Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Monday Speaker Abstracts

UNDERSTANDING HYPERTROPHIC CARDIOMYOPATHY (HCM) ACROSS THE THICK AND THIN FILAMENT, BRIDGING IN-VITRO AND IN-SILICO MODELS OF DISEASE TO ACCELERATE PATHOMECHANISM DISCOVERY Christopher N. Toepfer 1 ; 1 University of Oxford, Oxford, United Kingdom Approximately 1 in 500 people inherit a gene that can cause hypertrophic cardiomyopathy, a disease that is typified by increased incidences of atrial fibrillation, heart failure, and sudden cardiac death. There are many genetic variants across a variety of disease-causing genes that drive HCM, and the disease driving pathomechanisms are not fully understood. Many of the genes involved in HCM are encoding the proteins that drive or regulate muscle contraction in the cardiac sarcomere. Some of these genes are in the proteins of the thick filament including myosin and myosin binding protein-C, which drive and adapt muscle contraction. Other variants are those of the thin filament, which regulate contraction altering myofilament sensing of calcium. We employ in-vitro iPSC-CM models twinned with CRISPR/Cas-9 to model functional changes of human cardiomyocytes in the dish. We then use this in-vitro data to model HCM in-silico by application of biological data to in-silico models of adult cardiomyocytes. This allows us to make predictions of the disease-causing mechanism. Meshing these two techniques has allowed us to understand the key contractile parameters that may best be targeted to help treat disease and define druggable targets within the cardiac sarcomere. With the aim of developing novel genetically targeted therapies in HCM.

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