La Spada Team - Molecular basis of cardiac complications in SBMA
Summary Description
The purpose of this grant project is to better understand the basis of cardiac disease in Kennedy’s disease (SBMA). SBMA patients can die of sudden cardiac arrest, but their risk for heart disease is seldom considered due to their more prominent and often debilitating muscle weakness. Degeneration of motor neurons is a driver of disease, but when androgen receptor function is rescued in the skeletal muscle of SBMA mice which rectifies the motor neuron disease in the spinal cord, these SBMA mice still develop dilated cardiomyopathy, strongly suggesting a distinct and previously unappreciated disease mechanism stemming from cell-intrinsic defects in the heart.
Here we will use fibroblasts from human SBMA patients to make pluripotent stem cells from which we can produce cardiac muscle cells. We will then study the function of these cardiac muscle cells from SBMA patients by comparing them with virtually genetically identical cardiac muscle cells made from control stem cells that lack the SBMA androgen receptor CAG repeat expansion mutation. We will also perform a molecular genetic profiling of the cardiac muscle cells, using advanced genetic analysis, to decipher the molecular pathology responsible for cardiac muscle cell dysfunction in SBMA / Kennedy’s Disease.
