Candidate. My long term goal is to secure a tenure track faculty position as an independent investigator in translational cardiovascular research. To achieve this aim, I have devised a multi-faceted career development plan with several strategic short term goals that include i) advanced academic training through upper graduate level courses, ii) develop my writing skills by participating in grant and manuscript related workshops, iii) networking for collaborative research, iv) attend and present at national meetings, and v) work to publish high impact papers. I intend to participate in these activities during the K99 phase so that I can effectively transition to the R0 phase to independently develop and manage my own research program and research proposals to submit independent grants. My training in basic science will focus on acquiring abilities to carry out advanced techniques in the study of integrative cardiac physiology (echocardiography and pressure-volume) and T-cell signaling mechanisms (TNF-TNFR1 axis) with the aim to ultimately integrate these diverse fields to establish a distinct and novel researc paradigm which will lay the foundation for my independent academic career. In the long term, I envision incorporating my multi-disciplinary training in drug delivery, pharmacology, toxicology, pharmacokinetics and cardiovascular diseases to understand pathophysiology of heart failure and devise novel translational strategies. With my unique background and support from this award, I aim to develop effective collaborations between academia and industry to successfully transition my research findings to the clinic. Environment. To support my long term career goals, I have included world renowned clinician scientists; Dr. Sumanth D. Prabhu, MD, and Dr. Louis J. Dell'Italia, MD, actively working in heart failure; Dr. Casey T Weaver, MD, expert in T-cell biology and Dr. Martin E. Young, PhD, expert in cardiac metabolism/circadian rhythms, in my mentoring team. This multi-disciplinary combination of investigators provides me an excellent and unique training environment conducive to creating a successful translational cardiovascular investigator. Dr. Prabhu and Dr. Weaver's laboratories are well equipped with all the resources, equipment, and methodologies required for successful execution of proposed studies. The Comprehensive Cardiovascular Center (CCVC) at UAB consists of several clinician scientists and basic research investigators with expertise in diverse disciplines including physiology, pathology, molecular biology, biochemistry, and imaging. This multidimensional research environment will significantly facilitate my development as an academic scientist and as a mentor. This excellent research environment, cutting edge core facilities available through UAB will provide crucial support for the successful completion of this proposal and my training. Research. Chronic inflammatory and immune responses are an integral part of post-infarct heart failure (HF) and dictate subsequent infarct healing and left ventricular (LV) remodeling. The identification of augmented levels of several pro-inflammatory cytokines resulted in therapeutic efforts directed toward their neutralization, which failed in clinical studies. The fact that increased cytokine levels is not the proximate cause of underlying pathology but is the result of activated inflammatory responses emphasizes a more complex role of inflammatory and immune reactions in cardiac repair after myocardial infarction (MI). In this regard, recent studies with CD4-/- mice indicated that during the acute phase CD4+ T-cells play a crucial role in the healing of ischemic hearts and hind-limb muscles by promoting neovascularization and reducing fibrotic tissue formation. However, global knockout mouse models (such as CD4-/-) fail to consider spatio-temporal alterations as we see during progression from acute to chronic HF. Nonetheless, the clinical correlates that can demonstrate the role of CD4+ T-cells during chronic HF are not known. During persistent tissue injury such as in HF, innate immune cells act as antigen presenting cells to activate differentiation and clonal expansion of effector T-cells and long lasting memory T-cells. Intense activation of monocytes and macrophages during the acute phase thus implies activation of T-cells also. Indeed, our preliminary results clearly show heightened activation and expansion of T-cells in the ischemic myocardium, circulation, and remodeled spleen during chronic HF. Our preliminary results also suggest global spatio-temporal alterations in T-cell phenotype, mediated by enhanced expression of TNF? and TNFR1, classical pro-inflammatory signaling molecules that have been shown to correlate with HF severity and cardiac dysfunction clinically. This, therefore, implies that T-cells exert a complex biphasic effect in the ischemic heart leading us to hypothesize that a pro-inflammatory phenotypic switch to TNFR1 expression during chronic HF pathologically alters CD4+ T-cells to promote cardiac tissue injury and pathological LV remodeling, and HF disease progression. Importantly, these are key cellular targets for immunomodulation. We will test this hypothesis by i) delineating global CD4+ T-cell trafficking and pro-inflammatory phenotype in HF, ii) establishing the pathophysiologic role of CD4+ T-cells in LV remodeling and chronic HF by reversibly and specifically ablating pathological T-cells in transgenic CD4-DTR mice, and iii) defining whether TNFR1+ CD4+ T-cells are both necessary and sufficient for adverse LV remodeling in chronic HF by adoptive transfer studies of TNFR1+or TNFR1- CD4+ T-cells.
Clinical correlates that define the role of T-cells in heart failure are not known. Our preliminary results suggest a TNFR1 mediated pro-inflammatory phenotypic switch in T-cells during chronic heart failure. In the proposed study, PI intends to study spatiotemporal dynamics of TNFR1 expression on CD4+ T-cells and its role in promoting LV remodeling and heart failure.
