APOPTOSIS IN TUBULAR ATROPHY OF PROGRESSIVE RENAL FAILURE

慢性肾衰竭主要由肾小球损伤引起，但 肾小管萎缩是肾脏疾病进展的更好预测因子， 尽管肾小管萎缩对预后有重要意义， 对于肾小管上皮细胞（RTC）和分子水平的缺失， RTC缺失的潜在机制尚不清楚。根据初步 这些数据表明，在慢性胰腺炎患者中， 肾衰竭，本提案的总体目标是确定是否 缺氧诱导Fas依赖性RTC凋亡。这个假设 指导这些实验的是，在慢性肾衰竭中，缺氧促进 RTC凋亡通过诱导RTC Fas表达。此外，委员会认为， RTC Fas配体与相邻靶RTC上上调的Fas的连接 诱导淋巴细胞非依赖性，自相残杀的细胞凋亡，通过激活 包括下调bcl-2和/或 刺激bcl-2磷酸化。该项目的目标将是 具体目标如下： 1.为了检测缺氧是否通过Fas诱导促进RTC凋亡， 将研究缺氧对Fas功能和细胞凋亡的影响。 2.为了检测Fas依赖性的自相残杀性细胞凋亡， 将表征配体相互作用。 3.探讨Fas诱导是否参与慢性肾脏病的发生 将进行表型、体内和体外研究以抑制Fas activation. 待建议的研究完成后，我们预期可提供更佳的 了解调节肾小管萎缩的机制，从而 形成了设计治疗策略的基础， 肾小管萎缩和慢性肾病的进展。

Chronic renal failure is initiated primarily by glomerular injury, but tubular atrophy is a better predictor of renal disease progression, despite its prognostic importance, tubular atrophy is only a description for the absence of renal tubular epithelial cells (RTC) and the molecular mechanisms underlying RTC deletion are unknown. Based upon preliminary data which demonstrates that Fas expression is increased in RTC in chronic renal failure, the overall goal of this proposal is to determine whether hypoxia induces Fas-dependent RTC apoptosis. The hypothesis which will guide these experiments is that in chronic renal failure, hypoxia promotes RTC apoptosis through induction of RTC Fas expression. Furthermore, ligation of RTC Fas ligand with up-regulated Fas on adjacent target RTC induces lymphocyte-independent, fratricidal apoptosis via activation on signaling pathways that include down-regulation of bcl-2 and/or stimulation of bcl-2 phosphorylation. The goals of this project will be approached with the following specific aims: 1. To test whether hypoxia promotes RTC apoptosis through Fas induction, the effects of hypoxia on Fas function and apoptosis will be investigated. 2. To test for Fas-dependent fratricidal apoptosis, the RTC Fas-RTC Fas ligand interaction will be characterized. 3. To test whether Fas induction contributes to the chronic renal disease phenotype, in vivo and in vitro studies will be conducted to inhibit Fas activation. Upon completion of the proposed studies, we expect to provide a better understanding of the mechanisms which regulate tubular atrophy, thereby forming a basis for the design of therapeutic strategies to inhibit tubular atrophy and the progression of chronic renal disease.