CHIRP Program Leadership

Director

Harvey B. Pollard, M.D., Ph.D.

Harvey B. Pollard, M.D., Ph.D.

Name: Harvey B. Pollard, M.D., Ph.D.

Department of Primary Appointment: Anatomy, Physiology & Genetics
Position: Department Chair
Title: Professor & Chair

Affiliated Departments: Molecular & Cell Biology, Neuroscience

Research Interests:
Neuroendocrine and Exocrine Secretory Processes

Email: harvey.pollard@usuhs.edu (link sends e-mail)
Office Phone: (301) 295-9365

Links
Department Website
PubMed Listing

Education

University
M. D. 1973, Ph.D., 1969 University of Chicago

Profile

Our laboratory focuses attention on the molecular basis of various secretory processes whose dysfunction results in human disease. Neurotransmitter and neurohormone release occur from nerve terminals, endocrine, and exocrine cells by a fusion mechanism sensitive to ionic calcium, GTP, protein kinase C, and other kinases. Two disease-related applications of these interests have been pursued: Synexin (annexin VII, ANX7) is a Ca2+ channel protein and newly identified member of the GTPase Superfamily which uniquely fuses membranes, and is regulated by Ca2+, GTP and various protein kinases. It is also a newly identified component of the "fusion machine" which is believed to mediate docking and fusion during exocytotic secretion. Defects in these processes have been implicated in the pathologies of hypertension and diabetes, among others. These exciting results have prompted Dr. Pollard to investigate how the protein works in vivo using methods of site directed mutagenesis, prokaryotic and eukaryotic mutant protein expression, adenovirus transduction, and transgenic and knockout technologies.

We have also applied our insights from synexin studies to the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), which is important for exocrine secretory processes. This protein, which is defective in the most common genetic disease, cystic fibrosis (CF), has nucleotide binding domains which are highly homologous with the annexin gene family. Like annexins, these domains interact specifically with the membrane, and mutations known to cause CF disrupt these interactions. Molecular analysis of the structure of these domains have led to our development of compounds which are currently being tested clinically for treatment of cystic fibrosis. In addition to conventional molecular methods employed for this study, our other approaches include fluorescence spectroscopy, confocal microscopy, lipid biochemistry, and organic synthesis.

Deputy Director

David W. Scott, Ph.D.

David W. Scott, Ph.D.

Name: David W. Scott, Ph.D.

Department of Primary Appointment: Dept. of Medicine
Position: USU Faculty
Title: Professor and Vice Chair for Research

Affiliated Departments: Emerging Infectious Diseases,

Email: david.scott@usuhs.edu (link sends e-mail)
Office Phone: (301) 295-3618
Fax Number: (301) 295-3618
Room: A3069

Profile

M.S. University of Chicago
Ph.D. Yale
Post-doctoral training: Oxford University, England

Research: Induction of tolerance for adverse immune responses in autoimmunity and hemophilia

The breakdown of self-tolerance in autoimmunity, as well the response to biotherapeutics for monogenic diseases, results in serious morbidity and potential mortality for millions of Americans. Understanding and applying the induction of immunologic tolerance to prevent and/or reverse these adverse immune responses is the primary focus of the Scott lab. This includes utilizing gene therapy with transduced B cells, as well as the design of engineered T regulatory cells for tolerance. The main systems involve the modulation of autoimmune diseases, like multiple sclerosis and type 1 diabetes, as well as prevention and reversal of inhibitory antibody formation in hemophilia. The basis of our approach has been the use of chimeric proteins comprised of an immunoglobulin (Ig) heavy chain and the target domains or peptides, and delivery into B cells as tolerogenic antigen-presenting cells. This has led recently to the discovery of putative regulatory epitopes in IgG that could serve to turn on regulatory T cells, and strong preliminary data in multiple disease models. Further work utilizes tolerogenic nanoparticles that have shown efficacy in several disease models. Our lab continues to be actively involved in the mechanisms by which T regulatory cells can modulate both innate and adaptive immune responses, and the creation of novel engineered human antigen-specific CAR Tregs and CD8 cells.

Movie showing interaction of tolerogenic B cells with specific T cells

Selected Publications

Zambidis E, Scott, DW. Epitope-specific tolerance induction with an engineered immunoglobulin. 1996. Proc Nat Acad Sci 93: 5019. PMID: 8643522

Agarwal RK, Kang Y, Zambidis E, Scott, DW, Chan C, Caspi R,R. 2000. Retroviral gene transfer of an immunoglobulin-antigen fusion protein protects from autoimmune disease. J Clin Invest 106:245. PMID: 10903340

Melo M, Qian J, El-Amine M, Agarwal R, Soukhareva N, Kang Y, Scott, DW. 2002. Gene transfer of immunoglobulin-fusion proteins into B cells prevents and treats autoimmune diseases. J Imm 168:4788. PMID: 11971030.

Lei T-C, Scott, DW. 2005.Induction of tolerance to fVIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B-cells as Ig fusion proteins. Blood 105:4865. PMID: 15769892.

De Groot, AS, Moise, L, McMurry, JA, Wambre, E, Van Overtvelt, L, Moingeon, P, Scott, DW, and Martin W. 2008. Activation of natural regulatory T cells by IgG Fc–derived peptide “Tregitopes.” Blood. 112:3303-11. PMID: 18660382.

Skupsky, J, Zhang, AH, Su, Y, and Scott, DW. 2010. B-cell Delivered Gene Therapy Induces Functional T Regulatory Cells and Leads to a Loss of Antigen-Specific Effector Cells. Molecular Therapy, 18:1527-35. PMID: 20485267.

Zhang AH, Skupsky J, Scott DW. 2011. Effect of B-cell depletion using anti-CD20 therapy on inhibitor formation and immune tolerance induction to human factor VIII in hemophilia A mice. Blood, 117: 223-226. PMID: 21160036.

Su, Y, Zhang, AH, Noben, N, and Scott, DW. 2011. B-cell gene therapy for tolerance induction: host but not donor B cell derived IL-10 is necessary for tolerance. Frontiers in Microbial Immunology, 2:154. PMID: 21811487.

Matheu, MP, Su, Y, Greenberg, ML, Blanc, C, Parker, I, Scott, DW, Cahalan, MD 2012. TLR4-activated B cells out-compete TLR9-activated B cells to establish peripheral tolerance, PNAS Plus, 109:E1258-66. doi: 10.1073/pnas.1205150109.

Scott DW, Pratt KP, and Miao CH. 2013. Progress Towards Inducing Immunologic Tolerance to Factor VIII. Blood (Invited peer-reviewed) 121 : 4449-4456.

Maldonado RA, LaMothe RA, Ferrari JD, Zhang AH, Rossi RJ, Griset AP, O’Neil C, Alreuter DH, Johnston L, Farokhzad OC, Langer R, Scott DW, von Andrian UH, Kishimoto TK. 2015. Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. PNAS, 112(2):E156-65. PMID: 25548186

Kim YC, Zhang AH, Su Y, Rieder SA, Rossi RJ, Ettinger RA, Pratt KP, Shevach EM and Scott DW. 2015. Engineered antigen-specific human regulatory T cells: Immunosuppression of FVIII-specific T- and B-cell responses, Blood 125: 1107. PMID: 25498909.

Gupta N, Culina S, Meslier Y, Dimitrov J, Arnoult C, Delignat S, Gangadharan B, Lecerf M, Justesen S, Gouilleux-Gruart V, Salomon BL, Scott DW, Kaveri SV, Mallone R, Lacroix-Desmazes S. 2015. Regulation of immune responses to protein therapeutics by transplacental induction of T cell tolerance. Sci Transl Med. 2015 Feb 18;7(275):275ra21. PMID: 25696000

CHIRP Core Directorates

Clifton Dalgard, Ph.D., Director, Laboratory Core

Name: Clifton Dalgard, Ph.D.

Department of Primary Appointment: Anatomy, Physiology & Genetics
Position: USU Faculty
Title: Director, Laboratory Core (CHIRP), Associate Professor

Affiliated Departments: Molecular & Cell Biology, Neuroscience

Email: clifton.dalgard@usuhs.edu (link sends e-mail)
Office Phone: (301) 295-1970
Room: B2038

Links
Department Website
PubMed Listing

Profile

Molecular and Cell Biology Program
Neuroscience Program
Course Director, Techniques in Neuroscience
Course Director, Advanced Topics in Genomics and Proteomics
Education: B.A. (1997) in Molecular and Cell Biology, University of California
at Berkeley; Ph.D. (2005) in Neuroscience, Uniformed Services University,
Postdoctoral Fellowship, University of California at San Francisco

Memory Adaptive Immunity in Mild Traumatic Brain Injury

cdalgard lab Despite the appearance of health, individuals that have recovered from mTBI may be susceptible to worse outcome after a subsequent second injury and may even result in sudden coma or death. Recently, it has been determined that the adaptive immune system can respond and develop memory to CNS injury and activate production of autoantibodies with pathogenic potential. However, the precise response and contribution of memory immune responses in pathogenesis after repeated mTBI events has not been investigated. Our laboratory focuses on the role of memory components of the adaptive immune system in mTBI. We are currently defining a role of memory lymphocyte generation on neuroinflammation and injury outcome in a model of repeated mTBI. Systems biology level evaluation of brain, spleen, lymph node, and peripheral blood lymphocyte populations are accomplished using multi-dimensional flow cytometry, complete transcriptome analysis by RNA-seq, and multiplex ELISA analysis of in vitro lymphocyte restimulation assays. In vitro lymphocyte cultures from experimental subjects are being utilized for identification of brain-associated immunogenic antigens in repeated mTBI. Since T and B lymphocytes have both potential neuroprotective and neuropathogenic roles, elucidating the response of the adaptive immune system to mTBI is of importance to develop preclinical strategies to improve neurological recovery after repeated injury.

Vincent B. Ho, MD, MBA, Chair (Department of Radiology), Director, Clinical Core

Name: Vincent B. Ho, MD, MBA

Department of Primary Appointment: Radiology & Radiological Services
Position: Department Chair
Title: Chair (Department of Radiology), Director, Clinical Core (CHIRP), Professor

Email: vincent.ho@usuhs.edu (link sends e-mail)

Links
PubMed Listing

Chittari Shivakumar, Ph.D., Director, Research Projects Core

Name: Chittari Shivakumar, Ph.D.

Department of Primary Appointment:
Position: USU Faculty
Title: Director, Research Projects Core (CHIRP)

Matthew D. Wilkerson, Ph.D., Director, Informatics Core

Matthew D. Wilkerson, Ph.D.

Matthew D. Wilkerson, Ph.D.

Name: Matthew D. Wilkerson, Ph.D.

Department of Primary Appointment: Anatomy, Physiology & Genetics
Position: USU Faculty
Title: Director, Informatics Core (CHIRP), Adjunct Associate Professor

Links
Lab Website

Profile

The Bioinformatics Core provides computational biology analysis and infrastructure for CHIRP genomic research studies. Our mission is to discover and characterize genomic alterations in patient specimens in order to enable precision medicine, such as characterizing the molecular etiology of disease, predicting disease risk and outcome, and discovering molecular subtypes of disease. We apply and develop computational methods for analyzing high throughput sequencing from the CHIRP sequencing core or from CHIRP affiliated investigators. Bioinformatics Core analysis spans low level analysis to biological hypothesis evaluation and exploration.

The CHIRP Bioinformatics Core is under the direction of Dr. Matthew D. Wilkerson (PubMed). Dr. Wilkerson’s prior academic research has resulted in the discovery of expression subtypes based upon genomewide expression profiles of various cancer types, such as lung adenocarcinoma, lung squamous cell carcinoma, and pheochromocytoma/paraganglioma among others (e.g., Fig 5A). He has published integrated genomic studies that characterized these novel expression subtypes with differential molecular pathogenesis (somatic mutations, germline mutations, copy number alterations, epigenetic alterations), differential patient profiles and environmental exposures, and differential patient survival and chemotherapy response of these molecular subtypes – thus establishing that these expression subtypes are an important classification for precision medicine. In addition, Dr. Wilkerson has developed original computational methods, including methods for identifying somatic mutations in patient-matched DNA and RNA sequencing, for genomic subtype discovery, and for structural comparative genomics. These methods also enable precision medicine, such as identifying actionable mutations in low purity tumors, which has important implications for targeted cancer therapy (e.g. Fig 5).

Schedule a Bioinformatics Core Consultation.

Jeronimo Mulato

Jerez Te, PhD

Xijun Zhang