Principal Investigator/Program Director (Last, First, Middle): Mulshine, James Lawrence F.2.6. Pilot and Collaborative Translational and Clinical Studies F.2.6. A. Introduction. Academic medical centers (AMC) have traditionally been the incubator for the development of clinician-scientists and translational researchers. Current trends in clinical revenue streams, GME funding and research regulation have imperiled this aspect of the AMCs mission. Thus, it is fitting that a major emphasis in the Clinical Translational Science Award (CTSA) is to rejuvenate and prioritize this critically important activity. Rush University Medical Center (Rush) has historically recognized the key role that such seed funding could provide and for many years has provided such support through small competitive grants ($10,000 to $20,000 per year) from the University Committee on Research and the Rush/John H. Stroger Jr. Hospital of Cook County Collaborative Research Program. More robust funding mechanisms at Rush are essential to meet the demands of the current research climate. In addition, there is a broad realization that the existing process for administering institutional grants needs reengineering to create a new culture of accountability, transparency and achievement. In the process of submitting our initial first round CTSA application the leadership of Rush understood the importance of these goals and set aside $500 thousand per year to fund a new category of translational two- year pilot projects for exceptionally promising translational research teams and programs. These funds were distributed in a competitive process in October, 2006 in advance of the review of our initial CTSA application, attesting to the strong institutional commitment to the promotion of translational research. In October 2008, a second round of two-year pilot projects were awarded and in October, 2009 a third round of one-year pilot projects will be awarded. The processes and procedures developed and subsequently refined to distribute these pilot funds serve as the basis for the program proposed in this CTSA application. In addition, the structure established for the distribution of these pilot funds and rigorous peer review was extended not only to the extant mechanisms of seed funding at Rush mentioned above, but also to targeted philanthropic initiatives including the Brian Piccolo/Gavers Cancer Research Fund, the Segal Foundation Research Award (women’s cancer), Bears Care (breast cancer research), and the Hasterlik Memorial Fund (capital equipment) (Table F.2.6.1.). As a result, during the 2007 - 2009 fiscal years, over $3.1 million in institutional funds were invested in pilot research projects. In addition, to foster collaborative interactions with our RTSC partner the Illinois Institute of Technology (IIT), a Request for Applications was issued in October 2009 for a one-year pilot project involving inter-institutional and interdisciplinary translational research. Each institution has set aside $25 thousand to award up to two projects. To be eligible for this award, at least one of the applicant PI’s must hold a primary faculty appointment at Rush or IIT (Assistant Professor or above) and at least one co- investigator should hold a primary faculty position at the partner institution. In this CTSA application, a leveraging of the core RUSH pilot funding in translational research projects is requested.

F.2.6. B. Specific Aims

- Specific Aim #1: To support high quality, interdisciplinary translational studies that will serve as a nidus for sustainable research programs of the RTSC.

- Specific Aim #2: To identify promising early-career, health care researchers and provide support for their transition to scientific independence in translational research.

- Specific Aim #3: To build translational disease-focused research teams which collectively cover the spectrum of disciplines from basic research to community interventions.

F.2.6. C. Criteria for Funding Pilot Projects. The Scientific Leadership Council (SLC) of the RTSC is responsible for allocating research funds for promising pilot projects. Members of the SLC are accomplished in their field as validated by NIH grant awards or comparable designations. As such, they have served on NIH Study Sections and Review Panels and are familiar with the NIH criteria for evaluating research grant applications. Therefore, the SLC will adopt similar rigor for the review of pilot project proposals. A six-member

PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 238 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Mulshine, James Lawrence subcommittee appointed by the SLC (the Pilot Project Evaluation Team, consisting of two basic researchers, two clinical researchers and two community-based researchers each of which will have two-year terms) containing experienced researchers/peer reviewers will be responsible for the selection of pilot projects to fund. One member of this team will serve as a liaison to the Community Advisory Board to insure that there is input from this body in the selection of the pilot projects. Ad hoc members of the team will be appointed if additional expertise is needed to evaluate a particular proposal.

TABLE F.2.6.1. Rush University Medical Center Intramural Research Grant Mechanisms

AMOUNT AWARDED AWARD ELIGIBILITY AMOUNT/YEAR NUMBER DURATION FY07 - FY09 Annual RTSC Pilot Award Member of $25,000 – 4 – 7* 1 – 2 Years $1,422,622 RTSC 100,000 University Committee Young $20,000 5 – 6 1 Year $319,724 on Research Award Investigators Collaborative Resarch Team Rush/Stroger from Both $10,000 2 – 3 1 Year $123,840 Hospital Institutions; Young Investigator

Episodic/Philantropic Hasterlik Memorial Capital Up to $250,000 6 Not $1,207,689 Fund Equipment Applicable Brian Piccolo/Gavers Breast Cancer Up to $50,000 3 3 Years $376,982 Cancer Fund Segal Foundation Women’s Cancer Up to $50,000 1 - 3 3 Years $398,909

Bears Care Breast/Ovarian $65,000 - 4 – 6 1 Year $130,020 Cancer $235,000 Haffner Fund Nursing Faculty $10,000 Up to 5 1 year $2,500 * This number will increase if this application is successfully funded

Specifically, the Pilot Project Evaluation Team (PPET) evaluates the significance and strategic value of the proposed project vis-à-vis the research portfolio of the RTSC; (i.e. the team will insure that the project is synergistic with ongoing research and addresses an important clinical problem that will advance scientific knowledge or clinical practice in terms of new technologies, treatments, preventions or interventions). The PPET will evaluate the approach to insure that the design, methods and analyses are appropriate to the aims of the project. The review also weighs innovation in hypotheses, methods, concepts, clinical paradigms and technology in the assessment of the proposed study. The quality of the investigators is a key element in the evaluation of pilot proposals. The review team assesses whether the applicants are appropriately trained to carry out the research. The previous track record of the applicant is scrutinized to determine the likelihood of achieving extramural funding, particularly NIH R01 awards, for the project. The involvement of a full spectrum interdisciplinary team of investigators including basic, clinical and community-based investigators is encouraged to insure the clinical relevance and scientific rigor of the study. Finally, the scientific environment is assessed. Particular attention is paid to departmental support, including protected time for research activities, the availability of mentors and collaborators and the availability of necessary laboratory and/or clinical research infrastructure. Through the Request for Applications process, investigators will be encouraged to creatively leverage the infrastructure available in the

PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 239 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Mulshine, James Lawrence Translational Technology and Resources Core (TTRC, section F.2.5) as well as the seed funding mechanisms described for the TTRC, the translational methodology development grants program and the “mini” sabbatical program (Section F.2.4,E.2. and F.2.4.E.3, Table F.2.6.4). Priority will be given to projects that involve interwoven training or mentoring opportunities. The RTSC recognizes the critical importance of mentorship in the pathway to the development of independent investigators and, for the past two years, has distributed funds to allow key senior faculty the protected time necessary to mentor the most promising young investigators. The expectation with this process is to prepare talented investigators qualified for appointment to the K12 program (if the present application is successfully funded) and success in competition for RTSC-funded pilot projects. To be eligible for funding, applicants are members of the RTSC, enrolled in or having completed the Masters in Clinical Research Program. Other young faculty with a proven track record in translational research are also eligible. In the review, preference is given to promising young investigators; to mature investigators who are pursuing new lines of translational research in areas that they have not been previously funded; and to promising interdisciplinary translational research with collaborative teams of basic scientists, clinicians and/or a community investigators. To insure a balanced portfolio of translational research, preference will also be given to projects that involve pediatric populations and projects that have a strong component of community- based research. In addition, the SLC actively recruits proposals from women and underrepresented minorities. There will be two types of pilots funded: 1) hypothesis-generating projects for up to $25 thousand for one year; and 2) hypothesis-driven projects for up to $50 thousand for each of two years. Proposals for pilot projects are reviewed and awarded yearly (for the larger, hypothesis-driven projects) or on a continuous basis (hypothesis-generating projects). Continued funding within the award period is contingent upon the demonstration of steady progress in the scientific aims of the project, as well as achievement of training goals. Each will be reviewed every six months by the PPET. Pilot projects under consideration by other granting agencies are eligible for funding within this mechanism. If an external grant is awarded, however, the project will no longer be eligible and any unused funds will be available for other pilot project proposals. For all proposals, the PPET will insure provisions for the protection of human subjects, inclusion of women and underrepresented minorities, inclusion of children (if appropriate), protection of vertebrate animals and, for clinical trials, when appropriate, the establishment of a data and safety monitoring board. The PPET has an additional review procedure involving an evaluation of the rigor and appropriateness of the statistical methodology. This review is performed by the Design, Biostatistics Core, and Clinical Research Ethics (Section F.2.2). In addition, the PPET will insure that young investigators involved in these projects are enrolled in relevant coursework. The measures of success of these projects are assessed every six months and include the scientific output (national presentations, peer- reviewed publications); advanced degrees awarded (PhDs, Masters in Clinical Research); and ultimately the ability of grantees to establish an independent scientific career, including success in obtaining competitive extramural funding. The SLC annually reviews the overall performance of the pilot project program to ensure a balanced research portfolio and to identify any strategic gaps. Using the criteria described above and summarized in Table F.2.6.2, the PPET has chosen the pilot studies described below. Rush investigators were asked for proposals that would, if successful: 1. allow clinical and translational trainees or researchers to generate preliminary data for submission of a federal research grant application; 2. seek to improve a process related to conducting translational research; 3. develop new technologies that have a bearing on translational research; 4. lead to the establishment of translational research teams or centers.

There is continued evaluation of the progress of these pilot programs, with particular emphasis on the scientific output and translational significance and plans. As noted above, these programs are evaluated at least every 6 months by the pilot project review team using the criteria enumerated in Table F.2.6.3. To date, all awarded projects have achieved satisfactory progress. Several projects achieved outstanding progress towards the objectives of the mechanism.

PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 240 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Mulshine, James Lawrence The Pilot and Collaborative Translational and Clinical Studies program is now in its third cycle and will be expanded upon successful receipt of this CTSA award. With the addition of institution funds, this allows the RTSC to increase the number of funded translational research projects and interdisciplinary translational research teams. F.2.6.C.1 Evaluation Tracking and evaluation of the effectiveness of the pilot project program is discussed in section F.3.2.B in the context of evaluating the progress of the RTSC as a whole. The Chair of the PPET with present quarterly reports to the SLC to update this body on the conformance of the activities to the proposed timeline and the outcomes of the funded projects. Particular attention will be paid to the balance of the distributed resources throughout the RTSC to ensure that pilot funds are being utilized to grow key strategic translational research programs. The effectiveness of the program will be based on quantitative metrics as much as possible including the sustainability of the research project, as measured by extramural grant awards, and the impact of the research on the field, as measured by the quantity and quality (impact factor) of the resulting publications. The outcome of each pilot project will be tracked by the PPET for at least two years since there is often a lag between the conduct of the research and its ultimate publication and/or its conversion into an extramural research grant. Outcomes of the pilot project award program during its early phases will inform the PPET and the SLC regarding the necessity for modifications in the duration and amount of awards, the review process and/or the strategic emphasis in the later phases of the program. F.2.6.C.2 Cost Sharing Currently Rush University Medical Center has been investing $500,000 per year in the Pilot Project Program and will continue to do so. In addition, the Illinois Institute of Technology has provided matching funds for projects in which one of the investigators has a primary faculty appointment at IIT. The tracking and evaluation process is intended to provide evidence of the return on investment of these funds to justify enhanced cost sharing with all the institutional partners of the RTSC, particularly IIT and Stroger Hospital.

Table F.2.6.2. Pilot Project Prioritization Review Criteria Significance What is the strategic scientific impact and level of overall quality of the project from a translational perspective? What is the public health impact? What will be the effect of the study on the concepts, methods, technologies, treatments, services, or preventive interventions that drive this field? Investigator(s) Are key personnel appropriately trained and well suited to carry out this work? Is the proposed work appropriate to the experience level(s) of the PI and other researchers? Does the investigative team bring complementary and integrated expertise to the project?

Innovation Does the project involve new approaches? Does the project challenge existing paradigms or clinical practice? Does the project address a critical barrier to progress in the field? How does it propose to integrate clinical, basic and other relevant disciplines? Does it employ novel concepts, approaches to increase ease and efficiency of translational research?

Approach Are the framework, design, methods and analyses adequately developed, well-integrated, well-reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Environment

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Does the scientific and administrative environments in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations or employ useful collaborative arrangements? Is there evidence of departmental/center support? Are departmental/center resources adequate for the proposed studies?

TABLE F.2.6.3. Pilot Project Progress Report Review Criteria

A. Progress Report Review Domains 1. Focus a. Have the aims of the grant changed? b. Does the reported data address the original aims/hypotheses? 2. Investigators a. Is the investigative team intact? b. Is there evidence of collaborative interactions? 3. Design, Data Acquisition and Analysis a. Has sufficient progress been made on the proposed studies? b. Has the data been analyzed with the appropriate statistical rigor? 4. Training a. Is there evidence that the proposed training component is being fulfilled? b. Is there evidence of ongoing mentorship? 5. Deliverables a. Has there been any published abstracts or manuscripts from this work? If not, what are the prospects for scientific publications? b. What are the prospects for future extramural funding?

B. Evaluation Categories 1. Satisfactory. The investigator updates the pilot project subcommittee with a report prior to the beginning of the next funding cycle. 2. Borderline. The investigator reports back in three months to ensure satisfactory progress. 3. Unsatisfactory. The investigator is notified of the specific concerns of the pilot project subcommittee. If sufficient progress is not made over the next three months, the grant is not renewed.

F.2.6. D. RTSC Funded Translational Pilot Projects 2006 - 2008 Progress Reports F.2.6. D.1. Project #1: Development of A Targeted Multiplex Proteomics Tool to Assess Women’s Reproductive Health F.2.6. D.1.a. Investigators: Greg Spear, PhD (Department of Microbiology/Immunology, Rush); Alan Landay, PhD (Department of Microbiology/Immunology, Rush); Sabrina Kendrick, MD (CORE Center, Division of Infectious Disease, Stroger Hospital) and Alan Tenorio, M.D. (Department of Internal Medicine, Section of Infectious Disease, Rush) F.2.6. D.1.b. Hypothesis: Vaginal mucosal immunity, vaginal flora and sexually transmitted infections each influence the other. The delineation of these relationships will provide the clinician a useful tool to assess women’s reproductive health. F.2.6. D.1.c. Specific Aims: Specific Aim # 1: Determine the utility of existing cytokine beads arrays (CBA) for detecting cytokines in female genital tract secretions. Specific Aim # 2: Develop CBA-type modules that detect innate and adaptive immune mediators. Specific Aim # 3: Develop CBA-type modules that detect common causes of vaginitis and healthy genital tract flora.

PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 242 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Mulshine, James Lawrence Specific Aim # 4: Determine the patterns of immune mediators associated with specific pathogens and healthy flora. F.2.6. D.1.d. Findings: Aim 1: A total of 84 patient samples were obtained for the study from the STD clinic at the Core Center of Cook County. Samples were run with all of the commerical kits as proposed. This represents 36 different bead sets, and 27 different cytokines (since some of the cytokines were duplicated in different kits). The data shows that some cytokines, such as IL-8, are detected in nearly all cervicovaginal lavage (CVL) sample, but at variable levels. Other cytokines, such as IL-2 are not detected in any CVL samples. Aim 2: Assays were developed for six additional markers of innate immunity; lactoferrin, myeloperoxidase, interferon-alpha, interferon-beta, beta-defensin2 (HBD2) and beta-defensin3 (HBD3). All of the patient samples were run with these assays. Lactoferrin, myeloperoxidase, HBD2 and HBD3 were detected in most samples, but at variable levels. Interestingly, no interferons were detected in the CVL samples. Aim 3: An assay was developed for trichomonas. Additionally, efforts were unsuccessful to generate an assay for lactobacilli that would be representative of healthy genital tract flora. The trichomonas immunoassay that was created correlated very well with the clinical diagnosis of the infection. Aim 4: All samples were run in the 43 assays and the data was analyzed for significant relationships between cytokines and infections. A large number of significant associations were noted. A pattern was discerned where “normal” women have lower levels (green) of many proinflammatory cytokines when compared to women with BV. The most dramatic examples include IL-8 and lactoferrin (LF). Statistical analysis of the data showed that CVL from women with BV and Trich had distinct patterns of altered cytokines when compared to normal CVL. Similar distinct patterns were observed for chalmydia also. Interestingly, women with Candida did not have a pattern that was different than normal. Vascular endothelial growth factor-a (VEGF) was first identified as a factor that potently increased vascular permeability and subsequently was found to promote proliferation, migration, and survival of endothelial cells. VEGF was detectable in lower genital tract mucosal fluid from all women attending the STD clinic and was significantly higher in Gonorrhea and Trichomonas. VEGF levels were positively associated with IL-1ß and IL-6. These findings suggest a role for VEGF during genital infection. F.2.6. D.1.e. Scientific Output: Publications: 1) Vascular endothelial growth factor-A (VEGF) is present in lower genital tract mucosal fluids from women and is increased in infection. Gregory T. Spear, Carolyn Pierce, Hua Yun Chen, Alan L. Landay, Tin T. Thomas, Mieoak Bahk, Robert Balderas, and Sabrina R. Kendrick. Submitted Manuscript. 2) Multiplex cytokine assay of cervicovaginal lavage (CVL) samples from women attending an urban std clinic. Sabrina R. Kendrick, Tin T. Thomas, Carolyn Pierce, Mieoak Bahk, Reza Zariffard, Hua Y. Chen, Robert Balderas, Alan Landay, and Gregory T. Spear. Manuscript in Preparation. 3). Multiplex Cytokine Assay of Cervicovaginal Lavage (CVL) Samples from Women Attending an Urban STD Clinic. Sabrina R. Kendrick, TT Thomas, C Pierce, M Bahk, MR Zariffard, HY Chen, R Balderas, A Landay, GT Spear. Poster presentation at STD2008 Conference. Grants: 1. Basic and Comparative Studies of CCR5 Inhibition to Prevent HIV Transmission. Principal Investigator: Michael Lederman Grant Number: 1U19AI076981-01, Project Period: 06/06/2008 – 05/31/2010. 2. HIV Susceptibility and Pathogenesis in the Female Genital Tract; Principal Investigator: Alan L. Landay, Grant Number: 1P01AI082971-01, Project Period: 9/30/2009 – 8/31/14 NIH Program Project

F.2.6. D.1.f. Training Component: Dr. Sabrina Kendrick from the Core Center Screening Clinic of Stroger Hospital and Dr. Alan Tenorio from the Section of Infectious Disease at Rush trained in translational research by participating in the bench portion of this proposal, under the mentorship of Drs. Spear and Landay of the Department of Immunology/Microbiology. The training consisted of weekly meetings with the entire lab group to discuss results and strategies, as well as weekly one-on-one meetings with mentors and weekly journal clubs. F.2.6. D.1.g. Translational Significance: The above findings advance our overall goal to develop a multiplex tool to objectively evaluate women’s reproductive health. The results of this work facilitate the development of a commercial test that quickly and objectively assesses the status of reproductive health in women and can be PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 243 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Mulshine, James Lawrence used in specific settings such as evaluating the status of healthy genital tract flora, identifying women at increased risk of aquiring genital tract infections and determining the effect of antibiotics, microbicides and other treatments on the genital environment. The tool will also potentially be useful for further long-term development of immune modulators including vaccines. For example, induction of constellations of types of immune mediators during an infection can point to a specific pathway that is stimulated, such as a Toll-like receptor pathway. Also, some pathogens prevent immune responses that have critical effector molecules and therefore the tool would identify a means of pathogen escape. F.2.6. D.1.h. Translational Plan: Discussions are underway with our commercial partner Becton Dickinson to discuss the results and assess the potential for what can be developed commercially.

F.2.6. D.2. Project #2: Circulating Inflammatory Markers And Medial Temporal Lobe Integrity F.2.6. D.2.a. Investigators: Debra Fleischman, PhD (Alzheimer’s Disease Center, Rush)., Jeremiah Kelly, MD (Alzheimer’s Disease Center, Rush), and Konstantinos Arfanakis, PhD (Department of Biomedical Engineering, IIT) F.2.6. D.2.b. Hypothesis: There is a relationship between elevated serum levels of pro-inflammatory cytokines, reduced cognitive function and reduced integrity of the medial temporal lobe gray matter and associated white matter structures and pathways. F.2.6. D.2.c. Specific Aims: Specific Aim # 1: Quantify levels of circulating inflammatory markers: serum IL-6, IL-6 soluble receptors (sIL-6r), IL-1 β, IL- β receptor antagonist (IL-1ra), TNF-α, IL-18 and C-reactive protein (CRP) in a subset of 150 randomly sampled participants with a range of cognitive abilities. Specific Aim # 2: Quantify the integrity of brain function and structure on those participants in the upper and the lower 10th percentile (N= 30) of the inflammatory marker measures. Specific Aim # 3: Measure, in the selected 30 subjects: a] the magnitude and spatial distribution of functional activation, using fMRI, in whole brain, and in regions-of-interest within (hippocampus, entorhinal cortex), and outside (frontal cortex, posterior cingulate cortex, primary visual cortex) the medial temporal lobe (MTL) during performance of an episodic memory task known to activate specific brain regions in healthy younger adults, and b] the macrostructural integrity (tissue density) of whole brain, and regions of interest (stated above) using voxel-based morphometry, and the microstructural integrity of connecting white matter fibers (e.g., perforant path, posterior aspect of the cingulum bundle) using diffusion tensor imaging. Specific Aim # 4: Examine the association of circulating inflammatory markers to: a] neuroimaging indices of neural integrity, and b] the level of five cognitive functions: episodic memory, semantic memory, working memory, perceptual speed and visuospatial ability. Specific Aim # 5: Circulating inflammatory markers will be related to: a] the magnitude and spatial distribution of functional activation in a medial-temporofrontal/ posterior cingulate network (hippocampus, entorhinal cortex prefrontal cortex, posterior cingulate cortex, but not primary visual cortex) on a task that invokes episodic memory; and b] the integrity of white matter tracts that connect gray matter regions of a medial-temporofrontal/posterior cingulate network (e.g., perforant path, posterior aspect of the cingulum bundle) and that support episodic memory. F.2.6. D.2.d. Findings: The investigators examined differences between old persons with low (LI) and high (HI) inflammation and compared these groups to two young persons on measurements in four regions of the MTL – hippocampus (volume only), entorhinal cortex (volume, surface area, thickness), perirhinal cortex (volume, surface area, thickness), posterior parahippocampal cortex (volume, surface area, thickness). Results showed that compared to the two young subjects, both old groups had reduced volume of hippocampus and entorhinal cortex, and reduced thickness of entorhinal cortex. In addition, the LI group had reduced posterior parahippocampal thickness, and the HI group had reduced perirhinal volume and surface area. Comparing the HI and LI groups, the HI group had greater hippocampal and posterior parahippocampal volumes, and lesser perirhinal volume and surface area. Using a whole-brain exploratory approach (as opposed to our MTL region- of-interest approach described above), we found group differences between the HI and LI groups in the regions PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 244 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Mulshine, James Lawrence tabled below. The high inflammation group had thinner cortex in each of these regions with the exception of the left-hemisphere inferior temporal cortex, in which the low inflammation group had thinner cortex. The labels of right hemisphere white matter, left hemisphere white matter and white matter hypointensities were combined to get the total white matter value. For total white matter, a trend toward a group difference in FA (fractional anisotropy) value emerged, with the HI group having less FA than the LI group (p = 0.07). When FA is measured in just the white-matter hypointense regions, however, the value of the HI group is significantly lower than the LI group (p = 0.01). Thus, the high inflammation group showed a trend toward lower FA in total white matter, and a significant difference in FA for hypointense regions within the white-matter. In summary, in this small sample of nondemented older persons, the investigators used cutting-edge neuroimaging techniques to examine the association between circulating inflammatory markers and medial- temporal lobe and whole-brain structural integrity. Preliminary analyses showed group differences between persons with high and low levels of inflammation in specific gray-matter regions both within and outside of the medial-temporal lobe. In addition, the investigators found that the structural integrity of white-matter, particularly in hypointense regions, is reduced in persons with high levels of systemic inflammation. This project has also supported the development of tractography methodology to examine the integrity of white- matter fiber tracts connecting gray-matter regions. Analyses are on-going. To examine associations with cognitive function. This project has yielded an exceptionally rich dataset which will be available to seed other projects F.2.6. D.2.e. Scientific Output: Publications: 1. Sturman MT, Kelly J, Barnes L, Fleischman D, Barnes L, Leurgans S, Bennett DA, Morris MC. Epidemiologic study of inflammation and cognition. Alzheimer's & Dementia 2008; 4: suppl 2, T700. 2. Sturman MT, Kelly J, Fleischman D, Barnes L, Leurgans S, Bennett DA, Morris MC. Epidemiologic study of dietary fats and inflammatory markers in older adults. The Journal of Nutrition, Health, and Aging 2008; 12 (7): 426. Grants 1. Neurobiology of Social Engagement and Physical Health and Well-Being in Aging Agency: NIA, App ID: 1R01AG034414-01, PI: Debra Fleischman, Ph.D. 2. Neurobiology of Mobility Disability in the Elderly, Agency: NIA, App ID: 1R01AG034083-01, PI: Aron Buchman, M.D. Both of these applications include the mentee of this project, Konstantinos Arfanakis, as a co-investigator.

F.2.6. D.2.f. Training Component: Dr. Arfanakis is a young and promising investigator from the IIT with expertise in medical physics and biomedical engineering. Dr. Arfanakis had 70% of his time protected for research and under the mentorship of Drs. Fleishman and Kelly and other investigators in the Rush Alzheimer’s Disease Center, is gained literacy in the areas of neuroscience and epidemiology. F.2.6. D.2.g. Translational Significance: The findings from this study could effectively translate into knowledge that will have a direct impact on 1) the development and monitoring of anti-inflammatory medications and anti-amyloid vaccines, 2) the development of pharmacological treatments targeted to specific neural systems, and 3) the identification of behavioral risk factors for inflammation that could lead to behavioral interventions at the community level. F.2.6. D.2.h. Translational Plan: This data has been used to support the submission of R01s that will extend this line of research to meet the translational goals described above.

F.2.6. D.3. Project #3: Predictors of Osteolysis And Aseptic Loosening of Total Joint Replacements F.2.6. D.3.a. Investigators: Nadim Hallab, PhD (Department of Orthopaedic Surgery, Rush), Joshua J. Jacobs, M.D. (Department of Orthopaedic Surgery, Rush), John Meyer, M.D. (Department of Diagnostic Radiology, Rush), Arthur Evans, M.D., MPH (Department of Medicine, Stroger Hospital). F.2.6. D.3.b. Hypothesis: Periprosthetic osteolysis in total hip replacements is correlated with systemic markers of inflammation, bone catabolism and peripheral blood mononuclear cell hyperreactivity to implant debris.

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F.2.6. D.3.c. Specific Aims: Specific Aim # 1: To determine the relationship between humoral (serum) measures of inflammation and inflammatory bone loss (serum markers of bone catabolism, serum matrix metalloproteinase levels, serum inflammatory cytokine levels) and implant performance (as assessed by the presence and magnitude of osteolysis determined with high-resolution CT and patient-derived outcome measures) in a total joint arthroplasty cohort with a known high prevalence of osteolysis. Specific Aim # 2: To determine whether the response of peripheral blood mononuclear cells (lymphocytes and monocytes) to soluble and particulate implant debris predicts implant performance in the same cohort. Specific Aim # 3: To derive a clinical prediction rule that will aid surgeons in the post-operative early diagnosis of excessive bioreactivity, allowing early, targeted interventions before osteolysis causes pain and disability due to implant loosening.

F.2.6. D.3.d. Findings: Methodology was developed to use routine 64-slice CT scan data to reconstruct a 3D volumetric measure of an osteolytic region. Calculation of osteolytic bone loss volume was limited to those subjects with CT scan data without high levels of radiographic artifact by the metal implant. The correlation of biomarker data within these initial subjects demonstrated two candidate biomarkers, leptin and IL-8. Subjects with a moderate to high level of osteolysis were tested for cellular reactivity to both soluble metals and metal and polymer particles. These subjects showed a high level of peripheral blood mononuclear cells (PBMC) reactivity to Ni and particles of polymethylmethacrylate (PMMA). Surprisingly, there was greater reactivity to PMMA than to Co-alloy particles. This data shows that these people with THA and osteolysis have lymphocytes that “hyper”-react to Ni and PMMA in vitro (e.g. stimulation index > 2), which is consistent with previously published data that have shown that groups of subjects with well functioning metal-on-metal implants (which have elevated levels of circulating metal compared to metal-on-polyethylene bearing couples) demonstrate increased reactivity to Ni, on average. With the as yet limited numbers of subjects analyzed for osteolysis volume, there was no direct correlation with LTT metal reactivity. In summary, these results show that of the detectable serum markers of inflammation, leptin and IL-8 demonstrated a significant correlation with volume of osteolysis. Other pro-inflammatory cytokines were not detectable with the exception of TNF alpha (presumably from activated macrophages), which did not demonstrate a correlation with volumetric osteolysis. While further studies are needed to more fully explore the findings of this investigation, these results support the pursuit of predictive/diagnostic biomarkers. The identification of serum biomarkers (such as leptin and IL- 8), which are elevated prior to or in concert with the onset of pronounced radiographic changes and/or the occurrence of pain, represents 1) an important step toward biological implant surveillance, 2) new targets for anti-inflammatory pharmacologic treatments, and 3) new methods for evaluating the efficacy of current pharmacological treatments for peri-implant bone loss. F.2.6. D.3.e. Scientific Output: Publications: 1. Caicedo, M; Tarabishy, A; Reddy, A ; Jacobs, J ; Hallab, N: Soluble Metal Debris Induce Pro- Inflammatory Cytokine Secretion In Human Monocytes Similar To Particulate Debris, Trans 2007 Society for Biomaterials, Chicago, IL, 2007; 2. Caicedo, M.S., Reddy, A., Samee, I., Jacobs, J.J., and Hallab, N.J. Cobalt Ions and Co-Cr-Mo Alloy Particles Induce Human Monocyte Co-stimulatory Molecules CD-86, ICAM-1 and the Cytokine IL-8: Implications for Innate Activation of Adaptive Immune Responses. Trans. 6th Combined Meeting of the Orthopaedic Research Societies, Poster #535, 2007. 3. Hallab N. J., Caicedo M. , Finnegan A. , and Jacobs J. J.. Th1 type lymphocyte reactivity to metals in patients with total hip arthroplasty. J.Orthop.Surg. 3:6, 2008. 4.Caicedo, M; Tarabishy, A; Reddy, A ; Jacobs, J: Hallab, N, Metal Particulate And Soluble Debris Induce Similar Cytokine Profiles In Human Primary Monocytes; Ann Meeting Orthopaedic Research Society Transactions Vol.32, San Diego, Ca, 2007. 5. Hallab, N.J., Desai, R., Meyer, J., Della Valle, C., and Jacobs, J.J. Predictors of Osteolysis and Aseptic Loosening of Total Joint Replacements. Transactions of the 55th Annual Meeting of the Orthopaedic Research Society, Poster #2458, 2009. Grants: Biomarkers of Periprosthetic Bone Loss, App ID RC1AR058433-01, PI: Joshua Jacobs, M.D.

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F.2.6. D.3.f. Training Component: Dr. Nadim Hallab, who has received a PhD in Biomedical Engineering, had protected time to participate in selected courses in the Master of Science in Clinical Research to enhance his breadth of knowledge in elements of translational science including clinical research methodology, biostatistics and the development and validation of clinical prediction rules. In addition, Ronak Desai is working on this project toward fulfillment of an MS in Anatomy and Cell Biology at RUSH. Mr. Desai is enrolled in a combined MD/MS Program at RUSH and is supported as a predoctoral student on an NIH T32 award (AR052272, “Training in Orthopaedic Skeletal Biology”). F.2.6. D.3.g. Translational Significance: This area of investigation could have a substantial impact on the management of patients undergoing total joint arthroplasty. Prior to surgical intervention, patients who may be hyperresponsive to particular implant materials could be identified helping to guide implant selection. Identification of biomarkers that may predict implant failure at an early or presymptomatic stage would facilitate early intervention with preventative strategies. Furthermore, in symptomatic patients with normal radiographic studies, serum biomarkers may prove to be an informative clinical discriminant. F.2.6. D.3.h. Translational Plan: The translational plan is to implement a bioreactivity testing protocol for those orthopedic patients that meet the following clinical criteria: a. Patients with a history of metal allergy (representing about 10% of the general population); b. Patients with an orthopedic implant with pain from an unknown cause; c. Patients with an orthopedic implant with no pain but identifiable bone loss. With the predictive modeling developed in the later stages of the project, this testing will risk-stratify these patients with regard to implant failure and identify patient subgroups that would benefit from close surveillance and/or implementation of preventive and therapeutic modalities. Successful development of this work will facilitate the establishment of a National Center of Excellence at Rush in orthopedic biomarker (biologic reactivity) testing.

F.2.6. D.4. Project #4: Early Pathogenesis of Cardiovascular Disease In Women F.2.6. D.4.a. Investigators: Lynda Powell, PhD (Department of Preventive Medicine, Rush)., James E. Calvin, M.D., (Section of Cardiology, Department of Internal Medicine, Rush), Miles Wernick, Ph.D. (Department of Biomedical Engineering, IIT), Arthur Evans, M.D., MPH (Department of Medicine, Stroger Hospital), John Hibbeln, M.D. (Department of Diagnostic Radiology, Rush). F.2.6. D.4.b. Hypothesis: Visceral adipose tissue (VAT) is an independent risk factor for subclinical cardiovascular disease in women, mediated by chronic inflammation. F.2.6. D.4. c. Specific Aim: Specific Aim # 1: To correlate the total plaque burden, as determined by 64-slice CT scanning and biomarkers of vulnerable plaque (ICAM, VCAM), with the extent of visceral adipose tissue (assessed by CT) and then to develop mediational models which determine if any association between visceral fat and plaque burden is mediated by biomarkers of inflammation (IL-6, CRP, CD40 ligand, MCP1, adiponectin, and leptin), a biomarker of altered clotting (fibrinogen), and abnormal lipoprotein patterns. F.2.6. D.4. d. Findings: Eighty subjects from the Chicago Study of Women’s Health Across the Nation (SWAN) study (40 Caucasian and 40 African American) were recruited who: (1) were post-menopausal; (2) not diabetic; (3) not on hormone therapy; (4) had not had a hysterectomy; and (5) had 2 or more visceral fat assessments over the course of the menopausal transition. All subjects completed the protocol by having blood drawn and receiving the CT scan. All assays were conducted using 3 separate laboratories and sent to the PVM Data Management Center. The current dataset has been cleaned and includes data from the biomarker assays, data collected from the 64-Slice CT scanner, and data collected in conjunction with the visceral fat study. Since all participants are in the parent SWAN study, data are collected as part of that protocol. SWAN data cleaning and release of the final dataset occur approximately 2 years after the data have been collected. Thus, key covariate information including socio-demographic information, weight, height, standard CV risk factors, and physical activity has not yet been released for use. This release is expected sometime in 2009. Once we receive these data, we will merge them with the data currently in the dataset and complete the analyses. A primary concern in this study was whether or not there would enough subclinical cardiovascular disease (SCD) in these women to make this study meaningful. Results indicate that there is an 18.6% prevalence of coronary calcium PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 247 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Mulshine, James Lawrence in this sample of women, thus ensuring our ability to answer our questions. Preliminary unadjusted correlations between visceral fat and key biomarkers are promising (rxy range = 0.16-0.29). Progress in the assessment of soft plaque has been made. Rush and IIT have collaborated to develop a computationally-efficient image-segmentation procedure for the detection of soft plaques in coronary arteries from MDCT images. The proposed method consists of the following 3 steps: (1) extraction of the arterial lumen centerline; (2) segmentation of the lumen and arterial wall based on a locally-adaptive mixture-model using the expectation-maximization algorithm; and (3) detection of soft plaques based on effective cross-sectional areas of the lumen and of the wall. This procedure was tested using a set of 12 clinical acquisitions. Following continued validation studies, the procedure will be applied to the 80 women in this study with the goal of linking visceral fat trajectories to soft plaque. F.2.6. D.4. e. Scientific Output: Grant: Developing and Intervention to Prevent Visceral Fat in Premenopausal Women, Grant Number 1U01HL097894-01, Project Period 9/25/09 – 6/30/14. F.2.6. D.4.f. Training Component: Disha Mukherjee, MD and Anu Sahu, MD were Fellows in Cardiology with interests in CT imaging. They worked with Dr. Hibbeln in the conduct of the 64-slice CT scans and joined the cardiology team in the reading of the results of the scans, under the supervision of Dr. Calvin. Assessment of soft plaque from these scans was developed in partnership with Drs. Yongyi Yang and Miles Wernick at the IIT. Preliminary algorithms for quantifying the soft plaque have been developed by by a master of student at the Institute, Felix Renard, who made this the subject of his master’s thesis entitled “Detection And Quantification Of Soft Plaque In Coronary Arteries From MSCT Images”. Analysis of the data was conducted primarily by Drs. Imke Janssen, PhD and Dr. Shelia Dugan, MD, both junior faculty in the Department of Preventive Medicine, under the supervision of Drs. Powell and Evans. F.2.6. D.4.g. Translational Significance: This pilot study draws on advances in clinical and basic science where novel biomarkers of early CVD risk and sophisticated imaging make it possible to study mechanisms by which visceral fat links to vascular disease. Evidence supporting a link between visceral fat and vascular disease, signals the importance of preventive screening in the community for visceral fat or for relevant biomarkers as a way to prevent the early development of atherosclerosis in women beginning to undergo the menopausal transition. F.2.6. D.4.h. Translational Plan: The investigators plan to develop a program project which is directed toward the link between visceral fat and vascular disease. It includes basic science in endocrinology and immunology, clinical sciences and population science (both observational epidemiology and intervention research). It features collaborations among the Rush Department of Radiology, Section of Cardiology, Department of Immunology, and Department of Preventive Medicine, and with the Section of Endocrinology at the University of Illinois, and the Illinois Institute of Technology.

F.2.6. D.5. Project #5: Epidemiologic Study of Dietary Fats And Metals, Inflammation And Cognition. F.2.6. D.5.a. Investigators: Martha C. Morris, ScD, (Department of Internal Medicine, Rush), Jeremiah Kelly, M.D., (Alzheimer’s Disease Center, Rush), Julie Schneider, M.D. (Alzheimer’s Disease Center, Rush), and David Bennett, M.D. (Alzheimer’s Disease Center, Rush). F.2.6. D.5.b. Hypothesis: Dietary intake of fats and metals is associated with neurodegenerative decline with age and dementia and this effect is mediated by chronic inflammation. F.2.6. D.5.c. Specific Aims: In a pilot sample of 600 participants of the Rush Memory and Aging Project (MAP): Specific Aim # 1: Quantify dietary intake levels of fish, copper and fats (n-3 fatty acids, saturated fat, trans fat, n-6 polyunsaturated fat, monounsaturated fat) to determine whether there is adequate distribution of intake levels to test study hypotheses in the larger MAP study.

PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 248 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Mulshine, James Lawrence Specific Aim # 2: Quantify levels of circulating inflammatory markers: serum IL-6, IL-6 soluble receptors (sIL-6r), IL-1 β, IL- β receptor antagonist (IL-1ra), TNF-α, IL-18 and C-reactive protein (CRP). Specific Aim # 3: Examine the cross sectional associations of dietary fats, fish and copper with cognitive function. Specific Aim # 4: Examine whether high intake of saturated/trans fat modifies the association between copper intake and cognitive scores. Specific Aim # 5: Examine whether dietary intake levels of fats, fish, and the interaction between copper and high fat diets are associated with inflammatory markers. Specific Aim # 6: Examine whether observed associations between fats (and saturated/trans fat interaction with copper intake) and cognitive scores can be explained by levels of circulating inflammatory markers.

F.2.6. D.5.d. Findings: Specific Aim #1 The investigators compared data from the MAP study to the dietary intake levels from the Chicago Health and Aging Project (CHAP), a population-based study of residents 65 years and older living in Chicago. It is in the CHAP study that associations were observed between fish and n-3 fatty acids with cognitive decline and Alzheimer’s disease, and high copper-high fat intake with greater cognitive decline. The nutrient distributions in the MAP pilot are very similar to those of the CHAP study, or in some cases (e.g. DHA copper, zinc) the range of intakes even exceed the CHAP levels. Fish consumption among MAP pilot participants was also somewhat higher than in the CHAP study. Specific Aim #2: Biochemical analyses were conducted of a number of inflammatory markers for 380 MAP participants. The inflammatory markers measured included Interleukin 1B (IL-1B), Interleukin 6 (IL-6), Interleukin 6 soluble receptor (IL-6R), Tumor necrosis factor alpha (TNFa), Interleukin 10 (IL -10), Vascular cell adhesion molecule 1 (VCAM), and Matrix metalloproteinase-9 (MMP-9). Specific Aim #3: These data indicate strong evidence for association of the n-3 fatty acids with cognitive performance. Both EPA and DHA, two long-chain n-3 fatty acids, were positively and linearly associated with perceptual organization. Specific Aim #4: The interaction term (saturated fat * copper) was negatively and marginally associated with the global cognitive score (β= -.004; p=0.13). The β coefficients were all negative for the saturated fat – copper interaction term in similar regression models of the individual cognitive domain scores, however, only the interaction term for working memory (β= -0.01; p=0.03) was statistically significant. Specific Aims #5: The highest quartiles of both polyunsaturated fat intake and trans fat intake were associated positively with the highest quartile of the summary measure of vascular inflammation. The highest quartile of polyunsaturated fats also was associated with the highest TNFa quartile. These data suggest that high dietary intakes of polyunsaturated fats and trans fats are associated with the highest levels of IL-6R and a summary measure of vascular-related inflammation in old age. Specific Aim #6: The highest quartile of the summary measure of IL-1B, IL-6, and TNFa (median level = 32 pg/ml) was associated with worse global cognition. (B coefficient = -.147, p value = .03) This association of the summary measure with global cognition was mostly due to an association with the highest TNFa quartile. The highest quartiles of TNFa and the summary measure also were associated negatively with working memory, perceptual speed, and perceptual organization. These data suggest that TNFa and a summary measure of age related inflammatory markers are associated with measures of global cognition, working memory, perceptual speed, and perceptual organization in old age. F.2.6. D.5.e. Scientific Output: Publications: 1. Sturman M, Fleischman D, Kelly J, Bennett D, Leurgans S, Morris MC. “Epidemiologic Study Of Inflammation And Cognition”. Presented at the 2008 International Conference on Alzheimer’s Disease, July 26-31, 2008 at the Hyatt Regency, Chicago, IL. Abstract published in: Alzheimer’s and Dementia 2008; 4 (suppl 2), T700. 2. Sturman M, Fleischman D, Kelly J, Leurgans S, Bennett D, Morris MC. “Epidemiologic Study of Dietary Fats and Inflammatory Markers in Older Adults”. Presented at the 3rd International Academy of Nutrition and Aging, August 1-2, 2008 at the Hyatt Regency Tamaya Resort & Spa in Albuquerque, New Mexico. Abstract published in: The Journal of Nutrition, Health, and Aging 2008; 12(7): 426. Grants: An NIH R01 grant application was submitted in February 2007 and resubmitted in March 2008 entitled “Epidemiologic Study of Fats and metals, Neuropathology, and Cognitive Decline”. This multidisciplinary 5-year study includes two subcontractors, one in Canada and one in Australia. The investigators plan to resubmit the application for review in February 2010.

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F.2.6. D.5.f. Training Component: Maureen Sturman, M.D., a geriatrician at Cook County Bureau of Health Services, was a trainee involved in this pilot study. Dr. Sturman oversaw the collection of dietary data and participated in all analyses. In 2008 she presented the findings to the International Conference on Alzheimer's disease and the International Conference on Nutrition and Aging. She is preparing two manuscripts for publication. F.2.6. D.5.g. Translational Significance: A number of animal and clinical studies found increased brain inflammation with cognitive impairment and Alzheimer’s disease. The data from this community population support such a relation and identify diet as a potential source of the inflammation. These pilot data demonstrate the translation of laboratory and basic science observations to a community-based cohort. Verification of these findings in a larger study would warrant dietary education and public policy to effectively prevent a devastating disease for which there is no cure, no effective treatment and few established preventable risk factors. Alzheimer’s disease is among the most important public health problem of the 21st century given that older age is exponentially related to increased rates of disease occurrence and the oldest age groups are the fastest growing segment of the population. F.2.6. D.5.h. Translational Plan: The translational plan is to obtain NIH funding to expand data collection to the entire study cohort and to follow the participants over time for incident disease. Participants are free of dementia at baseline and are examined annually for the development of cognitive impairment and dementia. Further, all participants have donated their brains at death. The study design allows for the relation of dietary intake and circulating inflammatory markers to the development of disease and cognitive decline as well as to post-mortem brain neuropathology and brain levels of fats, metals and inflammation. Studying how dietary intake of fats and metals affects brain functioning and tissue in humans is unprecedented and is an excellent example of translational science.

F.2.6. E. Overview of RTSC Pilot Project Program Rush has undergone a substantial transformation in the processes and procedures by which pilot project funds are distributed and monitored. A robust process is now operational to oversee this critical investment in translational research. As a whole, the current pilots reflect the substantial breadth and novelty of translational science that is possible on our campus in collaboration with our partners at Stroger Hospital and the Illinois Institute of Technology. The pilots have leveraged the strengths of several successful ongoing federally funded research programs in the neurosciences, orthopaedic surgery, preventive medicine and infectious disease/immunology. In doing so, they created new interdisciplinary research teams, over multiple institutions, focused on translational research. Two of the five funded pilot projects included investigators from both Rush and Stroger Hospital, one of the pilots includes investigators from Rush and the Illinois Institute of Technology and one of the pilots includes investigators from all three institutions. To foster the development of inter-institutional collaboration the Illinois Institute of Technology provided matching resources for the two pilot projects (#2 and #4) that included investigators whose primary appointment was at IIT. The Pilot Project Program outlined in this section is one of several initiatives to provide critical developmental resources for translational researchers in the RTSC. In addition to the standing intramural grant mechanisms summarized in Table F.2.6.1, this application seeks funding to leverage and expand the ongoing RTSC Pilot Project Program, seed funding to enhance core facilities utilization and development, and seed funding for novel technology development (Table F.2.6.4). Although only in its second cycle, the pilot project program has made a substantial impact on the Rush campus. The newly established selection and oversight process for the RTSC pilot project program, as administered by the SLC, has extended throughout the university to other extant funding mechanisms catalyzing the engagement of the entire university research community including the Department Chairs. The explicit focus on training, accountability, translational plans and productivity has positively impacted the research culture at Rush, promising to provide substantial returns on these strategic investments. To date, these investments have been responsible, in part, for the receipt of approximately $18,300,000 in NIH Grants (Pilot Projects #1 and #4).

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Table F.2.6.4 SUMMARY OF PROPOSED CTSA INTRAMURAL GRANT MECHANISMS FOR THE RTSC

CTSA- CTSA First Study Final supported Purpose RFA Eligibility Budget Year Section Approval grants Amount Total Novel Technologies grants Translational To develop new Special methodology methodologies peer- development and/or 4 RTSC $18,750/yr review SLC $75,000 grants technologies not times/year member for 2 years committee program supported by (see (F.2.4.E.2) current cores F.2.4.E.2) Provide investigators an mini- Special opportunity to sabbatical 2 RTSC peer- learn assays that $20,000 SLC $40,000 program times/year member review can be brought (F.2.4.E.3) committee back to the RTSC Pilot and Collaborative Translational and Clinical Studies grants To support Pilot Pilot Projects promising 1 RTSC Project $150,000 SLC $650,000* (F.2.6) researchers and time/year member Evaluation research teams Team TTRC grants Investigator- Assist TTRC initiated core researchers who 6 RTSC $5,000 Steering SLC $30,000 use have no budget times/year member Committee (F.2.5.D.1.c) for core expenses Core facilitator- Support new Core initiated 1 TTRC Core techniques within $30,000 Working SLC $30,000 development time/year facilitators existing cores Group grant (F.2.5..D.2.a TTRC Core start-up Support TTRC 1 RTSC program personnel costs $50,000 Steering SLC $50,000 time/year member (F.2.8.D.6.b for new cores Committee )

* $500,000 provided by Rush Institutional Support

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