Grant: Project Grant

Hypertrophic cardiomyopathy (HCM) is a common heart condition affecting about 1 in 200-500 people, often leading to heart failure or sudden cardiac death, especially in young individuals. It causes the heart muscle, particularly the left ventricle, to thicken abnormally, which can impair heart function. While some cases of HCM are linked to mutations in genes controlling heart muscle proteins, many genetic factors remain unknown, limiting our ability to fully understand or treat the disease. A recent breakthrough study compared the DNA of patients with HCM and DNA from healthy individuals and identified a new gene, SVIL, as a significant contributor to HCM. Rare changes in SVIL increase the risk of developing HCM by approximately ten times, making it a critical target for research. The SVIL gene produces supervillin, a protein that helps organize the cytoskeleton -the structural framework of heart muscle cells- and supports how cells respond to mechanical stress. The study showed that SVIL variants are linked to increased heart muscle contractility, a feature of HCM, whether the condition blocks blood flow (obstructive) or not (nonobstructive). This suggests SVIL plays a central role in how HCM develops, but we don't know exactly how these genetic changes lead to heart muscle thickening or how they interact with other factors in the disease. This grant proposal aims to study SVIL's role in HCM to uncover its impact on heart function. Our research will focus on two main goals: (1) understanding how SVIL variants disrupt the cytoskeleton and cause changes to the function of cardiac cells in vitro (2) examining how loss of SVIL affects heart function in mice. We will use advanced methods, such as base-editing, single-nucleus RNA sequencing and other assays to study SVIL's activity in cardiac cells. By studying SVIL, we aim to uncover new approaches to prevent heart muscle thickening, ultimately leading to more effective, personalized treatments for HCM patients.