J. Carter Ralphe, MD

3D Engineered Cardiac Tissue: A Novel Tool to Unravel Genotype/Phenotype Relationships in MYBPC3 - Associated Childhood Hypertrophic Cardiomyopathy
University of Wisconsin, Madison, WI
J. Carter Ralphe, MD – $50,000

One of the most common genetic causes of hypertrophic cardiomyopathy (HCM) involves defects in a protein called cardiac myosin binding protein C (cMyBP-C). Different mutations in the gene for cMyBP-C result in widely ranging disease severity and age of onset, with particularly severe forms presenting during infancy. Exactly how certain mutations result in childhood onset disease while others present in adulthood remains unclear. Unfortunately, as with many rare genetic diseases, the resources required to uncover the physiology of any specific mutation using traditional animal models are significant and demand an enormous time commitment. This study will focus instead on adapting a three-dimensional model of cardiac tissue made from mouse heart cells deficient in mouse cMyBP-C in which human MYBPC3 will be expressed to introduce specific HCM-causing mutations. Using this model system, abnormalities in function can be defined and the adaptive responses to the mutation that lead to hypertrophy characterized. This model should afford a rapid means to characterize mutations in important, but rare, human causes of HCM. Furthermore, by examining how specific mutations respond to physiologic stress, there will be a better understanding of why different mutations in the same protein lead to such a range in disease severity. Ultimately an improved understanding of the mechanisms behind the development of clinically significant HCM should lead to improvements in the care of children with cardiomyopathy.