PROJECT SUMMARY/ABSTRACT The overall objective of this proposal is to further our understanding of the biology and therapeutic potential of C-type natriuretic peptide in hypertrophic cardiomyopathy (HCM). Cardiac fibrosis a key risk factor for the development adverse outcomes in HCM, however, there is no proven medical therapy for HCM that modifies fibrosis in humans, which represents a critical unmet need. The natriuretic peptides ANP and BNP are increased in HCM. However, there is also a third natriuretic peptide, CNP, and we show that HCM is a state of CNP deficiency. CNP is the most potent anti-fibrotic natriuretic peptide, and augmenting CNP is a novel approach to target fibrosis in HCM. However, systemic delivery of CNP requires innovative approaches to minimize CNP degradation. C53 is a potent CNP analog with resistance to degradation. Our preliminary data demonstrate that administration of C53 attenuates the emergence of fibrosis in the 403/+ mouse model of HCM. The objective of this proposal is to validate the anti-fibrotic mechanism of C53 in HCM, and determine if C53 can attenuate or reverse fibrosis in established HCM. To further define the antifibrotic effects of C53 in HCM, the following Specific Aims will be addressed. 1) Define the mechanism by which C53 modifies fibrosis (K99 phase). With tailored training, the candidate will learn and perform established functional in vitro assays using pharmacologic modulators to define the mechanism by which C53 modifies fibrosis. 2) Develop expertise in small animal cardiac MRI to evaluate myocardial fibrosis in vivo (K99 phase). 3) Test the hypothesis C53 can attenuate or reverse established HCM, and validate the molecular and cellular mechanism of C53 in vivo (R00 phase). The candidate’s career goals are to become an independent physician-scientist focusing on innovative approaches to target fibrosis in HCM. The career development plan focuses on learning new skills for in vitro quantification of fibroblast activity, learning advanced histologic quantification of fibrosis, and learning small animal cardiac MRI for evaluation of cardiac fibrosis in vivo. The Merryman lab at Vanderbilt is an ideal environment to acquire such training as Dr. Merryman is an expert in cardiopulmonary mechanobiology and fibrosis. The training received throughout this award will enable the PI to secure an independent research position and lead a multi-faceted, R01-funded research laboratory focusing on fibrosis in HCM. In summary, the PI will utilize this K99/R00 award to establish a program aimed at uncovering new mechanisms of fibrosis in HCM, and evaluate new therapeutic targets. This project will lay the groundwork to further our understanding of the biology and therapeutic potential of natriuretic peptides as antifibrotic agents in HCM, and define the course of the PI’s goal of becoming an independent physician-scientist.