Federal Project Grant Award Summary

The National Heart, Lung, and Blood Institute (NHLBI) awarded the University of Washington a Project Grant of $882,498.00 under the Cardiovascular Diseases Research program (CFDA 93.837), with performance from May 1, 2026 through February 28, 2030. This grant funds the development of computational and experimental tools to elucidate the mechanisms by which single amino acid variants affect beta-myosin structure and function across multiple biological scales. The research addresses critical gaps in understanding myosin variants through creation of novel structure-based dynamics models of the chemo-mechanical cycle of beta-myosin, leveraging new human crystal and cryo-electron microscopy structures combined with established bovine muscle structures. The project employs molecular and Brownian dynamics simulations incorporating f-actin structure to investigate signaling pathways between the nucleotide binding pocket, actin-myosin interface, and converter domain, augmented by graph theory-based inter-protein pathway analysis.

The awarded research will deliver multiple experimental and analytical products to validate computational findings. These include stochastic-kinetic models simulating sarcomere contraction and relaxation with variable myosin variant concentrations; biochemical kinetic measurements of the chemo-mechanical cycle using myosin purified from gene-edited human induced pluripotent stem cells (hiPSCs); myofibril-level studies examining how mutations affect contractile function; and single-molecule super-resolution imaging characterizing high-resolution structural changes in thick filaments from hiPSC-derived cardiomyocytes. Collectively, these tools and findings will advance understanding of how myosin variants contribute to cardiovascular disease pathogenesis.