Glomerular disease remains a leading cause of kidney failure. Injury to the glomerular mesangial cell (MC) is associated with increased proliferation and apoptosis, and the balance of these processes determines the cell number. Proliferation is controlled by cell cycle regulatory proteins, and requires the activation of specific cyclin dependent kinases (CDK). CDK-inhibitors bind to and inactivate CDKs. In this grant proposal we will show that cell cycle proteins have a critical role in regulating cell apoptosis, independent of proliferation. The first SA is designed to show that CDK2 causes MC apoptosis, that blocking CDK2 activity will prevent cell death, and the effects of CDK2 are distinct from its role in cell proliferation. We will examine mechanisms and suggest that unregulated CDK2 activity leads to catastrophic progression through the cell cycle. In the second SA, we will show that a novel function of the CDK-inhibitor, p27, is to protect cells from death. We will test the hypothesis that p27 determines the onset, magnitude and threshold to apoptosis, which is mediated by restraining CDK2 activation. Our ultimate goal is to show novel roles for specific cell cycle proteins in glomerular disease so that specific therapeutic strategies can be developed. ? ?
