BIOCHEMICAL TOXICOLOGY AND MOLECULAR STRESS RESPONSES

描述（改编自研究者摘要）：肾脏是一种 包括毒品、化学品和环境污染物在内的有毒物质的主要目标 污染物 在肾脏中，近曲小管上皮（PTE）是最重要的 是毒物诱导细胞死亡重要靶点。 PTE的能力 表达应激蛋白来应对化学损伤是 对毒物的防御 然而，关于以下方面的资料很少： 应激基因表达如何在肾脏细胞保护中发挥作用。 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。 理解功能 是迈向治疗应用的第一步。 由于信息不多， 关于应激基因在细胞死亡中的参与和/或功能 在肾脏中，我们建议确定葡萄糖调节的作用， 蛋白质基因grp78和热休克蛋白基因hsp70的途径， 保护PTE细胞免受化学毒物的侵害。 我们将首先确定 使用肾毒性半胱氨酸缀合物在体内起作用。 则分子 它们通过这种机制产生细胞对化学物质的保护 体外损伤将使用基因操作和肾脏解剖 上皮细胞系 我们还将阐明应激基因在 在体内保护肾上皮细胞免于凋亡和坏死， 体外 这些研究将为压力的作用提供新的信息 基因在细胞死亡机制中的作用 我们的长期目标是发展 治疗策略，以提供更好的保护，防止肾损伤。 在体外有效的初始原型化合物将在 体内作为应用程序的一部分

DESCRIPTION (Adapted from the Investigator's Abstract): 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 PTE to express stress proteins in response to chemical damage is a first line of 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 either by apoptosis or necrosis, thus, the task of understanding how stress genes function in cell protection has become more complex. Understanding function is a first step toward therapeutic application. Since little information is available on the participation and/or function of stress genes in cell death in the kidney, we propose to determine the roles of the glucose regulated protein gene grp78 and the heat shock protein gene hsp70 in pathways which protect PTE cells from chemical toxicants. We will first determine their function in vivo using nephrotoxic cysteine conjugates. Then the molecular mechanisms through which they produce cellular protection against chemical damage in vitro will be dissected using genetic manipulations and a renal epithelial cell line. We will also elucidate the role of stress genes in protecting kidney epithelial cells from apoptosis and necrosis in vivo and in vitro. These studies will provide new information on the role of stress genes in mechanisms of cell death. Our long term goal is to develop therapeutic strategies to provide better protection against kidney damage. An initial prototype compound which is effective in vitro will be tested in vivo as part of the application