Project Summary (2000-2005)

The goal of this project is to evaluate the mammalian stress response to heavy metal injury and its role in the adaptation to adverse conditions posed by environmental chemicals. Researchers are focusing on the induction of the endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 (GRP78) in mammalian cells by lead (Pb) acetate and HgCl. These experiments are examining the molecular basis of the adaptive response to environmental injury. Specifically, project investigators are testing two hypotheses: that GRP78 is regulated transcriptionally following metal-induced alterations in signal transduction, and that this response affords cytoprotection against subsequent chemical insult. Gene regulatory mechanisms involved in cytoprotection are being examined in a rat mesangial clonal cell line, and a rat glioma cell line. Project investigators are determining if metal challenge perturbs Ca2+ homeostasis, redox status and/or protein phosphorylation, leading to activation of GRP78. Transcriptional and post-transcriptional mechanisms to gene induction and the role of xenobiotic-regulated cis-acting elements are also being investigated. These studies are providing valuable information about critical chemico-biologic interactions at Superfund sites.