR $100,000; MICH $45,000; Duration: 2009-2010

Project Title: NK cell function in HIV and Influenza PI: Dr. F. Plummer; Co-PI: Dr. Ofer Mandelboim; Funding Source(s): Manitoba Government, University of Manitoba, Hebrew University; Total Funding Amount: $300,000

Project Title: Nuclear events in thyroid carcinogenesis: Molecular mechanisms and diagnostic potential. PI: Klonisch T; Co-PI: Mai S. Project Description: Funding Source(s): CIHR; Total Funding Amount: $165,000 Duration: 2008-2010

Project Title: NXL104 synergy study Co-PI: George Zhanel; Funding Source(s): Novexel 20,000; Duration: 2009

Project Title: Oligomeric PrPres and amyloidogenic PrP fragments: their molecular structure, toxicity, and role in prion disease pathogenesis. PI: Valerie Sim; Co-PI: Stephanie Booth, Byron Caughey, Régis Pomès, Simon Sharpe, Peter Tieleman, David Westaway; Collaborators: Jay Ingram; Project Description: Protease-resistant prion protein (PrPres) is the major protein component of the infectious agent in prion diseases. How pathogenesis develops is unclear, but it is strongly influenced by the conformation of PrPres, the size of PrPres oligomer, and its interaction with membranes. This project will examine these three aspects of pathogenesis using a multi-disciplinary approach combining organotypic culture assays, microarray analyses, solid state NMR, and computer simulations. In the infected brain, the earliest morphological changes are the loss of persistent dendritic spines and the emergence of dendritic varicosities. The new prion organotypic slice culture assay (POSCA) may allow observation of these morphological changes in vitro, by confocal microscopy. PrPres oligomers of differing size, generated by sonication and field flow fractionation, will be applied to the cultures, and the relationship between size of oligomer and nature of dendritic change will be determined. Transcriptional profiles will also be obtained and compared with those from infected animals. Structural studies of PrPres oligomer-membrane interactions are impractical for many reasons, so we will perform solid state NMR and computational studies on short amyloidogenic fragments of prion protein (PrP), whose oligomeric forms can interact with lipids and cause toxicity in cell culture. These studies will provide insight into the molecular basis of toxicity. To better understand why these synthetic peptides generally cause rapid apoptosis (hours) in vitro whereas cell death takes months to years in vivo, we will take the synthetic oligomers and expose them to the organotypic cultures to monitor for morphological changes. If similar dendritic spine changes are seen after exposure to PrPres and the synthetic peptides, an argument can be made that structural features of these fragments are representative of PrPres. Our approach allows us to connect many levels of prion study, from the structure of PrP aggregates to their neuropathogenic mechanisms. Funding Source(s): PrioNet Canada; Total Funding Amount: $400,000; Duration: 2009-2011

Project Title: Open-label, non-comparative, study of intravenous anidulafungin, followed optionally by oral voriconazole or fluconazole therapy, for treatment of documented candidemia/invasive candidiasis in intensive care unit patient populations. (Protocol A8851019) PI: Eric Bow; Co-PI: E. Rubinstein. Collaborators M. Rubinger, B. Schacter, M. Seftel, D. Szwajcer Funding Source: Pfizer Canada, Inc. Total Funding Amount: not yet finalized; Duration of Study: Started 2008 - Projected 2 years

Project Title: Organization of CANR website PI: George Zhanel; Funding Source(s): multi-company; Total Funding Amount: $250,000; Duration:ongoing

Project Title: PARTNERS STUDY: HSV and HIV PI: Connie Celum; Co-PI: Allan Ronald (Kampala Site); Project Description: Completion of follow-up and exiting of all couples Total Funding Amount: $325,000; Duration: 2009

Project Title: Pep35 synergy study PI: George Zhanel; Funding Source(s): Cangene; Total Funding Amount: $20,000; Duration: 2009

Project Title: Perinatal HIV Transmission to Canadian Children Co-PI: King SS, Project Collaborators: Singer J, Forbes J, Lapointe N, Samson L, Vaudry W, Embree, J Project description: This is an ongoing surveillance program of the incidence and changing epidemiology of the transmission of HIV from infected mothers to their children in Canada. Duration: Ongoing since 1993.Funding: PHAC

Project Title: PHAC/CIHR Influenza Research Network (PCIRN) PI: SA Halperin; Co-PI: E Rubinstein, G Hammond, T Booth, et al; Project Description: The PHAC/CIHR Influenza Research Network (PCIRN) will provide a pan-Canadian research network to undertake applied public health research in preparation for and during an influenza pandemic. PCIRN will address 5 objectives to test methodologies for the performance of rapid clinical trials, to assess the safety and immunogenicity of a novel pandemic influenza vaccine, to provide population-based estimates of vaccine safety and effectiveness, to measure vaccine coverage, and to facilitate the rapid implementation of pandemic influenza vaccine programs. These five research themes will be supported by an integrated coordinated data management, information technology, and laboratory system linked to pre-existing public health infrastructure. PCIRN will provide Canada with an established research network at the time of an influenza pandemic that will be able to provide the Public Health Agency of Canada with timely information on the safety and effectiveness of the pandemic influenza mass immunization program. This information will assure Canadians that the public health immunization response to the pandemic is safe, effective, and reaching all segments of the population who require it. Funding Source(s): CIHR, Public Health Agency of Canada - CIDPC (Ottawa, Ontario); Total Funding Amount: $ 10.8 million; Duration: 2008-2010

Project Title: Phages for treatment Co-PI: George Zhanel; Funding Source(s): CIHR – Emerging Team; Total Funding Amount: $300,000; Duration:2008-2009

Project Title: A Phase 2 Study to Evaluate Dose and Duration of Treatment of Drotrecogin Alfa (Activated) Using Serial Managements of Protein C in Patients with Severe Sepsis and Multiple Organ Dysfunction PI: Bruce Light; Co-PI: A. Kumar, D. Funk, D. Easton, D. Bell, B. Paunovic; Funding Source(s): Eli Lilly; Total Funding Amount: $20,178; Duration: 2007-2009

Project Title: A Phase II Study of Posaconazole for the Early Treatment of Refractory Fungal Infections. The "EARLY-POS" study (Protocol P05090) PI: Eric Bow; Co-PI: E. Rubinstein; Funding Source: Schering-Plough Canada Inc.;Total Funding Amount: $30,000.00; Duration of Study: Started 2008: Projected 2 years, currently recruiting

Project Title: A Phase 3, Multicentre, Randomized, Placebo-Controlled, Double-Blind, Three-Arm Study to Evaluate the Safety and Efficacy of Tifacogin (Recombinant Tissue Factor Pathway Inhibitor) Administration in Subjects with Severe Community-Acquired Pneumonia. PI: Bruce Light; Co-PI: A. Kumar and B. Paunovic; Funding Source(s): Novartis; Total Funding Amount: $50,000; Duration: 2006-2008

Project Title: Phenogenomics platform PI: Hicks G; Co-PI: Klonisch T. et al. Funding Source(s): CFI; Total Funding Amount: $5,300,000; Duration: 1 year

Project Title: A population-based characterization of potential microbial etiologies of IBD using geographically defined high and low rate prevalence/incidence areas in Manitoba. PI: Bernstein, C. N., Springthorpe, S., and Krause, D. O; Project Description: This collaborative study is based on epidemiological studies by Bernstein which have identified hot and cold spots of IBD in Manitoba. In this project urban water from hot and cold spots in the province will be analyzed for microbial contamination. Funding Source(s): The Broad Foundation USA; Total Funding Amount: $392,000 Budget of $80,000/year for two years for microbiology. Duration: 2009 – 2011

Project Title: Population Genetics Analysis Program on West Nile Virus PI: Mark Loeb et al; Collaborators: Michael Drebot; Project Description: This project is one of six population genetics research programs funded in 2004 by NIH (NIAID) to assess genetic determinants of susceptibility to infectious diseases or vaccine responsiveness. Our hypothesis is that severity of West Nile virus (WNv) infection in humans is a consequence of genetic factors that result in increased WNv replication and subsequent immune pathology in individuals with neuroinvasive disease. To assess the association between known and discovered candidate immune response genotype sets and susceptibility to neuroinvasive disease in patients infected with WNv, we are conducting a case-control study. Through a collaboration with public health units, individuals from nine states and two provinces most affected by West Nile since 1999 are enrolled if they meet CDC laboratory definition for West Nile virus. Cases are defined as patients who meet the criteria for WNv infection and who have evidence of neuroinvasive disease (meningitis, encephalitis, acute flaccid paralysis). Controls are individuals who meet criteria for infection but who did not develop neuroinvasive disease. Cases will be matched to controls (1:1 ratio) on the basis of ethnicity. We will generate a first panel of 1536 SNPs from 156 candidate genes. By applying gene and cytokine profiling to a cohort of newly WNv infected patients with and without neuroinvasive disease, we will determine the second and third panels (approximately 150 genes in each panel) to be tested. A total of 1200 cases and 1200 controls will be enrolled to detect alleles with a frequency > 0.05 which increase the risk of neuroinvasive disease by a factor of two or more. Funding Source(s): NIH; Total Funding Amount: $ 3,373,365 per year; Duration: 2005-2009

Project Title: Preclinical evaluation of antimicrobial ultrashsort aminoglycoside-peptide antibiotics PI: Frank Schweizer; Co-PI: George G. Zhanel; Funding Source(s): CIHR-POP grant; Total Funding Amount: $150,000; Duration: 2009-2011

Project Title: Pre_Exposure Prophylaxis in HIV Discordant Couples Collaborators: University of Washington – Drs. Connie Celum and Jared Baeten; Allan Ronald; Project Description: As above; Funding Source(s): Gates Foundation;Total Funding Amount: $5 million; initial allocation $855,000; 2008 - 2013

Project Title: Prevalence of Echinococcus spp. in Canine Fecal Samples and anti Echinococcus antibody in Human Sera from Red Earth, SK PI: Dr. Stuart Skinner; Co-PI: Dr. Chelsea Himsworth; Collaborators: Dr. Emily Jenkins, Dr. Janet Hill, Dr. Mandiangu Nsungu, Dr. Athena McConnell, Dr. Momar Ndao; Project Description: This study looking at the prevalence of Echinoccous spp. exposure in humans in this community, and also the prevalence of infection in dogs, the most likely source of infection for humans. In conjunction with this testing, we would like to conduct a survey in people participating in the seroprevalence (blood test) study to determine other possible sources of Echinococcus spp. exposure (i.e., hunting of wolves, coyotes, and foxes). Funding Source(s): University of Saskatchewan; Total Funding Amount: $7500; Duration: 2008-2009

Project Title: Prevalence of lamivudine resistance mutations among treatment-naïve endemically-exposed chronic hepatitis B individuals is low and cannot be linked to demographic predictors PI: Dr. E. Jenny Heathcote (Toronto Western Hospital, University of Toronto); Co-PI: Karen Ng and Carla Osiowy; Collaborators: David K.H. Wong (Toronto Western Hospital, University of Toronto); Project Description: BACKGROUND: Lamivudine resistance mutations in treatment-naïve chronic hepatitis B (CHB) have been described with varying frequencies in different populations. Although alternatives exist, lamivudine remains the standard of care in many countries. We sought both the mutation prevalence and the associated clinical or demographic predictors of such mutations among CHB individuals. METHODS: Demographic ascertainment and antiviral resistance testing were performed on consecutive treatment-naïve CHB adults recruited from a tertiary referral liver clinic between May 2008 and April 2009. Treatment-naïve status was obtained from medical records and then verified in person for all subjects. Resistance mutations were detected by sequence analysis and the INNO-LiPA HBV DR v2/3 kit (LiPA: Innogenetics). Amplicon products generated by LiPA-specific primers were also sequenced to allow determination of the HBV genotype using the NCBI genotyping tool. RESULTS: To date 175 subjects have been analyzed. Mean age is 4515 years with 57% male, 99% Asian, 13% cirrhotic, 23% HBeAg positive, and mean HBV DNA level 4.72.4 log10 IU/L. Genotypes A, B, C and D comprised 4%, 48%, 45% and 4%, respectively. Only 10% were Canadian-born; 48% were born in China, 29% in Vietnam and 7% in the Philippines, and the mean number of years since arrival to Canada was 17, 22 and 18 years, respectively. A total of 8.6% had cohabitated with someone treated for CHB. Relevant mutations were detected in 10.4% (n=16) subjects with instances of L180M (n=4), A181T (n=5), M204I (n=1), S202C (n=5), I233V (n=4), and T194A (n=3). There were no cases of M204V. The prevalence of lamivudine-resistance-associated rt180/rt181/rt204 mutations was very low at only 3.0%. No additional rt180/rt181/rt204 mutants were discovered through sequencing. The T194A mutant was detected through sequencing but not via LiPA. In concordance with previous studies, patients with antiviral resistance mutations were more likely to be male (p<0.005), have a high viral load (p<0.005) and be HBeAg positive (p<0.005). Patterns of mutation did not correlate with age, country of origin, duration of life in Canada, previous use of herbal medications, cohabitation with individuals exposed to antiviral therapy, or prior residence in a refugee camp or prison. CONCLUSIONS: The prevalence of lamivudine resistance mutations among our treatment-naïve CHB population was low at 3.0% in spite of high rates of endemic exposure, and the lack of demographic predictors supports the hypothesis that resistant sequences in a treatment-naïve population arise from random mutation. Funding Source(s): Public Health Agency of Canada; Total Funding Amount: n/a

Project Title: Prevention of colibacillary diarrheal disease in weanling piglets using charcoal as an alternative to antibiotics. PI: Krause, D. O., and Nyachoti, C. N; Project Description: This project is the ARDI matching funding for the Pancosma industry funded; Funding Source(s): Agri-Food Research and Development Initiative (ARDI); Total Funding Amount: $53,000; Duration: 2009 – 2011 Project Title: Production-scale deployment of next-generation sequencing instruments PI: Rob Holt, Steven J.M. Jones (BC), Marco Marra; Co-PI: Martin Hirst; Project Description: We will develop technologies for both the Illumina Genome Analyzer and ABI SOLiD devices, with a goal of exploiting the relative advantages of each platform. Funding Source(s): Genome Canada; Total Funding Amount: $1,998,651 CDN Duration: 2008 – 2009

Project Title: A propensity matched analysis of combination versus mono-antimicrobial therapy of septic shock. PI: Anand Kumar; Funding Source(s): Pfizer Unrestricted Research Grant; Total Funding Amount: $20,000; Duration: 2008

Project Title: A Prospective, Randomized Trial Comparing the Efficacy of Anidulafungin and Voriconazole in Combination to that of Voriconazole alone when used for Primary Therapy of Proven or Probable Invasive Aspergillosis (Protocol A8851009) PI: Eric Bow; Co-PI: M. Rubinger, B. Schacter, M. Seftel, D. Szwajcer. Funding Source: Pfizer Canada, Inc. Total Funding Amount: not yet finalized; Duration of Study: Onset 2008: Projected 3 years, currently accruing

Project Title: Protein kinases in the pathogenesis of prion diseases PI: Luis Schang; Co-PI: Stephanie Booth; Project Description: Although much progress has been made in understanding the transmissible spongiform encephalopathies (TSEs), relatively little is yet known about their pathogeneses. Protein kinases play major roles in pathogenesis of neurodegenerative diseases such as Alzheimer’s or Parkinson’s. They have also been proposed to participate in TSE pathogenesis. Gleevec (an inhibitor of c-Abl and c-Kit kinases) resulted in the degradation of PrPSC and its delayed invasion of the central nervous system. Other protein kinases may participate in PrPSC-induced apoptosis of cultured neurons. We are analyzing the global deregulation of protein kinases during TSE progression to identify those critical for TSE pathogenesis. Such kinases are potentially drugable targets to inhibit disease progression. Our hypothesis is that neuronal deregulation of protein kinase signaling mediates TSE pathogenesis. Our first objective was therefore to develop kinomic assays. We selected 156 protein kinases following these main criteria: those deregulated in scrapie, BSE, other neurodegenerative diseases (Alzheimer's, Parkinson's disease, Multiple Sclerosis, Amylotrophic Lateral Sclerosis) or pathologies associated with TSEs (neuronal degeneration, apoptosis, glial activation, gliosis), even representation of the kinome, and existence of specific antibodies. The multiple western blot conditions of the selected antibodies were optimized with brain extracts of uninfected mice. One hundred fifteen antibodies detected their cognate proteins in uninfected brains. The other 41 detect protein kinases expressed in non- neuronal cells constitutively, but in neurons only under pathological conditions; they are being optimized with non-neuronal cells. We have also started to evaluate the kinomic changes in TSEs. We will characterize the expression and activation of 156 protein kinases using kinomics and hierarchical clustering, to focus on those consistently up- or down-regulated over the course of disease. Their expression profiles will then be used to select approximately 20 deregulated together and related by function, signaling pathway, or pattern of expression. Kinases deregulated together and otherwise related are most likely to mediate, or be deregulated as a consequence of, pathogenesis. In the coming years, we will differentiate kinases that mediate pathogenesis or are deregulated as its consequence by specific inhibition. We have therefore set up kinomic assays by multiple western blot, and are using them to identify protein kinases involved in signaling pathways deregulated during TSE pathogenesis. These experiments may identify protein kinases suitable as pharmacological targets to inhibit disease progression. Funding Source(s): PrioNet Canada; Total Funding Amount: $412,000; Duration: 2008-2011

Project Title: Protein-protein interations PI: Alberto Severini; Co-PI: Michael Carpenter; Collaborators: Jim Strong, Garrett Westmacott, Keding Cheng Project Description: Protein-protein interactions are essential for the functional activity of any biological system. Viruses, because of their absolute reliance on the host cell, must physically and functionally interact with their host cell proteome with consequences that can range from relatively benign to life threatening pathologies. Therefore, the identification of human proteins with which virus proteins interact would not only provide insight into the mechanisms of virus pathogenesis but may also identify new therapeutic targets. Recently, a high- throughput technique, tandem affinity purification (TAP), has been developed which allows for expression and subsequent purification of an epitope tagged “bait” protein in an in vivo context. Because the purification is performed under gentle lysis conditions, physically interacting proteins are co-purified and can be identified by mass spectrometry. Here, we propose to use TAP, in conjunction with mass spectrometry, to identify host cell (human) proteins that interact with proteins from clinically important viruses including papillomaviruses, hepatitis C virus and filoviruses (Marburg and Ebola). Interaction data will be confirmed by co-immunoprecipitation and cellular co-localization studies and where possible the functional relevance will be determined, where possible, by knocking-down the expression of the cellular target and observing the effect this has on virus replication and/or cellular pathogenesis. Funding Source(s): Genomics R&D, Health Canada/NRC; Total Funding Amount: $611,000 Duration: 2008-2011

Project Title: Proteomics of Influenza Virus-Infected Human Cells PI: Kevin M. Coombs; Co-PI: Darwyn Kobasa, Oleg Krokhin, John Wilkins; Project Description: The hypothesis that drives this research is that both viral and cellular protein factors contribute to influenza virus pathogenesis. Overall goals of this research are to use “SILAC” (Stable Isotope Labeling with Amino acids in Cell culture) coupled with multi-dimensional liquid chromatography/MALDI-Qq-TOF mass spectrometry to delineate the total cellular Proteome and the changes effected in human cells by influenza virus infection. A hallmark of influenza virus is the virus’ genetic variability. The virus' ability to undergo antigenic drift (through frequent random mutations) and antigenic shift (reassortment – through gene mixing) leads to rapid generation of antigenically- distinct virus clones. Thus, the human immune system normally does not recognize new flu strains that arise on a nearly yearly basis, and most vaccine preparations offer little, if any, cross-protection against new strains. All viruses are highly dependent upon host cells to replicate. Virus infection causes profound changes in infected cells, including apoptosis, morphological changes and signaling. Genomics (“Gene arrays”) have allowed us to determine particular viral and cellular genes that are either up-, or down-regulated as a result of virus infection. However, the way(s) viruses affect host protein synthesis remains poorly understood in most virus systems. We are using Proteomics coupled with SILAC to delineate protein alterations that occur after influenza virus infection. A variety of human tissue-cultured cell lines, including physiologically-relevant lung cells (A549 and Calu-3), plus a few other non-lung cells, will be grown in media supplemented with either normal “light” amino acids, or “heavy” amino acids. “Heavy” cells will be mock-infected; “Light” cells will be infected with each of various influenza viruses, including non-pathogenic prototype lab strain A/PR/8/34 (an H1N1 virus) and A/NY/55/2004, a prototype H3N2 virus (both of which are BSL-2 agents). In addition, and in collaboration with the National Microbiology Laboratory’s BSL-4 facility, a small number of relevant highly pathogenic strains, including the 1918 “Spanish Flu” will be grown. Equal amounts of the differentially-SILAC-labeled cells will be mixed and cells extracted with NP-40 detergent to both lyse the cells, as well as completely neutralize all virus’ infectivity. Inactivation of the BSL-4 infections will also include irradiation and confirmation prior to removal of samples from the BSL-4 facility. Extracted cells will then be processed by SDS-PAGE and multi-dimensional liquid chromatography/mass spectrometry to identify, and measure, host proteins that are either up-regulated or down-regulated. Analyses of multiple virus types and cell types will provide us with information about viral-specific and cell-specific parameters of pathogenesis, which, when coupled with other on-going studies including siRNA knock-down of each of various human host cell proteins, is hoped to lead to better anti-viral strategies. If post entry infection events by different virus strains involve similar mechanisms, it may be possible to identify common pathways that could be targeted to impact viral replication and release. These studies will also offer a means to compare the different strain effects on host cells and potentially identify factors that impact on pathogenicity. Funding Source(s): CIHR Pandemic Preparedness RFA; Total Funding Amount: $ 244,553; Duration: Feb. 2007 – Jan. 2009

Project Title: Pyrosequencing and assembly of viral quasispecies Co-Leaders: Dr. Frank Plummer and Dr. Gary Van Domselaar; Project Team: Ma Luo, Morag Graham, Anton Andonov, and Carla Osiowy; External Collaborators: Mike Domaratzki (Univ. of MB), Steven Jone (Univ. of MB), Mihai Pop (Univ. of Maryland); Project Description: The commercial availability of pyrosequencing has sparked interest with microbial genomics researchers for its potential to generate genomic sequence data for certain viruses that are difficult to sequence using conventional approaches, including the Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), the Hepatitis C Virus (HCV), and others. These viruses possess high mutation rates that result in the generation of a population of highly similar, but still unique viral genomes, called viral quasispecies, within infected hosts. Determining the genomic makeup of these viruses is important for understanding the biology and evolution of these viruses at a molecular level, and for developing control strategies, vaccines, and antiviral therapies. The conventional Sanger-based) approach for sequencing viral quasispecies requires full genome cloning followed by genome sequencing of multiple clones. However, the difficulties in amplifying entire viral genomes, the low efficiency of cloning full-length viral genomes, the high cost and labour, and the limited throughput of conventional sequencing technology make the sequencing of viral quasispecies populations impractical except on a small scale. Because pyrosequencing can sequence mixed populations of genomic material without cloning and with extremely high throughput, the need for laborious, inefficient, and costly full genome amplifications, cloning and colony picking is eliminated. However, the large amount of short fragment (200-to-300 base-pair) sequences generated by the current pyrosequencing technology poses a bioinformatics challenge in correctly assembling those fragments back into their parent genomes. We propose to develop and make available assembly software and strategies for viral quasispecies genome pyrosequencing, thus substantially reducing the effort and cost of generating viral quasispecies genome sequence data, and ultimately enabling scientists to characterize viral quasispecies populations in large cohort studies. Such studies are essential to understand the viral and host genetic factors influencing diversity and evolution of these viruses, and to develop vaccines and antiviral therapies. Funding Source(s): Federal Intramural Genomics Fund Total Funding Amount: $223,764.00 per year; Duration 2008-2009

Project Title: Rabies virus-induced injury to neuronal processes: role of oxidative stress PI: Alan C. Jackson; Co-PI: Paul Fernyhough; Collaborators: Robert E. Schmidt; Project Description: Because pathologic changes in rabies are not prominent under natural conditions, neuronal dysfunction has until recently been thought to be the basis for the severe acute neurological infection. Recent studies by the principal applicant have provided evidence that rabies virus infection of neurons induces structural changes in neuronal processes without prominent associated changes in perikarya or neuronal death. The involvement of neuronal processes can best be explained by the consequences of oxidative stress, which lead to severe neurological disease with a fatal outcome. The central hypothesis is that rabies virus infection impairs calcium homeostasis and mitochondria function in dendrites and axons and triggers enhanced production of reactive oxygen species (ROS) and that this oxidative stress causes abnormal axoplasmic structural protein function, which results in impaired axonal transport and degeneration of dendrites, axons, and axon terminals. The absence of these structural proteins and ATP-generating organelles leads to axonal degeneration and explains our recently reported neuropathological findings. We will characterize the morphological features of infection with the challenge virus standard (CVS) strain of fixed rabies virus (vs. mock infection) on neuronal processes and evaluate bioenergetics with the intracellular ATP content and mitochondrial membrane potential. The effects of CVS infection on calcium signaling and mitochondrial physiology will be comprehensively evaluated with direct measures of intracellular calcium, mitochondrial respiration, mitochondrial ROS generation, and electron transport complex and Krebs cycle enzyme activity. This work focuses on evaluating mechanisms for neuronal process degeneration in rabies virus infection with particular attention on the role of oxidative stress. This work will improve our understanding of how rabies virus infection of neurons produces clinical disease and help lead the way to the development of novel therapeutic approaches to successfully treat this ancient disease. Funding Source(s): Canadian Institutes of Health Research Operating Grant (2009 – 2010) and Canadian Institutes of Health Research / Manitoba Health Research Council Operating Grant (2010 – 2011): Total Funding Amount: $200,000; Duration: 2009 – 2011

Project Title: A Randomized, Double-Blinded Controlled Trial Comparing High vs Standard Dose Oseltamivir in Severe Influenza Infection in the ICU: An Investigator-Initiated, Multi-centre Study. PI: Anand Kumar; Funding Source(s): Public health Agency of Canada, Roche Pharmaceuticals; Total Funding Amount: $3,250,000; Duration: 2009-2011

Project Title: A randomized trial of influenza vaccination in Hutterite children PI: M. Loeb and the Hutterite Influenza Team (includes PVan Caeseele, Fred Aoki); Funding Source(s): National Institutes of Health and CIHR; Total Funding Amount: $3,623,676 USD (NIH), $500,000 (CIHR); Duration: 2008- 2011

Project Title: A real-time PCR assay for the direct detection of Mycobacterium tuberculosis from acid-fast stain positive specimens PI: Philippe Lagacé-Wiens. Co-investigators : Kanchana Manickam, James Karlowsky DSM Operating grant $10,300; 2009-2010.

Project Title: Research Alliance for the Prevention of Infectious Diseases PI: Dr. Andrew Potter; Co-PI: 9 full-time members and 7 part-time members (including Stuart Skinner) Project Description: The “Research Alliance for the Prevention of Infectious Disease”, or RAPID, is a multidisciplinary team of researchers located at the University of Saskatchewan, Saskatoon Health Region and University of Calgary focused on the development of strategies for the prevention of infectious diseases of importance to the Province of Saskatchewan including, Tuberculosis (TB), West Nile Virus, Chlamydia and Gonorrhoea and hepatitis C. The long term goal of the Research Alliance for the Prevention of Infectious Disease (RAPID) is to develop immunization technologies and infrastructure which can be used to reduce the burden of disease in Saskatchewan in a timely fashion, targeting high risk populations of interest to the Province. This will be guided by computer-aided disease modeling as well as characterization of organisms causing disease and the ability of high risk individuals to respond to vaccines in an appropriate fashion. Our ultimate goal is to develop technologies and information that can be used to guide policy and decision makers within Saskatchewan in the establishment of cost-effective immunization strategies which target the unique diseases and populations within the Province, thus enhancing the quality of life for residents and decreasing the cost of health care associated with preventable diseases. Funding Source(s): Saskatchewan Health Research Foundation; Total Funding Amount: 2.4 million; Duration: 2008-2013

Project Title: Relative Oral Bioavailability of Oseltamivir in Ill Patients with Respiratory Failure in the Intensive Care Unit: An Investigator-Initiated Study. PI: Anand Kumar; Funding Source(s): Roche Pharmaceuticals;Total Funding Amount: $300,000; Duration: 2009

Project Title: Relaxin and small GTPases in the thyroid PI: T. Klonisch Funding Source: NSERC Discovery Grant; Total Funding Amount: $96,000; Duration: 2007-2010

Project Title: Remediation after a Bioterrorism attack PI: Dr. Merv Fingas, Environment Canada; Collaborators: K. Bernard, J. Krishnan, J. Berry, PHAC in Ottawa, other partners; Project Description: Further explore remediation anticipated after a BT attack; Funding Source(s): CRTI 04-0018; Total Funding Amount: >$2 million of which ½ is inkind contribution; Duration: 2005-2009

Project Title: Response of weaned pigs fed diets containing Inovapure to an enterotoxigenic Escherichia coli K88 challenge. PI: Nyachoti, Martin., and Krause, D. O. Project Description: Dr. Nyachoti and I have together refined an infectious diseases model using E. coli K88. This project evaluated a lysozyme enzyme supplement for pigs. Dr. Nyachoti is responsible for animal production parameters in the project. Funding Source(s): Neova Technologies; Total Funding Amount: $30,000; Duration: 2008-2009

Project Title: A Retrospective Review of a Comprehensive Cohort of Fungal Septic Shock: Impact of Echinocandin Therapy on Outcome. PI: Anand Kumar; Funding Source(s): Astellas Unrestricted Research Grant ($150,000); Pfizer Unrestricted Research Grant ($20,000); Duration:2009

Project Title: Reverse Engineering Meets Three-Dimensional (3D) Rapid Prototyping: From Advanced Reconstructive Surgery to Unique 3D Histopathology PI: Klonisch T; Co-PI: Torchia M; Funding Source(s): Virtual Reality Center Funds, Provincial Funding Total Funding Amount: $50,000; Duration: 1 year

Project Title: Risk factors and geographic variation in antibiotic susceptibilities of methicillin resistant staphylococcus aureus in a Canadian pediatric population PI: Embree, JE; Co-PI: Fanella, Sergio; Project Description: This study will determine the differences in MRSA strains affecting children in various communities in Manitoba and will explore epidemiological, clinical and bacterial factors that affect these differences. Funding Source(s): Children’s Hospital Foundation; Total Funding Amount: $21,500; Duration: 1/07/08 – 30/06/10

Project Title: Robotic Intravenous Automation: In Situ Validation of Vial Stopper Decontamination PI: Michelle Alfa; Project Description: As above; Funding Source(s): Intelligent Hospital Systems Total Funding Amount: $9,061; Duration: 2008-2009

Project Title: Role of Bacteroides spp. and Escherichia coli in inflammatory bowel disease PI: Denis Krause; Co-PI: Bernstein, C. N.; Project Description: As above; Funding Source(s): Crohn’s and Colitis Foundation of Canada; Total Funding Amount: $439,934; Duration: 2007-2010

Project Title: Role of cannabinoids in neurogenesis and neuroprotection in Parkinson’s Disease PI: Marylou V. Solbrig; Project Description: The major goal of this project is to identify cannabinoid pharmacologic manipulations and signal mechanisms to support proliferation and survival of neural progenitor cells in viral- induced nuerodegeneration. Funding Source(s): The Charles and Diane Karp Foundation; Total Funding Amount: $50,000; Duration: Aug 1 2008-Aug 1 2010

Project Title: Role of dendritic cell in infection mediated inhibition of allergy PI: Xi Yang; Study description: As above; Duration: 2004-2009; Funding: CIHR; $735,000

Project Title: Role of NKT cell in chlamydial genital tract infection PI: Xi Yang; Co-PI: Weiming Zhao; Funding Source(s): CIHR; Total Funding Amount: $150,000 Duration: 2009-2012

Project Title: Role of relaxin-like peptides in the thyroid gland. PI: Thomas Klonisch; Project Description: Same as above; Funding Source(s): Natural Sciences and Engineering Research Council of Canada (NSERC); Total Funding Amount: CAN$ 96,000; Duration: 2007-2010

Project Title: Scaling up HIV prevention in Karnataka and southern Maharashtra, Phase II PI: Stephen Moses; Co-PI: James Blanchard, Reynold Washington, BM Ramesh; Project Description: The goal of this development project is to reduce the transmission of HIV and STIs in the Indian state of Karnataka, focusing on high risk groups such as female sex workers and men who have sex with men.; Funding Source(s): Bill & Melinda Gates Foundation; Total Funding Amount: $21,291,723.00 USD; Duration: November 20, 2008 – March 31, 2014

Project Title: SCAN1 to cancer: A rare genetic disease identifies a novel target for cancer therapy PI: C. Boerkoel; Co-PI: Steven Jones, Sam Aparicio; Project Description: We have developed a method to screen for compounds that inhibit Tdp1 and will use this to identify such compounds and, with additional testing, characterize their therapeutic utility. Funding Source(s): CIHR; Total Funding Amount: $198,622 CAD Duration: 2009 – 2010

Project Title: Sentinel network to monitor influenza vaccine effectiveness during annual outbreaks and pandemics Co-PI: Y. Li; Funding Source(s): CIHR Team Operating Grant; Total Funding Amount: $496,850/year; Duration: 2008-2011

Project Title: Sequencing for Discovery of Candidate Mutations in Lymphoma Transcriptomes PI: Marco Marra; Co-PI: Steven J.M. Jones (BC), Joe Connor, Randy Gascoyne, Martin Hirst, Doug Horsman Project Description: We will assemble fresh-frozen biopsy material and constitutional DNA from patients with diffuse large B cell (n=92) lymphoma who are uniformly staged, treated and followed in British Columbia. Funding Source(s): NIH-SAIC-Frederick; Total Funding Amount: $4,478,773 US; Duration: 2008 – 2010

Project Title: Short Sequencing Assembly and Finishing of Large Genomes PI: Steven Jones, Inanc Birol; Project Description: With this project, we propose to develop ABySS into a short sequence assembly and finishing tool that alters this paradigm. Instead of designing primers and/or building reduced representation libraries, this new paradigm will make use of paired end sequencing technology and experiments with various insert sizes in an iterative manner to finish genomes. Funding Source(s): Genome BC; Total Funding Amount: $95,000 CAD; Duration: 2009 – 2015

Project Title: Spondylodiscitis in Hemodialysis Patients: An Outcome Analysis PI:John Embil; Co-PI: James Zacharias, Keevin Bernstein; Project Description: Using a case-control methodology, it is the objective of this study to: establish the prevalence of spondylodiscitis amongst the hemodialysis population; describe the diagnostic modalities used to establish the diagnosis; from a retrospective chart review of the subjects, and controls, determine risk factors for the establishment of this condition; establish patient demographics and burden of illness; and establish the therapeutic interventions for the management of this condition and their outcomes. Funding Source(s): Unfunded; Duration: 2007-2009 Project Title: Strategy for inducing heterotypic cross-protection with low pathogenicity virus strains against the highly pathogenic avian H5N1 virus PI: Darwyn Kobasa; Co-PI: Shawn Babiuk; Collaborators: Gary Kobinger, Veronika von Messling; Project Description: We have demonstrated that infection with some low pathogenicity influenza viruses, other than related H5N1 virus strains, can induce fully cross-protective immunity in the ferret, chicken and mouse models of lethal infection with highly pathogenic avian H5N1 viruses. We are further investigating the antigenic determinants that provide the heterotypic cross-protection. Funding Source(s): Public Health Agency of Canada, CIHR;Total Funding Amount: $50,000; Duration: 2008-2010

Project Title: Structure/function of reovirus core: Host Proteomic perturbations PI: Kevin Coombs; Project Description: as above; Funding Source(s): CIHR Operating Grant; Total Funding Amount: $ 717,535 ($143,507 p.a.); Duration: Oct. 2008 to Sept. 2013

Project Title: Study of cancer drug efficacy using 19F and 1H magnetic resonance imaging and spectroscopy PI: B. Tomanek; Co-PI: D. Bartusik, M.L.H. Gruwel; Project Description: Testing of cancer drugs using a bio- reactor and combined NMR and MRI.; Funding Source(s): Canadian Breast Cancer Research Alliance.; Total Funding Amount:$43,100; Duration: 2008-2009.

Project Title: Study to compare Gram stain quality and culture results from specimens collected using Copan M40 Transystem nylon swabs and Copan nylon flocked ESwabs PI: Karlowsky JA; Project Description: Study to compare Gram stain quality and culture results from specimens collected using Copan M40 Transystem nylon swabs and Copan nylon flocked ESwabs; Funding Source(s): Diagnostic Services of Manitoba (DSM); Total Funding Amount: DSM internal funding; Duration: 2009

Project Title: Studies on roles of NS1 protein of avian influenza A H5N1 in evasion of innate and adaptive immunities using an interferon sensitive vaccinia virus recombinant system PI: Jingxin Cao; Collaborators: George F. Gao, Institute of Microbiology, Beijing, Chnia; Project Description: It is a realistic concern that recent sporadic outbreaks of human infection with avian influenza H5N1 subtype virus will evolve to a pandemic human infectious disease. To contain and prevent such an emerging infectious disease, we need to understand the mechanisms on how the avian H5N1 virus becomes capable of infecting and causing serious disease in humans. To break the species barrier, the virus must be able to evade or suppress the immune systems of the new host species. Influenza virus NS1 protein has been shown to suppress interferon (IFN) and tumor necrosis factor (TNF) mediated innate immune defense and compromise subsequent adaptive immune response. However, the studies on how the NS1 protein of an avian H5N1 virus (H5N1-NS1) modulates human innate and adaptive immunities are limited. Two main technical obstacles limit studies on the roles of the H5N1- NS1 in inhibition human immune system. First, the choice of cell culture system and small mammalian animal model for avian influenza viruses is limited. Second, examination of NS1 function in the context of influenza virus infection requires extensive reverse genetic manipulation of the virus genome, which is an extremely laborious process. In this proposal, we plan to use a recombinant vaccinia virus (VV) based system to examine the functions of NS1 protein in modulating human IFN mediated immune responses. VV is well known for its broad range of host cell cultures and animals, and its safety and easiness for manipulation. The VV E3L protein and influenza NS1 protein share a functional similarity in that they both bind to dsRNA and inhibit IFN mediated and dsRNA-dependent antiviral activities. Deletion of the E3L open reading frame (ORF) from VV genome renders the mutant virus (VV ΔE3L) sensitive to IFN. We have created VV ΔE3L based system for studies on other viral proteins of potential suppressing human IFN mediated antiviral activities, in that expression of a viral IFN antagonist can reverse IFN resistance phenotype of VV ΔE3L. This proposal aims to explore three questions with this system. First, do the NS1 proteins of highly pathogenic avian H5N1 and the H5N1 isolate from serious human infection mediate stronger suppressing activity against human IFNs than those avirulent isolates? Second, since VV ΔE3L is completely attenuated for mice, what are the effects of H5N1 NS1 protein on pathogenesis of the recombinant VV ΔE3L virus expressing the NS1 protein in this small mammalian animal model? Third, does the expression of the NS1 protein in VV ΔE3L affect the adaptive immunity in comparison with VV ΔE3L itself? We believe information generated from this proposed studies are extremely valuable for designing effective therapeutic and prophylactic strategies for containing human infections with avian influenza virus H5N1. Funding Source(s): CIHR; Total Funding Amount: $90,000; Duration: from 2008-2011 Project Title: A Study of the Impact of Textiles on the Formation and Prevention of Skin Lesions and Pressure Ulcers PI: Wen Zhong; Project Description: The study would examine the physical and physiological interactions between fabric and skin, and their impact on the formation and prevention of skin lesions and pressure ulcers. This study will contribute to the groundwork for further research for the development of fabrics with optimum properties for preventing these distresses. Funding Source(s): MHRC establishment; Total Funding Amount: $100,000; Duration: 2007-2010

Project Title: SynTarg Discovery Program: Use of a Genome Wide siRNA Screen To Identify Targets that will Enhance Platinum-Containing Chemotherapy when used in First Line Therapy of Non-Small Cell Lung Cancer PI: Marcel Bally; Co-PI: S. Aparicio, S. Jones, J. Laskin, M. Marra; Project Description: The long term aim of the project is to identify targeted drugs that can be used in the development of a combination chemotherapy strategy that includes cisplatin for first line treatment of advanced NSCLC. Funding Source(s): CIHR; Total Funding Amount: $477,534 CAD; Duration: 2008 – 2011

Project Title: Synthetic studies on hydroxyproline rich glycopeptides PI: Schweizer, Frank; Project Description: Funding Source(s): NSERC; Total Funding Amount: 210,000 Duration: 2008-2013

Project Title: Tornado Bedpan Washer Evaluation PI: Michelle Alfa; Project Description: as above; Funding Source(s): St. Boniface General Hospital CPD Total Funding Amount: $3,000; Duration: 2008-2009.

Project Title: Towards Single Cell Genomics PI: Carl Hansen, Marco Marra; Co-PI: Steven J.M. Jones (BC), Martin Hirst, Sam Aparicio; Project Description: New approaches to comprehensively characterize single cells at genome-scale ideally would allow analysis across the entire genome, and would be of sufficient throughput to process thousands of cells simultaneously. Funding Source(s): Genome Canada CDN; Total Funding Amount: $1,756,372; Duration: 2008 – 2010

Project Title: Treating CNS viral injury by restoring neurogenesis PI: Marylou V. Solbrig; Project Description: The major goal of this project is to identify pharmacologic agents to support neural and oligodendroglial progenitor cells in viral-induced injury and neurodegeneration. Funding Source(s): University of Manitoba Medical Group; Total Funding Amount: $100,000; Duration: August 1 2008- August 1 2011.

Project Title: Transport in fibrous materials and biomembranes PI: Wen Zhong; Project Description: To Characterize the relationship between the structures and the transport properties of fibrous materials and biomembranes; Start April 2007; Funding Source(s): Nserc/Discovery; Total Funding Amount: CAD 25,340 x4; Duration: 4 years

Project Title: Travel-related illnesses in children who travel abroad to visit friends and relatives (TRIP-VFRs) PI: Maryanne Crockett; Collaborators: Lee Ford-Jones, Charles Hui, Susan Kuhn, Jay Keystone; Project Description: Active surveillance of travel-related illnesses among Canadian pediatric VFRs; Funding Source(s): MMSF/MICH; Total Funding Amount: $22,000; Duration: 2008-2009

Project Title: Two-Phase Flow Cleaning of Endoscopes PI: Dr. Mohammed Labib; Co-PI: Dr. Michelle Alfa; Project Description: Developmental project to optimize two phase flow cleaning of the Novaflux prototype unit for flexible endoscopes; Funding Source(s): Novaflux (NIH Project); Total Funding Amount: $153,000 total – US; Duration: 2007 - 2009

Project Title: Ultra sensitive immunoassays for SARS virus employing bispecific antibodies PI:M. R. Suresh; Collaborators:T. F. Booth; Project Description: Immunology Competitive Grant UO1A1061233- 01; Funding Source(s): NIH; Total Funding Amount: $250,000; Duration: 03/2005 – 02/2010

Project Title: “Understanding the biological, clinical, and psychosocial determinants of health outcomes in inflammatory bowel disease: A research program” PI: Charles Bernstein; Collaborator: Dennis Krause; Project Description: We have the first prospective longitudinal population-based cohort study of subjects with IBD in North America. This study represents an important opportunity to identify predictors of disease presentation and clinical outcomes. We are currently undertaking research on predictors of disease exacerbations, of phenotypic outcomes, of conventional and alternative drug utilization and of health care utilization. We will also explore complex aspects of IBD such as etiology of fatigue, nutrition, its relationship to disease status, and changes in nutrition over time, prevalence of underlying psychiatric comorbidity, incidence and determinants of osteoporosis and fractures, and medication adherence over time. Another unique aspect of our study is that we will hone methods to analyze complex longitudinal datasets, a valuable spin-off that can be applied by researchers in other fields of study of chronic diseases. The Manitoba IBD Cohort Study will continue to provide unique research opportunities and findings to promote an understanding of how to improve the outcomes and QOL for persons with IBD. Funding Source(s): CIHR; Total Funding Amount: $1.5 million; Duration: 2007- 2012

Project Title: Understanding the migration patterns and associated HIV/AIDS vulnerability among rural female sex workers and men in northern Karnataka and southern Maharashtra. PI: James Blanchard; Co-PI: Stephen Moses, John O’Neil, B.M. Ramesh, Sushena Reza Paul, Shiva Halli, Reynold Washington; Project Description: Migration has been cited as an important factor in the global, regional and local spread of HIV. In many settings, mobile populations have shown higher HIV infection rates than those that do not move, independent of the HIV prevalence at the site of migration origin or destination. Moreover, extensive migration can serve to expand HIV epidemics geographically by bridging high-risk sexual networks in multiple locations. Therefore, policy makers and program planners have placed a high priority on prevention programs that focus on mobile male populations such as long-distance truckers, military personnel and labour migrants. Male migration and mobility is a dominant social, cultural and economic phenomenon in India. Accordingly, India’s National AIDS Control Programme, Phase 2 (NACP-2) has specific provisions for preventive interventions targeting migrant men and truckers. Avahan, the India AIDS Initiative (IAI) of the Bill and Melinda Gates Foundation has placed a substantial programming emphasis on long-distance truck drivers, and has also focused on high-risk men, including migrants, for preventive interventions. However, migration is not a cause of HIV/AIDS per se, but is rather a potential risk factor. The underlying assumption is that male migrants are more likely than non-migrants to engage in risky sexual behaviour because of a preponderance of predisposing factors such as isolation from their family and social supports and increased opportunities and resources to find new commercial and non-commercial sexual partners. However, this assumption has not been systematically validated in India. Furthermore, there is substantial diversity in the patterns of migration and the points of origin and destination, which are likely to modify the pattern of risk behaviour. Perhaps more importantly from an epidemiological and strategic perspective, the actual and potential role of male migrant populations on HIV transmission dynamics needs to be clarified. Specifically, it is important to better understand the relative contribution of male migration to the overall HIV transmission dynamics and epidemic expansion, particularly into India’s large rural populations. Whereas much programming emphasis has been placed on migrant males, little attention has been focused on mobile female sex workers (FSWs). FSWs are among the most vulnerable population sub-groups for HIV acquisition and are often important members of sexual networks that facilitate the expansion of HIV epidemics. Therefore, there are both social and public health imperatives to develop effective programs to reduce the vulnerability of FSWs to HIV. In India, there are many examples of effective HIV prevention programs for FSWs but most of these focuses on a single site or location of sex work. However, in addition to the global movement and trafficking of FSWs, there is strong evidence that a substantial proportion of FSWs in India are mobile within the country, both locally within states and between states. This mobility can affect HIV transmission dynamics in two important ways. First, mobile sex workers are likely to be more vulnerable to HIV due to inconsistent access to preventive programs and services. When FSWs move to a new environment, they might be less able to adopt and negotiate safer sex practices, including condom use, due to the lack of relationship and influence with those who control the sex work environment. Moreover, mobile sex workers who move away from their traditional residence they are less likely to have clients that are familiar to them, either individually or from a socio-cultural perspective, and therefore might be less empowered to negotiate condom use. This is compounded when FSWs migrate to places where most clients do not speak their language, creating a basic communication barrier that makes negotiation of condom use even more difficult. Understanding mobility and migration of FSWs is therefore crucial for designing effective HIV prevention programs at the structural/environmental and individual levels. In addition to the challenges presented for program and service delivery, the mobility of female sex workers is likely also of great importance for HIV transmission dynamics by forming linkages between commercial sexual networks, especially if the mobile FSWs move from rural areas and back. Perhaps nowhere in India are the issues of mobility of men and FSWs more consequential for the HIV epidemic than in the “migration corridor” of northern Karnataka and southern Maharashtra. Evidence based on HIV surveillance data and other research suggests that the HIV epidemic in India is most severe, and in some important ways centered, in several largely rural districts along the border between northern Karnataka and southern Maharashtra. Historically, all of these districts were part of the “Bombay” administrative zone, and there remains extensive migration within this “corridor” from northern Karnataka up to Pune and Mumbai. The adult HIV prevalence in the northern Karnataka districts of Bijapur, Bagalkot and Belgaum is estimated to exceed 3%. A further crucial observation is that the HIV prevalence in the rural populations of these districts is as high or higher than in the urban populations. In addition to substantial “to and fro” male migration within this corridor, there is a longstanding history of FSW migration from the rural areas of these northern Karnataka districts to the nearby Maharashtra districts and to the large urban centres of Pune and Mumbai. The overall goal of the project is to increase knowledge about the patterns of migration of rural female sex workers and men and the impact of this migration on HIV risk and vulnerability and transmission dynamics in a defined geographic area of south India. There are four main research objectives: to describe the migration patterns and determinants among female sex workers in northern Karnataka and southern Maharashtra; to describe the individual, structural, societal and contextual factors that contribute to the risk and vulnerability among migrant and non-migrant FSWs; to analyze and describe the patterns of sexual risk behaviour and determinants associated with different types of male migrants and to compare these patterns with those of non-migrants; and to analyze the impact of mobile FSWs and men on the transmission dynamics in rural areas of northern Karnataka.; Funding Source(s): Bill & Melinda Gates Foundation; Total Funding Amount: $836,000; Duration: Four years

Project Title: Use of Multi Locus Sequence Typing scheme to characterize Canadian Isolates of Corynebacterium diphtheriae PI: Kathryn Bernard; Collaborators: S. Schindle, D. Wiebe, A. Reimer, T. Burdz, C. Dawson, F. Bolt, A. Baldwin. Project Description: NML strains of C. diphtheriae and C. ulcerans were typed using MLST approach and collated with respect to antibiogramme, geographic location, patient demographics; Funding Source(s): in house funding Total Funding Amount: ~$28-30k; Duration: 2008-2009

Project Title: Use of on-farm composting to dispose of Johne's infected cattle PI: Krause, Denis, Kimberly Ominski, and Jan Plaizier; Project Description: As above; Funding Source(s):Manitoba Rural Adaptation Council; Total Funding Amount: $66,000; Duration: 2007 - 2009

Project Title: Use of potato starch and probiotics to control inflammatory bowel disease in humans: infectious diseases model in pigs PI: Krause, D. O., Bernstein, C. N., Nyachoti, C. M. and Rodriguez-Lecompte, J. C; Project Description: This project investigates the effects of a colicinogenic producing E. coli strain when fed to pigs challenged with adherent invasive E. coli believed to cause inflammatory bowel disease in a subset of humans. Funding Source(s): Agri-Food Research and Development Initiative (ARDI).Total Funding Amount: $48,000; Duration: 2009 – 2011

Project Title: Use of tannin-containing legumes in beef cattle production systems PI: Ominski, Kimberly, Martin Entz, Denis Krause, Katherina Wittenberg, and Qiang Zhang Project Description: As above; Funding Source(s): Agri-Food Research and Development Initiative Total Funding Amount: $68,000; Duration: 2007 - 2009

Project Title: The use of water suspendable yeast culture and a colicinogenic Escherichia coli probiotic to prevent post-weaning diarrhea in piglets PI: Krause, Denis O; Project Description: As above; Funding Source(s): Agri-Food Research and Development Initiative; Total Funding Amount: $62,700; Duration: 2007 – 2009.

Project Title: Using immunology to fight pandemic Influenza: Developing rapid diagnostics and assessing protective immunity. PI:Keith Fowke Co-investigator: Yoav Keynan; Project Description: The problem: 1. In the event of a pandemic outbreak, rapid diagnostics will be needed to assess new infections from pre- existing immunity. Such assays are not yet available. 2. In every infectious outbreak, not all individuals are equally susceptible to infection and disease. Little is known about the extent of cross-protective immunity to influenza that can be afforded by the cellular immune response. Goals: 1. Develop the bead array assay to be able to differentiate new infections from pre-existing infections. Influenza vaccination will be used as a model of exposure. 2. Assess CMI in vaccine experienced and vaccine naïve cohorts to determine the role of cross-protection afforded cell mediated immunity. Funding Source(s): Public Health Agency of Canada. Total Funding Amount: $273,450 Duration: April 2008-March 2009

Project Title: Variant Epitope Specificity and Immunodominance of effector and memory CD8+ T cells in acute and chronic HIV infection PI: Francis Plummer; Co-investigator:Keith Fowke; Project Description: That the specificity and function of HIV specific Tcm and Tem responses differ to HIV epitopes and to naturally occurring epitope variants; that we can distinguish these T cell populations on the basis of phenotype, clonality (TCR Vb usage), functional cross reactivity, and ability to suppress virus in culture; that unique aspects of Tcm responses will better correlate with protection from disease progression. Funding Source(s): CIHR. Total Funding Amount: $360,750. Duration: April 2008-March 2011

Project Title: The Viral Hepatitis Northern Network: A Platform for Addressing the Problem of Viral Hepatitis in the Canadian North PI: Gerald Minuk; Co-PI: Carla Osiowy, Julia Uhanova, Bryce Larke, Jutta Preiksaitis, John Morse, Isaac Sobol Project Description: In 1983-85, applicants of the present proposal traveled throughout the North and documented the prevalence of Hepatitis B viral infection in over 14,000 Canadian Inuit, Dene and Caucasians. The results of that undertaking revealed rates of hepatitis B infection that were 10-20 times higher in the Inuit and First Nations populations than Caucasians. Over the past 20-25 years, significant improvements have been made in our understanding, treatment and ability to prevent hepatitis B infections. The purpose of the present proposal is to apply what has been learnt about HBV to this “at risk” population by establishing lines of communication between investigators and experts in the field and community representatives, caregivers and government officials. Specifically, the applicants will travel to regional capitals of Yellowknife and Iqaluit to review the results of the 1983-85 survey and provide in service seminars and computer based software programs on how to decrease the predicted 20-50% mortality rates associated with this disease. The applicants will also take the opportunity to hold clinics for known hepatitis B carriers to assess the extent of their liver disease and obtain serum samples that will provide additional information regarding how the virus causes liver disease. Finally, the applicants will test the 14,000 stored sera to identify who has hidden virus (occult hepatitis B) and determine whether these individuals are also at increased risk of dying from liver disease. These activities will not only enhance the care of the estimated 5-15% of Northern Canadians with chronic hepatitis B but also provide important new data that are essential for developing strategies to eradicate hepatitis B from all circumpolar populations. Funding Source(s): International Polar Year (Government of Canada, Committee on International Polar Year, Indian and Northern Affairs Canada); Total Funding Amount: $500,000 (shared with molecular evolution project); Duration: 2006/07 – 2010/11

Project Title: What beliefs influence nevirapine use for prevention of maternal to child transmission in Kisumu, Kenya? PI: Lisa Avery Co investigator: Elizabeth Ngugi Funding Source:Kenya Free of AIDS Centre for HIV Prevention Research. 12 000 US 2009- 2010

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