BIOCHEMICAL TOXICOLOGY AND MOLECULAR STRESS RESPONSES

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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