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Principal Investigator: Jay Reddy
Organization: UNIVERSITY OF NEBRASKA LINCOLN
Fiscal Year: 2020
Award: $183,198
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
An estimated 33% of American adults (85.6 million) have some form of cardiovascular disease, with a
projected incidence of 43.9% by 2030. Despite heart disease's status as the leading cause of death in humans,
there remains a significant gap in our knowledge of its pathogenesis. Myocarditis is a common occurrence in
young children and adolescents that can lead to dilated cardiomyopathy (DCM), and approximately half of
DCM patients undergo heart transplantation due to the lack of effective chemotherapeutic options. Without a
knowledge of how DCM develops, the ability to develop combative therapeutic strategies is limited. The long-
term goal is to delineate the immune mechanisms of DCM and atrial fibrillation and identify strategies for their
prevention. The objective of this application is to establish T cell receptor (TCR) transgenic (tg) mouse
models specific to cardiac myosin heavy chain-α (Myhc) 334-352 and to sarcoplasmic reticulum calcium
ATPase (SERCA2a) 971-990 to evaluate the role of antigen-specific T cells in DCM and atrial fibrillation. Both
Myhc and SERCA2a have been identified as target autoantigens in the development of DCM, and SERCA2a
has been implicated in the induction of both atrial myocarditis and DCM. In addition, evidence suggests an
association between autoimmunity, DCM, and atrial fibrillation, as indicated by autoantibodies, suggesting that
autoreactive T cells may be the disease mediators, as cytokines produced by antigen-specific T cells are
critical for production of autoantibodies and especially to protein antigens. The central hypothesis—that
cardiac-specific CD4 and CD8 T cells contribute to the pathogenesis of DCM—is supported by strong
preliminary data produced by the applicants. The hypothesis will be tested via two specific aims: 1)
characterize Myhc 334-352-specific TCR tg mice and evaluate the therapeutic utility of hyaluronic acid-lipid
nanoparticles to induce T cell tolerance, and 2) establish SERCA2a 971-990-specific TCR tg mice as a novel
disease model for DCM and atrial fibrillation. Methods to be used include functional characterization of Myhc tg
CD4 and CD8 cells, assessment of hyaluronic acid-lipid nanoparticles in the induction of regulatory T cells, and
derivation of SERCA2a 971-990-specific TCR tg mice. The project is innovative as it aims to explore
delineation of the functional role of CD4 and CD8 T cells that display two diverse functions (CD4 T cells –
helpers, and CD8 T cells – killers) in DCM and atrial fibrillation pathogeneses. The proposed studies are
significant, as these mouse models may serve as valuable tools in elucidating the role of antigen-specific T
cells in the causation of inflammatory heart diseases arising from infectious or non-infectious causes, and in
identifying antigen-specific T cell therapies and T cell vaccinations, including biomarker discovery in future
studies.
Terms: <0-11 years old><21+ years old><A/J Mouse><Acute Myocarditis><Address><Adolescent><Adolescent Youth><Adult><Adult Human><Allergy><American><Animal Model><Animal Models and Related Studies><Antigenic Determinants><Antigens><Atrial><Atrial Fibrillation><Auricular Fibrillation><Autoantibodies><Autoantigens><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Autologous Antigens><Backcrossings><Binding Determinants><C57BL/6 Mouse><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Calcium><Cardiac><Cardiac Atrium><Cardiac Diseases><Cardiac Disorders><Cardiac Failure Congestive><Cardiac Muscle Myosins><Cardiac Myosins><Cardiac Transplantation><Cardiomyopathies><Cardiovascular Diseases><Causality><Cause of Death><Cell Body><Cell-Mediated Lympholytic Cells><Cells><Child><Child Youth><Children (0-21)><Congestive Cardiomyopathy><Congestive Heart Failure><Coronary Disease><Coronary heart disease><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Data><Derivation><Derivation procedure><Development><Dilated Cardiomyopathy><Disease><Disease model><Disorder><Encapsulated><Endoplasmic Reticulum><Epitopes><Ergastoplasm><Etiology><FOXP3><FOXP3 gene><Fertilized Egg><Fertilized Ovum><Forkhead Box P3><Foundations><Future><Generations><Genomics><Goals><Graft Rejection><Heart><Heart Atrium><Heart Decompensation><Heart Diseases><Heart Grafting><Heart Transplantation><Heart failure><Human><Hyaluronic Acid><Hybridomas><Hypersensitivity><Immune><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Incidence><Inflammation><Inflammatory><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><JM2><Knowledge><Lead><MHC Receptor><Major Histocompatibility Complex Receptor><Mediating><Mediation><Mediator><Mediator of Activation><Mediator of activation protein><Methods><Mission><Modeling><Modern Man><Mouse, Founder, Transgenic><Myocardial Diseases><Myocardial Disorder><Myocardial Ischemia><Myocardiopathies><Myocarditis><Myocardium><Myosin Heavy Chains><NIH><National Institutes of Health><Negotiating><Negotiation><Outcomes Research><Pathogenesis><Patients><Pb element><Prevention><Production><Proteins><Public Health><Receptors, Antigen, T-Cell><Regulatory T-Lymphocyte><Research><Rodent><Rodentia><Rodents Mammals><Role><SCURFIN><SERCA3><Self-Antigens><Specificity><System><T cell based therapeutics><T cell based therapy><T cell targeted therapeutics><T cell therapy><T-Cell Receptor><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Transgenic Mice><Transgenic Model><Transgenic Organisms><Transplant Rejection><Transplantation Rejection><Treg><United States National Institutes of Health><Up-Regulation><Upregulation><Vaccination><Vaccines><Work><adoptive T cell transfer><adoptive T-cell therapy><adulthood><antigen-specific T cells><atherosclerotic heart disease><atrium><autoimmune antibody><autoimmune disorder><autoreactive T cell><biomarker discovery><cardiac failure><cardiac graft><cardiac inflammation><cardiac ischemia><cardiac muscle><cardiovascular disorder><cardiovascular transplantation><causation><children><childrens'><chronic heart failure><chronic myocarditis><combat><coronary disorder><coronary ischemia><cytokine><developmental><disease causation><disorder model><effective therapy><effective treatment><heart disorder><heart ischemia><heart muscle><heart transplant><heavy metal Pb><heavy metal lead><immunogen><innovate><innovation><innovative><juvenile><juvenile human><killer T cell><lipid nanoparticle><model of animal><model organism><mouse model><murine model><myocardial ischemia/hypoxia><myocardium disease><myocardium disorder><myocardium ischemia><myosin heavy chain><novel><overexpress><overexpression><prevent><preventing><regulatory T-cells><sarcoplasmic reticulum calcium ATPase><self reactive antibody><social role><therapeutic T-cell platform><therapeutic target><thymus derived lymphocyte><tool><transgenic><transgenic trait><youngster><zygote>