Hypertrophic cardiomyopathy (HCM) affects nearly 1 in 500 people in the US and causes the walls of the heart to thicken, leading to outcomes as severe as heart failure and sudden death. Genetic mutations play a large role in causing HCM, with one of the most common sites of mutation being cardiac Myosin Binding Protein-C (cMyBP-C). However, the exact molecular mechanism by which cMyBP-C mutations cause disease remains unclear. This ISCRM Fellowship will allow Tristan to build a human stem cell–derived heart muscle model in which cMyBP-C can be rapidly swapped out and replaced with mutant versions, making it possible to characterize many mutations in the same cellular context. In parallel, he will use molecular dynamics simulations to model how these mutations alter the structure of cMyBP-C and its interactions with myosin. By investigating this disease pathway across multiple biological scales, Tristan aims to more clearly elucidate the mechanisms that drive contractile dysfunction
