DOCSLIB.ORG

2017 Program (PDF)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
2017 Program (PDF) The Proceedings of the 15th Annual Research Day Department of Medicine May 1 & 2, 2017 Pages Schedule of Events 3 - 4 Keynote Speaker: Pages Tadataka Yamada, MD 5 Pages Oral Presenters: May 1, 2017 6 - 25 Pages Oral Presenters: May 2, 2017 26 - 41 Pages List of Judges 42 - 44 Poser Author Index & Abstracts: Pages 45 - 103 Residents - May 1, 2017 Poser Author Index & Abstracts: Pages Session A – May 2, 2017 104 -204 Poser Author Index & Abstracts: Pages Session B – May 2, 2017 205 -298 Pages Acknowledgments 299 2 | Page CLINCAL RESEARCH: RESIDENTS MAY 1 - UNIVERSITY CLUB 5:00 pm Registration & Poster Viewing 5:15 pm Welcome & Opening Remarks Mark Gladwin, MD Chair, Department of Medicine Director, Vascular Medicine Institute Professor of Medicine, Division of PACCM Alison Morris MD, MS Vice Chair, Clinical Research Professor of Medicine Director, University of Pittsburgh HIV Lung Research Center UPMC Chair, Translational Pulmonary and Critical Care Medicine 5:30-6:30 pm Oral Presentations Sokratis Apostolidis, MD Emily Guhl, MD Shelly Kakar, DO Yijia Li, MD 6:30-7:30 pm Poster Viewing Session & Discussion 7:30-8:00 pm Keynote Speaker Introduction Tadataka Yamada, MD “An M.D. Degree – A Life Full of Options” Venture Partner with Frazier Healthcare Partners 8:00 pm Awards Presentation 3 | Page RESEARCH DAY MAY 2 – BIOMEDICAL SCIENCE TOWER SOUTH FOYER & S-100 9:00 am Registration & Continental Breakfast Available 9:30-11:30 am Session A: Poster Viewing & Judging 11:30 am Lunch Available 12:00-1:00 pm Keynote Speaker Tadataka Yamada, MD “Lessons from Global Health” Venture Partner with Frazier Healthcare Partners 1:15-3:15 pm Session B: Poster Viewing & Judging 3:30-4:30 pm Oral Presentations Jill Allenbaugh, MD Neelesh Nadkarni, MD, PhD, FRCPC Natasha Parekh, MD Francois Yu, PhD 4:30 pm Awards Presentation 4 | Page Keynote Speaker Tadataka Yamada, MD Dr. Tadataka Yamada is a Venture Partner with Frazier Healthcare Partners. Prior to joining Frazier he was Executive Vice-President, Chief Medical & Scientific Officer and a Board Member of Takeda Pharmaceuticals. Dr. Yamada has served as President of the Bill & Melinda Gates Foundation Global Health Program. In this position, he oversaw grants totaling more than $9 billion in programs directed at applying technologies to address major health challenges of the developing world including TB, HIV, malaria and other infectious diseases, malnutrition and maternal and child health. He was formerly Chairman, Research and Development and a Member of the Board of Directors of GlaxoSmithKline and before that he was Chair of the Department of Internal Medicine and Physician-in-Chief at the University of Michigan Medical Center. Dr. Yamada holds a bachelor's degree in history from Stanford University and obtained his M.D. from New York University School of Medicine. In recognition of his contributions to medicine and science he has been elected to membership in the National Academy of Medicine (US), the Academy of Medical Sciences (UK) and the National Academy of Medicine (Mexico) and he has received an honorary appointment as Knight Commander of the Most Excellent Order of the British Empire (KBE). He is a Past-President of the Association of American Physicians and of the American Gastroenterological Association and he has served as a member of the President's Council of Advisors on Science and Technology and the Advisory Committee to the Director of the National Institutes of Health. He is currently Vice Chair of the Council of the National Academy of Medicine and serves on the Board of Directors of the Clinton Health Access Initiative. 5 | Page Oral Presenter – May 1, 2017 Sokratis Apostolidis, MD Resident - International Scholar Bio: Sokratis is a PGY-2 Internal Medicine resident in the IST scholars’ track of the UPMC Internal Medicine Residency program. He was born and raised in Greece and completed his medical school studies in the University of Athens. Halfway through his medical training, he became drawn to immunology and rheumatologic diseases and shortly after his graduation, he joined the Rheumatology Lab of Dr. Tsokos in Beth Israel Deaconess Medical Center. As a post-doctoral fellow in Boston, he performed research on lupus nephritis and the role of the Protein Phosphatase 2a in Systemic Lupus Erythematosus pathogenesis. His research work on autoimmunity and immune tolerance has been published in the Journal of Immunology, Journal of Biological Chemistry and Nature Immunology. During his internal medicine residency, his research interests focus on identifying the underlying mechanisms contributing to vascular injury in scleroderma patients. Presentation: Single cell RNA sequencing reveals a signature of endothelial injury in scleroderma skin. Background: Vascular injury is a hallmark event in the pathogenesis of Systemic Sclerosis (SSc). Endothelial dysfunction happens early in the course of the disease and drives some of the most prominent clinical manifestations of scleroderma, including Raynaud’s phenomenon, telangiectasias and gastric antral vascular ectasias, pulmonary arterial hypertension and scleroderma renal crisis. The exact mechanisms that lead to endothelial cell injury and propagate the vasculopathy in scleroderma are not well understood. Single cell RNA sequencing provides a robust platform for cellular identification, allows gene expression analysis at the single cell level and accounts for cellular heterogeneity. Methods: The study was completed in the Scleroderma Center of UPMC in collaboration with the Boston University Scleroderma Center and the Broad Institute of Boston. Scleroderma patients and healthy matched controls at UPMC and Boston University Scleroderma Centers were 6 | Page recruited. Skin biopsies were obtained and the tissues were digested to form single cell suspensions. We then implemented single cell FACS-sorting and subsequent RNA sequencing of the isolated cells from scleroderma and healthy control skin. The analysis was performed using R software. We used t-distributed stochastic neighbor embedding (t-SNE) with k-means clustering to identify the various cell types. We performed pathway analysis using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA). Finally, we independently verified distinct markers using immunohistochemistry on skin biopsies and qPCR in primary endothelial cells isolated from skin of scleroderma patients and healthy controls. Results: In order to be able to visualize and ultimately define the various cell subsets in the dataset, we used t-distributed stochastic neighbor embedding (t-SNE), a method of unsupervised learning for dimensionality reduction. 2D projection of the t-SNE coupled with k-means clustering effectively reduced the dimensionality of the data revealing clustering patterns that had the potential to represent distinct cellular populations, as shown in Figure 1. Figure 1. 7 | Page The purpose of our analysis was to identify endothelial cells. In order to define the cluster that represents the endothelial cell population in our dataset, we employed known endothelial cell markers, such as Von Willebrand factor (gene name VWF), platelet endothelial cell adhesion molecule (gene name PECAM1) and vascular endothelial cadherin (CDH5). We overlaid the expression of these genes on the t-SNE projection plot and were able to positively identify the endothelial cells among the sorted single cells from healthy and scleroderma skin. Cluster 4 in Figure 1 is the cluster that represents the endothelial cells based on the expression of the abovementioned genes (the expression of the genes is not depicted in Figure 1). After defining the endothelial cells in our dataset, we focused our analysis on the endothelial cell subpopulation and identified differentially expressed genes between healthy control ECs and SSc ECs. As it can be seen in Figure 2, the two fold upregulated genes (top bin) contains already established markers of endothelial injury and activation including the Apelin receptor APLNR and stabilin-1 (gene name STAB1), as well as previously identified markers of endothelial injury and negative regulation of angiogenesis in scleroderma, such as THBS1 and VWF. It also includes components of the extracellular matrix, such as the heparin sulfate proteoglycan 2 (gene name HSPG2) that was previously shown to be implicated in fibrotic processes including scleroderma- associated fibrosis, wound healing and to be regulated in a TGF-β dependent manner. In order to highlight pathways that are enriched in our dataset and to find gene signatures that are positively or negatively regulated in scleroderma endothelial cells compared to their healthy counterparts, we used Gene Set Enrichment Analysis (GSEA) (45) and Ingenuity Pathway Analysis (IPA, Qiagen). Using GSEA we were able to demonstrate that the SSc endothelial cell expression profile is enriched in processes associated with extracellular matrix (ECM) generation as well as epithelial-to-mesenchymal transition (EMT). In addition, using Ingenuity Pathway, we found that scleroderma endothelial cells show enrichment in pathways associated with inhibition of angiogenesis, acute phase response, complement activation and matrix metalloproteinases (Figure 3). 8 | Page Figure 2. 9 | Page Figure 3. Finally, two of the top differentially expressed genes, HSPG2 and APLNR, were independently verified. Primary endothelial cells isolated from scleroderma skin expressed higher 10 | Page levels of APLNR compared to endothelial cells isolated from healthy skin. HSPG2
Load more

Recommended publications
  • Spider-Venom Peptides As Therapeutics
    Toxins 2010, 2, 2851-2871; doi:10.3390/toxins2122851 OPEN ACCESS toxins ISSN 2072-6651 www.mdpi.com/journal/toxins Review Spider-Venom Peptides as Therapeutics Natalie J. Saez, Sebastian Senff, Jonas E. Jensen, Sing Yan Er, Volker Herzig, Lachlan D. Rash and Glenn F. King * Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, 4072, Australia; E-Mails: [email protected] (N.J.S.); [email protected] (S.S.); [email protected] (J.E.J.); [email protected] (S.Y.E.); [email protected] (V.H.); [email protected] (L.D.R.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: 61-7-3346-2025; Fax: 61-7-3346-2021. Received: 16 November 2010; in revised form: 17 December 2010 / Accepted: 17 December 2010 / Published: 20 December 2010 Abstract: Spiders are the most successful venomous animals and the most abundant terrestrial predators. Their remarkable success is due in large part to their ingenious exploitation of silk and the evolution of pharmacologically complex venoms that ensure rapid subjugation of prey. Most spider venoms are dominated by disulfide-rich peptides that typically have high affinity and specificity for particular subtypes of ion channels and receptors. Spider venoms are conservatively predicted to contain more than 10 million bioactive peptides, making them a valuable resource for drug discovery. Here we review the structure and pharmacology of spider-venom peptides that are being used as leads for the development of therapeutics against a wide range of pathophysiological conditions including cardiovascular disorders, chronic pain, inflammation, and erectile dysfunction.
    [Show full text]
  • Targeting Ion Channels in Cancer: a Novel Frontier in Antineoplastic Therapy A
    66 Current Medicinal Chemistry, 2009, 16, 66-93 Targeting Ion Channels in Cancer: A Novel Frontier in Antineoplastic Therapy A. Arcangeli*,1, O. Crociani1, E. Lastraioli1, A. Masi1, S. Pillozzi1 and A. Becchetti2 1Department of Experimental Pathology and Oncology, University of Firenze, Italy; 2Department of Biotechnology and Biosciences, University of Milano-Bicocca, Italy Abstract: Targeted therapy is considerably changing the treatment and prognosis of cancer. Progressive understanding of the molecular mechanisms that regulate the establishment and progression of different tumors is leading to ever more spe- cific and efficacious pharmacological approaches. In this picture, ion channels represent an unexpected, but very promising, player. The expression and activity of different channel types mark and regulate specific stages of cancer progression. Their contribution to the neoplastic phenotype ranges from control of cell proliferation and apoptosis, to regulation of invasiveness and metastatic spread. As is being in- creasingly recognized, some of these roles can be attributed to signaling mechanisms independent of ion flow. Evidence is particularly extensive for K+ channels. Their expression is altered in many primary human cancers, especially in early stages, and they frequently exert pleiotropic effects on the neoplastic cell physiology. For instance, by regulating membrane potential they can control Ca2+ fluxes and thus the cell cycle machinery. Their effects on mitosis can also de- pend on regulation of cell volume, usually in cooperation with chloride channels. However, ion channels are also impli- cated in late neoplastic stages, by stimulating angiogenesis, mediating the cell-matrix interaction and regulating cell motil- ity. Not surprisingly, the mechanisms of these effects are manifold.
    [Show full text]
  • Potent Neuroprotection After Stroke Afforded by a Double-Knot Spider-Venom Peptide That Inhibits Acid-Sensing Ion Channel 1A
    Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a Irène R. Chassagnona, Claudia A. McCarthyb,c, Yanni K.-Y. China, Sandy S. Pinedaa, Angelo Keramidasd, Mehdi Moblie, Vi Phamb,c, T. Michael De Silvab,c, Joseph W. Lynchd, Robert E. Widdopb,c, Lachlan D. Rasha,f,1, and Glenn F. Kinga,1 aInstitute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia; bBiomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; cDepartment of Pharmacology, Monash University, Clayton, VIC 3800, Australia; dQueensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia; eCentre for Advanced Imaging, The University of Queensland, St. Lucia, QLD 4072, Australia; and fSchool of Biomedical Sciences, The University of Queensland, St. Lucia, QLD 4072, Australia Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 6, 2017 (received for review September 1, 2016) Stroke is the second-leading cause of death worldwide, yet there are extracellular pH that occurs during cerebral ischemia. ASIC1a is the no drugs available to protect the brain from stroke-induced neuronal primary acid sensor in mammalian brain (9, 10) and a key mediator of injury. Acid-sensing ion channel 1a (ASIC1a) is the primary acid sensor stroke-induced neuronal damage. Genetic ablation of ASIC1a reduces in mammalian brain and a key mediator of acidosis-induced neuronal infarct size by ∼60% after transient middle cerebral artery occlusion damage following cerebral ischemia. Genetic ablation and selective (MCAO) in mice (7), whereas pharmacologic blockade with modestly pharmacologic inhibition of ASIC1a reduces neuronal death follow- potent ASIC1a inhibitors, such as amiloride (7) and nonsteroidal anti- ing ischemic stroke in rodents.
    [Show full text]
  • ION CHANNELS S72 Acid-Sensing (Proton-Gated) Ion Channels (Asics) Alexander Et Al
    ION CHANNELS S72 Acid-sensing (proton-gated) ion channels (ASICs) Alexander et al Acid-sensing (proton-gated) ion channels (ASICs) Overview: Acid-sensing ion channels (ASICs, provisional nomenclature) are members of a Na þ channel superfamily that includes the epithelial Na channel, ENaC, the FMRF-amide activated channel of Helix aspersa, the degenerins (DEG) of Caenorhabitis elegans (see Waldmann & Lazdunski, 1998; Mano & Discoll, 1999) and ‘orphan’ channels that include BLINaC (Sakai et al., 1999) and INaC (Schaefer et al., 2000). ASIC subunits contain two putative TM domains and assemble as homo- or heterotetramers to form proton-gated, Na þ permeable channels. Splice variants of ASIC1 (provisionally termed ASIC1a (ASIC-a) (Waldmann et al., 1997a) and ASIC1b (ASIC-b) (Chen et al., 1998)) and ASIC2 (provisionally termed ASIC2a (MDEG1) and ASIC2b (MDEG2); Lingueglia et al., 1997) have been cloned. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H þ -gated currents. Transcripts encoding a fourth member of the ASIC family (ASIC4/SPASIC) do not produce a proton-gated channel in heterologous expression systems (Akopian et al., 2000; Grunder et al., 2000). ASIC channels are expressed in central and peripheral neurons and particularly in nociceptors where they participate in neuronal sensitivity to acidosis. The relationship of the cloned ASICs to endogenously expressed proton-gated ion channels is becoming established (Escoubas et al., 2000; Sutherland et al., 2001; Wemmie et al., 2002; 2003). Heterologously expressed heteromutimers of ASIC1/ASIC2a, ASIC2a/ASIC2b, ASIC2a/ASIC3 ASIC2b/ASIC3 and ASIC1a/ASIC3 form ion channels with altered kinetics, ion selectivity, pH-sensitivity and sensitivity to block by Gd3 þ (Bassilana et al., 1997; Lingueglia et al., 1997; Babinski et al., 2000; Escoubas et al., 2000).
    [Show full text]
  • Pain Research Product Guide | Edition 2
    Pain Research Product Guide | Edition 2 Chili plant Capsicum annuum A source of Capsaicin Contents by Research Area: • Nociception • Ion Channels • G-Protein-Coupled Receptors • Intracellular Signaling Tocris Product Guide Series Pain Research Contents Page Nociception 3 Ion Channels 4 G-Protein-Coupled Receptors 12 Intracellular Signaling 18 List of Acronyms 21 Related Literature 22 Pain Research Products 23 Further Reading 34 Introduction Pain is a major public health problem with studies suggesting one fifth of the general population in both the USA and Europe are affected by long term pain. The International Association for the Study of Pain (IASP) defines pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’. Management of chronic pain in the clinic has seen only limited progress in recent decades. Treatment of pain has been reliant on, and is still dominated by two classical medications: opioids and non-steroidal anti-inflammatory drugs (NSAIDs). However, side effects such as dependence associated with opioids and gastric ulceration associated with NSAIDs demonstrates the need for new drug targets and novel compounds that will bring in a new era of pain therapeutics. Pain has been classified into three major types: nociceptive pain, inflammatory pain and neuropathic or pathological pain. Nociceptive pain involves the transduction of painful stimuli by peripheral sensory nerve fibers called nociceptors. Neuropathic pain results from damage or disease affecting the sensory system, and inflammatory pain represents the immunological response to injury through inflammatory mediators that contribute to pain. Our latest pain research guide focuses on nociception and the transduction of pain to the spinal cord, examining some of the main classical targets as well as emerging pain targets.
    [Show full text]
  • Trypsin-Like Proteases and Their Role in Muco-Obstructive Lung Diseases
    International Journal of Molecular Sciences Review Trypsin-Like Proteases and Their Role in Muco-Obstructive Lung Diseases Emma L. Carroll 1,†, Mariarca Bailo 2,†, James A. Reihill 1 , Anne Crilly 2 , John C. Lockhart 2, Gary J. Litherland 2, Fionnuala T. Lundy 3 , Lorcan P. McGarvey 3, Mark A. Hollywood 4 and S. Lorraine Martin 1,* 1 School of Pharmacy, Queen’s University, Belfast BT9 7BL, UK; [email protected] (E.L.C.); [email protected] (J.A.R.) 2 Institute for Biomedical and Environmental Health Research, School of Health and Life Sciences, University of the West of Scotland, Paisley PA1 2BE, UK; [email protected] (M.B.); [email protected] (A.C.); [email protected] (J.C.L.); [email protected] (G.J.L.) 3 Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast BT9 7BL, UK; [email protected] (F.T.L.); [email protected] (L.P.M.) 4 Smooth Muscle Research Centre, Dundalk Institute of Technology, A91 HRK2 Dundalk, Ireland; [email protected] * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Trypsin-like proteases (TLPs) belong to a family of serine enzymes with primary substrate specificities for the basic residues, lysine and arginine, in the P1 position. Whilst initially perceived as soluble enzymes that are extracellularly secreted, a number of novel TLPs that are anchored in the cell membrane have since been discovered. Muco-obstructive lung diseases (MucOLDs) are Citation: Carroll, E.L.; Bailo, M.; characterised by the accumulation of hyper-concentrated mucus in the small airways, leading to Reihill, J.A.; Crilly, A.; Lockhart, J.C.; Litherland, G.J.; Lundy, F.T.; persistent inflammation, infection and dysregulated protease activity.
    [Show full text]
  • The Role of Asic1a in the Regulation of Synaptic Release Probability
    The Role of ASIC1a in the Regulation of Synaptic Release Probability THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Soluman Culver Graduate Program in Pathology The Ohio State University 2013 Master's Examination Committee: W. James Waldman, Adviser Candice Askwith John Enyeart Copyright by Soluman Culver 2013 Abstract Extracellular pH plays an important role in neuronal signaling. As primary receptors of pH signals, acid-sensing ion channels (ASICs) are able to translate fluctuations in the extracellular pH into membrane potentials and calcium signals. ASICs and pH signaling are thought to play important roles in anxiety, affect, and pain, although the mechanism by which they are able to influence these processes remains poorly understood. During conditions of dysregulated pH aberrant ASIC activity is known to result in cellular dysfunction and death, making a mechanistic explanation of ASIC function of broad importance to our understanding of downstream consequences during pathophysiological circumstances. One significant role of ASIC is in its ability to modulate synaptic vesicle release, a property which may contribute to neuronal dysfunction secondary to disruptions in pH signaling. This study demonstrates that the mechanism of ASIC-dependent regulation of synaptic vesicle does not rely upon rapid local signaling, but rather requires several hours of ASIC block to be interrupted, suggesting that it may take place through the induction of gene regulation and cause global changes in cellular physiology. Similarly, our results suggest that ASIC1a may be responding to endogenous proton flux to accomplish this regulation, refining our understanding of the cause and context of ASIC1a activation in health and disease.
    [Show full text]
  • Versatile Spider Venom Peptides and Their Medical and Agricultural Applications
    Accepted Manuscript Versatile spider venom peptides and their medical and agricultural applications Natalie J. Saez, Volker Herzig PII: S0041-0101(18)31019-5 DOI: https://doi.org/10.1016/j.toxicon.2018.11.298 Reference: TOXCON 6024 To appear in: Toxicon Received Date: 2 May 2018 Revised Date: 12 November 2018 Accepted Date: 14 November 2018 Please cite this article as: Saez, N.J., Herzig, V., Versatile spider venom peptides and their medical and agricultural applications, Toxicon (2019), doi: https://doi.org/10.1016/j.toxicon.2018.11.298. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT MANUSCRIPT ACCEPTED ACCEPTED MANUSCRIPT 1 Versatile spider venom peptides and their medical and agricultural applications 2 3 Natalie J. Saez 1, #, *, Volker Herzig 1, #, * 4 5 1 Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia 6 7 # joint first author 8 9 *Address correspondence to: 10 Dr Natalie Saez, Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 11 4072, Australia; Phone: +61 7 3346 2011, Fax: +61 7 3346 2101, Email: [email protected] 12 Dr Volker Herzig, Institute for Molecular Bioscience, The University of Queensland, St.
    [Show full text]
  • The Nav1.7 Channel Subtype As an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons Tânia C
    The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons Tânia C. Gonçalves, Evelyne Benoit, Michel Partiseti, Denis Servent To cite this version: Tânia C. Gonçalves, Evelyne Benoit, Michel Partiseti, Denis Servent. The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons. Frontiers in Pharmacology, Frontiers, 2018, 9, pp.1000. 10.3389/fphar.2018.01000. hal-02019554 HAL Id: hal-02019554 https://hal.archives-ouvertes.fr/hal-02019554 Submitted on 10 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. fphar-09-01000 October 23, 2018 Time: 12:20 # 1 REVIEW published: 04 September 2018 doi: 10.3389/fphar.2018.01000 The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons Tânia C. Gonçalves1,2, Evelyne Benoit2,3, Michel Partiseti1 and Denis Servent2* 1 Sanofi R&D, Integrated Drug Discovery – High Content Biology, Paris, France, 2 Service d’Ingénierie Moléculaire des Protéines, CEA de Saclay, Université Paris-Saclay, Gif-sur-Yvette, France, 3 Institut des Neurosciences Paris-Saclay, UMR CNRS/Université Paris-Sud 9197, Gif-sur-Yvette, France Although necessary for human survival, pain may sometimes become pathologic if long-lasting and associated with alterations in its signaling pathway.
    [Show full text]
  • Creating Ion Channel Blocking Antibodies by Fusing Knottins Into Peripheral CDR Loops Aneesh Karatt Vellatt
    KnotBodiesTM: creating ion channel blocking antibodies by fusing Knottins into peripheral CDR loops Aneesh Karatt Vellatt Precision Medicine and Ion Channel Retreat 2017 Vancouver Confidential Antibody discovery at IONTAS Antibody drug discovery company founded in Oct 2012 Powerful track record – 24 antibody discovery projects with 14 European and US organisations to Q1 2017 100% record of success! Protein Lead Primary Lead Secondary Lead/back Target Selection production Isolation Screen Optimisation Screening up IgG Phage library 4 x 1010 clones High proportion of insert Bi-specific Mammalian display scFv KnotBodiesTM Fab Production Research Targeting ion channels with antibodies Plasma membrane VGSC Challenging target class for antibody generation Difficult to express and purify, low stability Limited epitope availability Dynamic molecules with multiple conformations Sea anemone ShK Kv1.3 blocker Velvet Tarantula ProTx-II Nav1.7 blocker Conus snail Ziconotide Cav2.2 blocker Black Mamba Mambalgin1 ASIC blocker Casewell et al Trends in Ecology and Evolution (2013) Knottins: nature’s ion channel inhibitor scaffold PcTx1 Huwentoxin-IV ω-conotoxin-MVIIA ASIC1 blocker Nav blocker : Cav blocker 30-40 amino acids, 3-4 disulfide bonds Forms a conserved (Inhibitory Cystine Knot) structural motif high sequence and functional diversity despite the structural conservation Also found in non venomous species and modulate wide variety of biological functions Knottins: therapeutic development Ziconotide (PRIALT®; Primary Alternative to Morphine)
    [Show full text]
  • On the Quest of Small Molecules That Can Mimic Psalmotoxin-1, a Powerful Peptidic Modulator of the Acid Sensing Channel Asic1a
    On the Quest of Small Molecules that Can Mimic Psalmotoxin-1, a Powerful Peptidic Modulator of the Acid Sensing Channel ASIC1a Francesco Pietra ( [email protected] ) Accademia Lucchese https://orcid.org/0000-0003-3215-5376 Research Article Keywords: ion channels, spider toxins, PcTx1, QM-MM, MEP Posted Date: June 15th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-467127/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/15 Abstract Acid-sensing ion channels (ASICs) are thought to play a key role in a number of pathologies, from neuronal injury to pain sensation, while no drug has yet been approved as their modulator. This work was devised to asses roughly, yet from rst principles, the relative energies of binding in the most important acidic pocket of cASIC1a, thereby paving the way to nd small molecules that can mimic Pctx1, the most powerful peptidic modulator of cASIC1a. To this end, MD simulations for the overall conformation, and QM-MM simulations specically for the location of hydrogen atoms, allowed disentangling the relative weight of the various non-bonded interactions between PcTx1 and cASIC1a. Main weight could be attributed to deeply buried salt bridges formed by the guanidinium end chains of residues Arg26 and Arg27 on PcTx1 and carboxylate end chain of distant residues Asp and Glu on cASIC1a. Rewardingly, in a preliminary attempt at exploiting these observations toward a small-molecule modulator, a Arg26-Arg27 stretch, excised from the PcTx1-cASIC1a complex and slightly simplied, on automated rigid docking on ligand-free receptor was observed to form most of the above salt bridges.
    [Show full text]
  • Modulation of Asic1a Function by Sigma-1 Receptors: Physiological and Pathophysiological Implications
    University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School 2-27-2009 Modulation of ASIC1a Function by Sigma-1 Receptors: Physiological and Pathophysiological Implications Yelenis Herrera University of South Florida Follow this and additional works at: https://scholarcommons.usf.edu/etd Part of the American Studies Commons Scholar Commons Citation Herrera, Yelenis, "Modulation of ASIC1a Function by Sigma-1 Receptors: Physiological and Pathophysiological Implications" (2009). Graduate Theses and Dissertations. https://scholarcommons.usf.edu/etd/2011 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Modulation of ASIC1a Function by Sigma-1 Receptors: Physiological and Pathophysiological Implications by Yelenis Herrera A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences Department of Molecular Pharmacology and Physiology College of Medicine University of South Florida Major Professor: Javier Cuevas, Ph.D. Keith R. Pennypacker, Ph.D. Eric S. Bennett, Ph.D. Jay B. Dean, Ph.D. Alison Willing, Ph.D. ZhiGang Xiong, Ph.D. Date of Approval: February 27, 2009 Keywords: intracellular calcium, whole-cell currents, AKAP150, calcineurin, G protein, neurotransmission, glutamate, VGCC, NMDA receptor © Copyright 2009, Yelenis Herrera DEDICATION Those who have inspired me throughout my life and scientific career are those that I love the most. This dissertation is dedicated to them - my husband and family. I would like to thank my Mom and Dad for giving me the opportunity to be free, succeed and pursue my education.
    [Show full text]