SIGNAL TRANSDUCTION MECHANISMS AND LEAD TOXICITY

描述：（改编自研究者摘要）铅的毒性有

DESCRIPTION: (Adapted from the Investigator's Abstract) Lead toxicity has been identified as the most important environmental health hazard affecting children in the United States, but the mechanism for this toxicity is unknown. Several studies have established that protein kinase C (PKC) is exquisitely sensitive to Pb2+, thereby suggesting that this kinase plays a pivotal role in Pb2+-mediated toxicity. Previous work in this area, however, has focused on the effects of Pb2+ on PKC in enzymatic assays and on its cellular localization. Studies have not addressed the effects of Pb2+ on PKC activity or on protein phosphorylation in cultured cells or in vivo. In order to study this problem, erythrocytes will be examined because they are a target for Pb2+, proteins phosphorylated by PKC have been described, and they are more accessible in studies in vivo than other tissues. The first long term goal of this study is to determine whether Pb2+ stimulates phosphorylation of erythrocyte membrane proteins by activating PKC. This will be accomplished in Aim 1 by a definitive immunological and biochemical analysis of membrane phosphoproteins from human erythrocytes that were exposed in vitro to Pb2+. In addition, the mechanism of activation will be elucidated by examining the physical interaction that occurs between Pb2+ and PKC. The second long term goal is to determine whether exposure to Pb2+ in vivo increases erythrocyte membrane protein phosphorylation. For this purpose, information gained from the in vitro system will be used in Aim 2 to study protein phosphorylation in erythrocytes isolated from Pb2+-exposed rats. Ultimately, a protein that is phosphorylated in rats with elevated levels of Pb2+ may provide a biomarker to monitor Pb2+.