ROLE OF IERG ACTIVATION IN THE LEAD ENCEPHALOPATHY

Hugo W. Moser Res Inst Kennedy Krieger, Baltimore MD

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Abstract

DESCRIPTION: The biochemical and molecular biological mechanisms responsible for cerebral micro-vasculopathy following acute lead toxicity remain poorly-defined. Increasing evidence points to a role for protein kinase C (PKC), an enzyme that regulates many cellular processes such as growth and differentiation. The proposed experiments were designed to test the hypothesis that lead activation of PKC interferes with the cascade of PKC-mediated processes that regulated protein phosphorylation, gene expression, and microvascular cell behavior. The goals of the current proposal are to determine the mechanism by which lead increased expression of c-fos in the vitro and in the vivo. In the aim 1 the investigators will determine if lead increases mRNA levels of immediate early response genes(IERGs) by enhancing gene transcription or slowing mRNA degradation. If transcriptional events are implicated than lead-sensitive c-fos transcriptional regulatory elements will be determined. Aim 2 will determine if lead induced increases in the IERG proteins and AP-1 activity can regulate the expression of other important genes. Aim 3 was designed to determine if lead alters IERG expression in the vivo. The fundamental goal of the experiments is to define the biochemical and molecular mechanisms essential to a more complete understanding of lead toxicity within the central nervous system.