Molecular basis of telomere dysfunction in cardiac dystrophy

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Project Summary/Abstract Duchenne Muscular Dystrophy (DMD) is the most common childhood form of muscular dystrophy and arises from mutations in the dystrophin gene. DMD is associated with early loss of ambulation and respiratory muscle compromise, followed by the onset of cardiac complications. Although cardiomyopathy is a major cause of death in DMD patients, most therapeutic interventions have focused on skeletal muscle therapies. We recently showed that telomere dysfunction in conjunction with the dystrophin mutation leads to significant structural and functional cardiac defects in mice, with all of the hallmarks seen in DMD patients. The studies proposed here will investigate telomere induced foci in dystrophic cardiomyocytes (Aim 1), identify the role of unknown telomeric mechanisms leading to cardiac failure (Aim 2) and determine the extra-telomeric function of a telomere protein (Aim 3). Understanding the mechanism acting in the progression of cardiac dystrophy will provide new therapeutic possibilities. These studies will also form the foundation for future investigation of similar telomeric mechanisms in other cardiovascular diseases.