Serotonin-2B receptor in hypertrophic cardiomyopathy

Active Project Grant Awarded Last action

Award ID
F31HL172640
Recipient
Awarding agency
Obligated
$490,012

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 67% complete
Place of performance
Nashville, TN 37232, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

Action Obligated Date
Amendment $576
Amendment $49,538
Amendment $49,538
Amendment $564
Amendment $564
Amendment $48,974
Amendment $48,974
Amendment $48,974
Amendment $48,974
Amendment $1,280
Amendment $1,280
Amendment $47,694
Amendment $47,694
Amendment $0
Amendment $0
Amendment $47,694
Amendment $0
Original award $47,694
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Quick answers

Who received award F31HL172640?

F31HL172640 was awarded to Vanderbilt University by National Heart Lung and Blood Institute (National Institutes of Health) on May 24, 2024.

How much is award F31HL172640 worth?

$490,012 has been obligated on F31HL172640.

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