Mani S. Mahadevan, MD, FRCP (Canada), a professor in the School of Medicine’s Department of Pathology, was recently awarded an R01 grant from the NIH providing $3,227,992 in funding over the next four years to investigate the cellular and molecular drivers of cardiac pathology associated with myotonic muscular dystrophy. Dr. Mahadevan will be collaborating with Fredrick H. Epstein, PhD, Mac Wade Professor of Biomedical Engineering and Associate Dean of Research, School of Engineering and Applied Science, who is a global leader in developing cardiac MRI.
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults and children, affecting over one million people worldwide. It is a genetic disease, and within a family, its onset is earlier and more severe from generation to generation. DM1 is a degenerative disease that leads to muscle wasting, heart problems resulting in irregular heartbeats and sudden death, eating and swallowing difficulties, excessive sleepiness, impaired brain function, cataracts, breathing difficulties; all leading to poorer quality of life and often shortening life.
Dr. Mahadevan has been involved in DM1 research for over 30 years, including discovering the gene and the mutation responsible for DM1 and developed the first diagnostic assay for DM1. Since then, his lab has worked on solving how the mutation causes the disease and showed that DM1 was the first example of a disease due to the gene making a “toxic mRNA.” Subsequently, they have developed animal models of DM1 and worked with drug companies to show that targeting and degrading the toxic RNA could potentially reverse or slow/halt the disease.
The current grant aims to understand how the toxic RNA affects the heart. Cardiac conduction problems are present in up to 75% of DM1 cases, and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of heart disease in DM1 is unclear. The Mahadevan Lab has identified cells in the heart that play a key role in causing the fibrosis and fatty replacement of healthy heart tissue in DM1, and they have identified signaling molecules that are driving this change. The lab will use their mouse model of RNA toxicity in DM1 to: 1) study and characterize the drivers of this pathology in the heart, and 2) and in collaboration with major pharmaceutical companies, study the heart’s response to potential treatments under development. The ultimate goal of this proposal is to elucidate critical players in the primary pathologies associated with RNA toxicity in the heart, and to identify pathways and therapies that may mitigate morbidity and mortality associated with cardiac disease in DM1.