BIOCHEMICAL TOXICOLOGY AND MOLECULAR STRESS RESPONSES

描述(改编自《调查者摘要》)：肾脏是 毒物的主要目标包括药物、化学品和环境 污染物。在肾脏中，近端小管上皮(PTE)是最多的 毒物诱导细胞死亡的重要靶点。PTE的能力 表达应激蛋白对化学损伤的反应是第一条线 防御毒物。然而，关于这方面的信息很少。 应激基因表达在肾脏细胞保护中的作用。 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，细胞要么死于 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。理解功能 是迈向治疗应用的第一步。因为很少有信息是 应激基因在细胞死亡中的参与和/或作用的研究进展 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在 保护PTE细胞免受化学毒物的伤害。我们将首先确定他们的 使用肾毒性半胱氨酸结合物在体内发挥作用。然后是分子 它们产生针对化学物质的细胞保护的机制 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 体内保护肾上皮细胞凋亡和坏死的实验研究 在试管中。这些研究将提供有关压力作用的新信息。 细胞死亡机制中的基因。我们的长远目标是发展 治疗策略，以提供更好的保护，防止肾脏损害。 一种在体外有效的初步原型化合物将在 Vivo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