APOPTOSIS IN TUBULAR ATROPHY OF PROGRESSIVE RENAL FAILURE

慢性肾功能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指标， 尽管肾小管萎缩对预后很重要，但它只是一种描述。 对于肾小管上皮细胞(RTC)和分子的缺失 RTC缺失的机制尚不清楚。基于初步的 资料显示慢性肾小管上皮细胞Fas表达增加 肾功能衰竭，这项提案的总体目标是确定 低氧诱导Fas依赖的RTC细胞凋亡。这个假说将会 指导这些实验的是，在慢性肾功能衰竭中，缺氧促进 通过诱导RTC Fas表达诱导RTC细胞凋亡。此外， RTC Fas配体与邻近靶点RTC上上调Fas的连接 通过激活细胞外基质诱导淋巴细胞非依赖性、致死性细胞凋亡 包括bcl-2和/或下调的信号通路 刺激bcl2的磷酸化。该项目的目标将是 为实现以下具体目标而采取的行动： 1.检测低氧是否通过诱导Fas诱导RTC细胞凋亡。 低氧对Fas功能和细胞凋亡的影响将被研究。 2.为了检测Fas依赖的碎裂细胞凋亡，RTC Fas-RTC Fas 配基相互作用的特征将被描述。 3.检测Fas诱导在慢性肾脏疾病中的作用 将进行表型、体内和体外研究以抑制Fas 激活。 在完成建议的研究后，我们预计会提供更好的 了解调节肾小管萎缩的机制，从而 形成了设计抑制的治疗策略的基础 肾小管萎缩与慢性肾脏疾病的进展。

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.