Function of Omi/HtrA2 in Renal Tubular Cell Death

描述（由申请人提供）：急性肾功能衰竭（ARF）是一种严重的医学问题，发生在所有住院患者的5%。ARF的预后很差，在过去三十年中没有变化，死亡率约为50%。虽然ARF是多种原因的结果，但最常见的原因是肾小管上皮细胞（RTEC）的损伤。这些细胞一旦受到损伤，就会根据损伤的性质和严重程度而死于坏死或凋亡。严重的损伤通常引发坏死，而对肾脏的轻度损伤则引起RTEC的凋亡性死亡。坏死是难以预防的，而细胞凋亡可以被潜在地调节以维持细胞活力。因此，识别细胞凋亡通路的不同组成部分，特别是在肾脏中起主要作用的组成部分，有助于我们了解肾损伤诱导的细胞凋亡。这些新成分还可以为急性肾功能衰竭患者提供特异性和新颖的干预靶点。我们的研究集中在最近分离和表征的促凋亡蛋白酶Omi，也被称为HtrA2，及其在肾损伤中的作用。这种蛋白存在于线粒体中，在诱导细胞凋亡时被释放到细胞质中。在这方面，Omi在结构和功能上都是独一无二的。在细胞质中，Omi可以通过caspase依赖性和caspase非依赖性途径诱导细胞凋亡。本研究的目的是研究Omi在RTEC中发生的凋亡细胞死亡中的潜在作用。我们的研究将探讨Omi在肾损伤中的作用及其激活后导致细胞凋亡的分子事件。此外，通过使用一种特定的抑制剂阻断Omi的蛋白水解活性，一种潜在的保护和维持细胞活力的新方法将被测试。

DESCRIPTION (provided by applicant): Acute renal failure (ARF) is a serious medical problem that occurs in 5% of all hospitalized patients. The prognosis of ARF is poor and has remained unchanged over the past three decades carrying a high mortality rate of about 50%. Although ARF is the result of many causes, the most common cause is injury to the renal tubular epithelial cells (RTEC). These cells, once injured, die by necrosis or apoptosis depending on the nature and severity of the insult. Severe injury usually triggers necrosis whereas milder insults to the kidney cause apoptotic death of the RTEC. Necrosis is difficult to prevent, whereas apoptosis can potentially be modulated to maintain cell viability. Therefore, identifying the different components of the apoptotic pathway, especially the ones that play a major role in kidney, can help us understand renal injury-induced apoptosis. These new components can also provide specific and novel targets for intervention to help patients with acute renal failure. Our studies are focused on a recently isolated and characterized pro-apoptotic protease Omi, also known as HtrA2, and its role in renal injury. This protein is present in the mitochondria and is released to the cytoplasm upon induction of apoptosis. In this capacity, Omi is unique both in its structure as well as its function. In the cytoplasm, Omi can induce apoptosis through a caspase-dependent as well as in a caspase-independent pathway. It is the aim of this proposal to investigate the potential role of Omi in the apoptotic cell death that occurs in RTEC. Our studies will investigate the involvement of Omi in renal injury and the molecular events that follow its activation leading to apoptosis. Furthermore, by blocking the proteolytic activity of Omi using a specific inhibitor, a new approach to potentially protect and maintain cell viability will be tested.