Role of Cell Cycle Proteins in Apoptosis

描述(由申请人提供)：肾小球疾病仍然是肾衰竭的主要原因。肾小球系膜细胞(MC)的损伤与增殖和凋亡的增加有关，这些过程的平衡决定了细胞的数量。细胞增殖是由细胞周期调节蛋白控制的，需要特定的细胞周期蛋白依赖蛋白(CDK)的激活。CDK抑制剂与CDK结合并使其失活。在这项拨款提案中，我们将展示细胞周期蛋白在调节细胞凋亡方面具有关键作用，与细胞增殖无关。第一个SA旨在证明CDK2导致MC凋亡，阻断CDK2活性将防止细胞死亡，CDK2的作用与其在细胞增殖中的作用不同。我们将研究机制，并建议不受调控的CDK2活性导致细胞周期的灾难性进展。在第二个SA中，我们将展示CDK抑制剂p27的一个新功能是保护细胞免于死亡。我们将检验这样的假设，即p27决定了细胞凋亡的起始、大小和阈值，这是通过抑制CDK2的激活而介导的。我们的最终目标是展示特定细胞周期蛋白在肾小球疾病中的新作用，以便开发特定的治疗策略。

DESCRIPTION (provided by applicant): 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.