BIOCHEMICAL TOXICOLOGY AND MOLECULAR STRESS RESPONSES

肾脏是包括药物在内的有毒物质的主要目标， 化学品和环境污染物。在肾脏中，近端小管 上皮细胞(PTE)是毒物诱导细胞死亡的最重要靶点。 PTE表达应激蛋白的能力对化学物质的响应 损害是对抗毒物的第一道防线。然而，几乎没有 应激基因表达如何在细胞保护中发挥作用的信息 肾脏。此外，试图将内在应激反应作为一种 治疗策略并不成功。最后，细胞会死于 因此，了解应激基因是如何 在细胞保护中的作用变得更加复杂。持续的长期 目的是了解应激基因如何预防肾损伤，并利用 应激基因激活，临床受益。 在这个续篇中，我们应用了这样的假设：“内质网的应激反应 保护肾毒素，但不同的ER信号通路和 “介导对不同形式的细胞损伤的耐受性的蛋白质”将被测试。 葡萄糖调节蛋白基因GRP78、钙网织蛋白等的作用 保护PTE细胞免受化学毒物伤害的途径中的内质网应激基因， 将会被确定。深入的结构活性研究，以确定类型 内质网应激基因将保护其免受的伤害的研究将被进行。 内质网应激基因产生细胞保护的分子机制 在体外抗化学损伤的能力将通过基因操作进行解剖。 离散ER信号通路在保护肾上皮细胞中的作用 此外，还将阐明细胞在体内和体外的凋亡和坏死。 这些研究将提供关于应激基因在 肾细胞死亡的机制。其长期目标是开发治疗药物 更好地保护肾脏免受损害的策略。首字母A 一种原型化合物，有效地诱导应激反应基因和 在体外和体内对损伤的耐受性已经发展成为 申请。

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.