Cell Cycle and Podocyte Apoptosis

描述（由申请人提供）：肾脏疾病在美国的流行率正在增加。肾脏疾病的一个临床体征是尿中的蛋白质（蛋白尿）。这通常是由于正常过滤屏障的泄漏，部分原因是由于对称为足细胞的细胞的损伤。足细胞是专门的细胞，其功能是限制蛋白尿。然而，在包括糖尿病在内的许多疾病中，足细胞被损伤至死亡点，称为凋亡。此外，当足细胞死亡时，剩余的足细胞不能增殖并补充那些损失的足细胞，导致足细胞数量减少。这进一步降低了这些细胞的屏障功能，最终导致肾衰竭。这项资助的目的是确定足细胞死亡的新机制。我们的研究小组专注于细胞周期蛋白分子，它位于细胞核中。在这项资助中，我们将测试一种假说，即新发现的细胞周期蛋白cyclin I和cdk 5形成一种复合物，其功能是保护足细胞免受疾病死亡。我们还认为另一种称为p21的伙伴增加了这种保护功能。我们将探索在细胞培养系统中使用足细胞的可能性，以及在基因改变为出生时没有细胞周期蛋白I，cdk5和p21的小鼠中使用足细胞的可能性。总体目标是描绘足细胞存活和死亡调节的新范例，以便最终开发新策略来预防足细胞损失，提高肾脏存活率并减少肾脏疾病。

DESCRIPTION (provided by applicant): Kidney disease is increasing at epidemic rates in the US. One clinical sign of kidney disease is protein in the urine (proteinuria). This is typically due to a leak in the normal filtration barrier, and in part is due to injury to a cell called the podocyte. Podocytes are specialized cells that function to limit proteinuria. However, in many diseases including diabetes, podocytes are injured to the point of death, referred to as apoptosis. Moreover, as podocytes die, the remaining podocytes are unable to proliferate and replenish those lost, resulting in a decrease in podocyte number. This further reduces the barrier function of these cells and ultimately leads to kidney failure. The purpose of this grant is to define novel mechanisms underlying podocyte death. Our group has focused in molecules called cell cycle proteins, which reside in the nucleus of the cell. In this grant, we will test the hypothesis that newly discovered cell cycle proteins called cyclin I and cdk5 form a complex which functions to protect podocytes from death in disease. We also believe another partner called p21 adds to this protective function. We will explore possibilities using podocytes in a cell culture system, and also in mice that have been genetically altered to be born without cyclin I, cdk5 and p21. The overall goal is to delineate new paradigms in the regulation of podocyte survival and death, so that ultimately new strategies can be developed to prevent podocyte loss, enhance kidney survival, and reduce kidney disease.