Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY/ABSTRACT The overall objective of this proposal is to elucidate the cellular mechanism and therapeutic potential of targeting the serotonin-2B receptor (5-HT2B) to attenuate fibrosis in hypertrophic cardiomyopathy (HCM). HCM is the most common monogenic heart disease and the most common cause of sudden death in young adults. A hallmark of this disease is myocardial fibrosis, an early manifestation of HCM defined as pathological remodeling that leads to heart wall stiffening and diastolic dysfunction. Due to the lack of knowledge on HCM disease emergence and progression, there is an unmet need to identify new pathways and therapeutic opportunities targeting fibrosis in HCM. Cardiac fibroblasts (CFs) are the primary cell type that contribute to fibrosis, as their function to preserve the myocytes’ surrounding environment by degrading and synthesizing the extracellular matrix can lead to pathological remodeling of the myocardium. Previous studies have antagonized 5-HT2B in cardiopulmonary diseases and demonstrated a decrease in fibrosis; in a mouse model of myocardial infarction, 5-HT2B antagonism decreased both the fibrotic scar size and number of isotropic collagen fibers in the myocardium, preventing the fibrotic remodeling process and preserving systolic and diastolic function. Our preliminary data shows an increase in 5-HT2B expression in HCM patients and a correlation between 5-HT2B and ANP, a marker of cardiac hypertrophy. In our hands, the 403/+ mouse model of familial HCM confirms an increase in 5-HT2B expression and pro-fibrotic markers. Therefore, we hypothesize that ablating 5-HT2B activity will attenuate fibrosis in HCM. To investigate this hypothesis, the following aims will be addressed. 1) Clarify the CFs vs. cardiomyocytes contribution to attenuation of fibrosis in HCM through global and CF-specific genetic ablation of 5-HT2B. This will be tested through the creation of two mouse models that provide both global and CF-specific genetic deletion of 5-HT2B. 2) Test the therapeutic efficacy of 5-HT2B antagonism and subsequent mechanical characterization of the cell type responsible for 5-HT2B – mediated fibrotic remodeling in HCM. Collaboration with Dr. Craig Lindsley has led to the discovery of two novel compounds that are highly specific for 5-HT2B and are systemically restricted from entering the brain. Following 5-HT2B antagonism, CFs will be isolated and mechanically characterized for their proliferative, contractile, and migratory capabilities. The training received throughout this fellowship will enable the candidate to conduct a successful project that will enhance our understanding of the underlying pathology and therapeutic potential of 5-HT2B antagonism in hypertrophic cardiomyopathy.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).