Function of Omi/HtrA2 in Renal Tubular Cell Death

描述(申请人提供)：急性肾功能衰竭(ARF)是一种严重的医疗问题，发生在所有住院患者的5%。ARF的预后很差，在过去的三十年里一直没有变化，死亡率高达50%左右。虽然ARF的原因很多，但最常见的原因是肾小管上皮细胞(RTEC)的损伤。这些细胞一旦受伤，就会因坏死或凋亡而死亡，具体取决于损伤的性质和严重程度。严重的损伤通常会引发坏死，而轻微的肾脏损伤会导致RTEC的凋亡性死亡。坏死是很难预防的，而细胞凋亡可能会被调节以维持细胞的活力。因此，识别细胞凋亡途径的不同成分，特别是在肾脏中起主要作用的成分，有助于我们理解肾脏损伤诱导的细胞凋亡。这些新成分还可以为干预提供特定和新的靶点，以帮助急性肾功能衰竭患者。我们的研究集中在最近分离的一种具有促凋亡特性的蛋白水解酶Omi，也称为HtrA2，及其在肾脏损伤中的作用。这种蛋白质存在于线粒体中，在诱导细胞凋亡时被释放到细胞质中。在这一能力方面，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依赖和非caspase依赖的途径诱导细胞凋亡。这项建议的目的是研究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在肾脏损伤中的作用以及在其激活后导致细胞凋亡的分子事件。此外，通过使用特定的抑制剂阻断Omi的蛋白分解活性，将测试一种潜在地保护和维持细胞活力的新方法。

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.