BIOCHEMICAL TOXICOLOGY AND MOLECULAR STRESS RESPONSES

肾脏是包括药物在内的毒物的主要目标， 化学品和环境污染物。在肾脏，近端小管 上皮（PTE）是毒物诱导的细胞死亡的最重要的靶。 PTE表达应激蛋白以响应化学物质的能力 损伤是抵御毒物的第一道防线。然而， 关于应激基因表达如何在细胞保护中起作用的信息， 肾脏此外，试图调节内在应激反应作为一种 治疗策略尚未成功。最后，细胞死亡， 细胞凋亡或坏死，因此，了解压力基因如何 细胞保护的功能变得更加复杂。持续的长期 目的是了解应激基因如何预防肾损伤， 应激基因激活以获得临床益处。 在这个继续申请中，假设“ER应激反应 保护肾毒物，但不同的ER信号通路， 蛋白质介导对不同形式的细胞损伤的耐受性”将被测试。" 葡萄糖调节蛋白基因grp78、钙网蛋白等在糖尿病发病中的作用 ER应激基因在保护PTE细胞免受化学毒物侵害的途径中， 将被确定。深入的结构活动研究，以确定 内质网应激基因可以保护免受的伤害。 ER应激基因产生细胞保护作用的分子机制 对抗体外化学损伤的方法将通过基因操作进行剖析。 内质网信号通路在肾上皮细胞保护中的作用 还将阐明体内和体外细胞凋亡和坏死。 这些研究将提供新的信息，压力基因的作用， 肾细胞死亡的机制。长期目标是开发治疗性 更好地保护肾脏免受损害的策略。初始 原型化合物，其有效诱导应激反应基因， 体外和体内对损伤的耐受性已经发展为 应用程序.

The kidney is a primary target for toxicants including drugs, chemicals and environmental pollutants. In the kidney, the proximal tubule epithelium (PTE) is the most important target for toxicant-induced cell death. The ability of the PTE to express stress proteins in response to chemical damage is a first line defense against toxicants. However, there is little information regarding how stress gene expression functions in cytoprotection in the kidney. Moreover, attempts to modulate the intrinsic stress response as a therapeutic strategy have not been successful. Finally, cells die by either apoptosis or necrosis, thus, the task of understanding how stress genes function in cell protection has become more complex. The continuing long-term goal is to understand how stress genes prevent renal injury and to exploit stress gene activation for clinical benefit. In this continuation application the hypothesis that, "The ER stress response protects against nephrotoxicants, but distinct ER signaling pathways and proteins mediate tolerance to different forms of cell injury" will be tested." The roles of the glucose regulated protein gene grp78, calreticulin and other ER stress genes in pathways, which protect PTE cells from chemical toxicants, will be determined. In-depth structure activity studies to determine the types of injury that ER stress genes will protect against will be carried out. Molecular mechanisms through which ER stress genes produce cellular protection against chemical damage in vitro will be dissected using genetic manipulations. The role of discrete ER signaling pathways in protecting kidney epithelial cells from apoptosis and necrosis in vivo and in vitro will also be elucidated. These studies will provide new information on the role of stress genes in mechanisms of kidney cell death. The long-term goal is to develop therapeutic strategies to provide better protection against kidney damage. An initial prototype compound that is effective in inducing stress response genes and tolerance to injury in vitro and in vivo has been developed as part of the application.