Wednesday, April 2, 2025
4/2/2025
FHOD3 Regulation of Autophagy Pathway in Cardiomyopathy - Project Summary Cytoskeletal remodeling and turnover are central contributors to left ventricular (LV) remodeling that underlies cardiomyopathy and heart failure. Formin homology 2 domain containing-3 (FHOD3) is a member of the formin protein family that regulates cardiac actin filament formation. FHOD3 is required for sarcomere formation during embryonic heart development and remodeling of the adult heart. We identified a common variant, FHOD3V1151I (rs2303510), associated with hypertrophic cardiomyopathy (HCM). To investigate the mechanistic basis of the association of FHOD3V1151I with HCM, we used CRISPR to create an Fhod3V1151I mouse model and discovered that Fhod3V1151I mice have normal heart size and contractile function in the absence of hypertrophic stimulus. Provocatively, though, Fhod3V1151I mice develop excessive cardiac hypertrophy and physiologic findings of heart failure, including activation of the fetal gene program with pressure overload. Using our state-of-the-art Autophagy Detecting Nanoparticle imaging technology we demonstrate that Fhod3V1151I mice have impaired autophagy. The role of autophagy defects are recognized in cardiomyopathy and are therefore emerging as an important modifier to the cardiac response to stress that could impact the development of HCM and associated symptoms. In this proposal, we will compare the response of Fhod3V1151I mice to autophagy stimulation (rapamycin) and inhibition (bafilomycin). Furthermore, we will test the role of the Fhod3 variant in the context of a mutation in Mybpc3, which serves as a mouse model of HCM known to have defective autophagy. Because Fhod3V1151I mice have reduced levels of the early autophagy regulator Beclin, we will assess whether the recombinant protein tat-Beclin can rescue the autophagy defect caused by Fhod3V1151I in the context of a Mybpc3 mutation that causes HCM. Finally, since extracellular vesicle (EV) formation is a direct consequence of autophagy and we demonstrate significant defects in EV production with FHOD3V1151I, we will evaluate the effects of FHOD3 on cellular component trafficking related to autophagy and EV production. Considering that the FHOD3V1151I allele is carried by approximately one third of humans of all races and ethnicities, and because of its established association with HCM as a risk allele, the potential impact of this study on human heart failure is substantial. By defining the mechanisms by which FHOD3 variants modify cardiac autophagy and LV remodeling, including the role of genotype-defined personalized medicine strategies that may modify this genetic risk, these studies have the potential to translate into improved heart failure management.
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