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-? (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.
The proposed research has relevance to public health because it is aimed towards establishment of robust transgenic mouse models that permits delineation of the role of heart-specific T cells in the development of dilated cardiomyopathy that can lead to heart failure. This research is relevant to the mission of NIH because the availability of transgenic mice expressing T cell receptors specific to heart antigens are valuable tools to address the role of heart-specific T cells in the pathogenesis of dilated cardiomyopathy arising from various infectious and noninfectious causes, including atrial fibrillation and coronary heart diseases, and antigen-specific T cell therapies and T cell vaccination.