Thursday, December 26, 2024
12/26/2024
Project Summary: The goal of this F30 proposal is to characterize novel pathways of T-cell activation that contribute to cardiac fibrosis and systolic dysfunction in heart failure (HF), and simultaneously train to be a successful physician scientist. HF is a leading cause of death worldwide, and consists of irreversible cardiac fibrosis, progressive loss of cardiac function, and cardiac inflammation. While both local and systemic inflammation have been observed in patients with HF, no anti-inflammatory therapies have successfully been used in HF, highlighting the need for a deeper mechanistic study of the cardiac inflammatory response. Damage associated molecular patterns (DAMPs) signal myeloid cells to promote antigen presentation to T-cells, which infiltrate the heart and participate in cardiac fibrosis and hypertrophy. DAMP signaling converges on two adaptor proteins: Myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adaptor inducing interferon-β (TRIF), which initiate both independent and overlapping pro-inflammatory pathways. MyD88 and TRIF, along with DAMP receptors, are also expressed in T-cells, implying T-cell DAMP sensing can impact T-cell activation in an antigen-independent manner, termed “bystander activation.” However, the significance of bystander T-cell activation in HF and mechanisms involved remain largely unexplored. My lab has shown that reconstitution of T-cell deficient mice (Tcra-/-), normally protected from HF induced by transverse aortic constriction (TAC), with type I helper T-cells (Th1) in the onset of TAC partially restores cardiac fibrosis. Mechanistically, this is dependent on Th1 cell adhesion to and activation of cardiac fibroblasts. I surprisingly found that reconstitution of Tcra-/- mice with Myd88-/- Th1 cells resulted in significantly higher numbers of cardiac T-cells and enhanced cardiac fibrosis than WT Th1 cells. I also found that Myd88-/- and Trif-/- Th1 cells showed opposite effects on T-cell effector functions and survival. In two specific aims, I will test the central hypothesis that DAMP signaling through MyD88 and TRIF differentially regulates T-cell effector functions and contributes to cardiac fibrosis and systolic dysfunction in HF. In SA1 I will investigate whether signaling through MyD88 and TRIF differentially contributes to T-cell activation and cell survival and the mechanisms involved. In SA2 I will characterize the contribution of T-cell MyD88 and TRIF to cardiac fibrosis and systolic dysfunction in experimental HF in vivo, and the specific mechanisms of cardiac fibroblast activation in vitro. Successful completion of these aims will uncover novel mechanisms of T-cell mediated cardiac fibrosis in HF, while supporting a tailored training plan that integrates clinical and research training to prepare me for a career as an independent physician scientist.
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