Jil Tardiff, MD, PhD

Development of a Model System for Tropomyosin-linked Early Onset Dilated Cardiomyopathy
Albert Einstein College of Medicine, Bronx, NY
Jil Tardiff, MD, PhD – $50,000

Dilated cardiomyopathy (DCM) is a very common form of cardiomyopathy and carries a particularly poor patient outcome. One of the most important observations in the field in the past decade has been that, like adults, dilated cardiomyopathy in children is often genetic in origin. Moreover, the genetic causes include mutations in known components of the cardiac sarcomere. These striking findings have led to a significant change in our view of the pathogenic mechanisms that cause DCM in children. A novel mutation in alpha-tropomyosin (D230N) a thin filament component of the sarcomere, was recently shown to cause a complex cardiomyopathy that presented in both early childhood with heart failure and sudden death and as a milder form in adults. This "bimodal" distribution of disease onset suggests that the primary DCM mechanism in childhood may change over time and suggests that the normal changes associated with cardiac growth in children are potentially involved. A better understanding of how these native changes in sarcomeric protein expression alter the disease state would provide a novel approach to developing therapies and interventions to alter the progression of this severe form of DCM. The proposed study will look at whether age-dependent changes in the cardiac forms of Troponin T, an important tropomyosin binding partner, drives the age-dependent cardiac remodeling that defines the disease. To fully investigate this hypothesis, a high-throughput in vitro screen and a novel transgenic mouse model carrying the D230N mutation will be utilized.