Research Summary

Structure and function studies of sarcomere proteins implicated in cardiomyopathies

Cardiomyopathy is a collective term used to describe diseases related to heart muscle, which often lead to heart failure. Cardiomyopathies can be broadly classified into hypertrophic (HCM), dilated (DCM), restrictive and arrhythmogenic right-ventricular cardiomyopathies. Among them, HCM and DCM accounts for the most common inherited form of cardiomyopathy. HCM is characterized by thickening of heart walls and decreased ventricular chamber volume. On the other hand, the DCM phenotypes include enlargement of ventricular chambers and thinning of heart walls. Both HCM and DCM results in decreased cardiac output, which can lead to sudden cardiac arrest and death. In addition to other acquired factors, so far more than 400 mutations in over a dozen genes have been implicated in cardiomyopathies. Most of these genes encode important protein components of heart muscle cells, which generate contractile forces responsible for heartbeat. An outstanding question is how mutations in proteins lead to observable changes in heart morphology and physiology. Therefore, the main goal of this proposal is to understand the molecular basis of mutations that leads to HCM and DCM disease. The structural, biochemical and biophysical approaches proposed here will pave the way towards developing therapeutic intervention for cardiomyopathy diseases.

Figure Legend: Top: Illustration of gross morphological changes that accompany cardiomyopathy causing mutations in sarcomere proteins. Bottom: Sarcomere is the basic contractile unit responsible for muscle contraction. During muscle contraction the thin filaments slide over thick filaments to create a constricted sarcomere unit. Simplified illustration (blown-up) of elements involved in muscle contraction.