Student Research Connects Molecular Cardiology to Improved Patient Care

Second-year MD student’s summer research could help identify new treatment targets for hypertrophic cardiomyopathy.
Alexis Perry, M27 and Michael Chin

By Alexis Perry, M27

This past summer, I had the exciting opportunity to work with Michael Chin, MD, PhD, in his lab at the Molecular Cardiology Research Institute (MCRI) at Tufts Medical Center on a research project studying how certain pathways contribute to the development of harmful changes, such as pathological hypertrophy and fibrosis, in the heart.

Our research focused on hypertrophic cardiomyopathy (HCM), a common inherited disorder affecting approximately 1 in 500 individuals. HCM is characterized by hypertrophy or thickening of the left ventricle, myocardial disarray, and cardiac fibrosis, which can make it harder for the heart to pump blood efficiently throughout the body. This can lead to complications including irregular heartbeat, fainting, mitral valve disease, heart failure, and even sudden cardiac death. The molecular and cellular mechanisms underlying the pathogenesis of HCM are not yet fully understood. HCM has traditionally been thought of as a disease of the sarcomere, the basic unit of muscle fibers responsible for helping the heart contract. However, genetic mutations affecting protein components of the sarcomere are carried in only thirty-five to forty percent of HCM patients.

My research focused on identifying how a specific mutation in a protein called alpha-crystallin B chain (CRYABR123W) causes HCM. This mutation was identified in a striking case of identical twins with obstructive HCM at Tufts Medical Center. Previous studies suggested that the CRYABR123W mutation causes HCM by enhancing the activity of calcineurin-NFAT signaling pathways in heart muscle cells. This effect happens through sarcomere-independent mechanisms and leads to abnormal calcium signaling when the heart is under stress upon pressure overload.

Using a mammalian two hybrid system, a laboratory technique used to study protein interactions, I assessed for direct interactions between the CRYABR123W variant and specific regions of another protein called Calcineurin A. In particular, loss of interaction at the region of Calcineurin A that usually keeps its activity in check, and a new interaction with a different part of Calcineurin A that directly activates it. This change in interaction could explain how CRYABR123W contributes to abnormal calcium signaling and the development of HCM.

A better understanding of the mechanism by which CRYABR123W promotes the HCM phenotype and pathologic Calcineurin-NFAT signaling may help to identify new therapeutic targets for HCM.

My experience working in the lab helped me to see the interconnection between translational cardiovascular research and clinical application. My day-to-day responsibilities involved molecular cloning, bacterial transformation using E. coli, plasmid purification, western blotting, cell culturing, transfection of myoblast cells, and measuring firefly luciferase expression. I learned how to identify novel disease-associated mutations in patients, and how to then test their function in biochemical assays and animal models as a way of informing future development of therapeutics that will hopefully improve outcomes and quality of life for patients.

I am truly grateful for the TUSM Harold Williams M.D. Summer Research Fellowship for affording me this experience and the opportunity to learn from Dr. Chin and his lab. I hope to continue developing my skills in these areas throughout my time at TUSM so that I may one day be able to apply these experiences to my future patients – combining compassionate clinical care with applied research efforts, expanding my impact as a physician through medical research and innovation.

 

Alexis Perry is a second year MD student at Tufts University School of Medicine. She is originally from Hanover, MA. Besides her research, she has also been involved in community outreach in the Chinatown community as a co-leader for the Music and Medicine Collaborative, as well as for Palliative Care and Legacy Medicine (PALM).