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Sami Chu, Graduate Student

My research is designed to understand the molecular mechanism of how the heart works, how it begins to fail in both inherited and acquired heart disease, and how this understanding can be used to design new treatments for heart disease. I am particularly focused on a type of heart failure known as hypertrophic cardiomyopathy (HCM), a devastating disease that affects about 1 in 500 people worldwide. Since inherited mutations in a specific protein, myosin, are a major cause of this disease, my work focuses on myosin.

 

 

In cardiac muscle, length-dependent activation of both myosin and actin contribute to the Frank-Starling mechanism, a primary determinant of cardiac function. Thick filament activation is hypothesized to control the number of force-generating myosin. Myosin is the protein in the heart that acts as a molecular machine, directly providing the force needed for pumping blood. Defects in myosin are a major cause of inherited heart disease. I am devising technology to detect the inner workings of myosin and thus to determine how it works in the heathy heart, and how it fails in heart disease.  How does myosin change its shape when the heart needs to relax and when it needs to pump blood?  How does this change in heart disease? 

 

 

The SRX is a low-ATPase-rate state of myosin hypothesized to not participate in the force generation cycle. The most prevalent hypothesis for the structural basis for the SRX seen in muscle fibers is the interacting heads motif (IHM), an auto-inhibited state that restricts the movement of myosin head. Myosin phosphate release requires lever arm and actin-binding cleft movement, therefore, it is likely that the IHM immobilizes the myosin heads on the thick filament, inhibiting the powerstroke and ATPase cycling. Since the SRX was seen in muscle fibers and IHM was seen in cryo-EM structures, there is need for a technique that allows for studies in both muscle fibers and in purified protein systems. To bridge the SRX and IHM research, I am developing time-resolved fluorescence resonance energy transfer (TR-FRET) sensors to observe structural and functional changes in cardiac myosin with known SRX modulators to validate this hypothesis, as well as test other biologically relevant myosin effectors.

 

The molecular models of healthy and diseased myosin, which will be developed in my studies, will provide more tools for researchers to test and design treatments for heart disease. Because FRET detection is so precise and can be carried out so rapidly, it holds great promise not only for understanding heart health and disease, but also for developing and testing new drugs to treat heart failure.