Deciphering the Molecular Basis of Hypertrophic Cardiomyopathy with Human Induced Pluripotent Stem Cells

• Applicant: Dr. Sebastian Diecke
• Subject Area: Cell Biology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 218479891

Familial hypertrophic cardiomyopathy (HCM) is the most common inherited genetic disorder and the leading cause of sudden cardiac death in young people. The hallmark of the disorder is a thickening of the heart muscle and a decrease in size of the heart chamber (myocardial hypertrophy) which results in obstruction of the ventricular outflow tract. Until now, studies in humans with HCM have been limited by a variety of factors, including ethical issues, variable environmental stimuli (e.g., diet, exercise, and lifestyle), the relative difficulty in obtaining human cardiac samples, and inadequate methods of maintaining human heart tissue in cell culture systems. Cellular reprogramming methods that enable derivation of human induced pluripotent stem cells (hiPSCs) from adult cells, which can then be differentiated into cardiomyocytes (hiPSC-CMs), are a revolutionary tool for creating disease-specific cell lines that may lead to effective targeted therapies. This project is focused on elucidating the molecular and cellular basis of HCM and hence should have significant impact in the field of cardiovascular biology. In this proposal, I will derive hiPSC-CMs from patients with HCM and healthy controls, then perform a battery of functional and molecular tests to determine the presence of cardiomyopathic disease and associated abnormal molecular programs. With these preliminary studies, I believe hiPSC-CMs with HCM phenotype will dramatically enhance the ability to perform future high-throughput drug screens, evaluate gene and cell therapies, and assess novel electrophysiologic interventions for potential new therapies of HCM. Using a multi-disciplinary approach, I will provide novel mechanistic insights into the pathological processes of HCM by deriving disease-specific hiPSCs. I believe the findings here should have broad clinical and scientific impact toward understanding the molecular and cellular basis of HCM.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Joseph Wu, Ph.D.