The investigators hypothesize that neurotoxic metals and teratogens disrupt neurogenesis in developing forebrain and hindbrain systems in vitro and in vivo, acting to inhibit proliferation by altering mitogenic growth factor receptors and cell cycles signaling pathways. There are increasing numbers of children who experience problems with learning, social interactions, and self-regulation, and exhibit difficulties with fine and gross motor control. Normal brain development depends on interactions among multiple factors including those from genetic, neurochemical, biochemical, social, and environmental sources. Significantly, recent studies indicate that environmental toxicants injure the developing brain, potentially contributing to cognitive and motor deficits. Toxicants affecting the brain, neurotoxicants, may act at multiple time windows, eliciting immediate stage-dependent effects in specific systems that influence subsequent ontogenetic processes as well. However, while negative effects of neurotoxicants on cell migration, differentiation, and survival have been well-characterized, little is known about the effects on the generation of neurons (neurgenesis) and underlying pathogenetic mechanisms. As child neurologists, the investigators frequently evaluate children for abnormal brain development in clinic, concerned about attention, learning, behavior, and autism spectrum disorders. Further, as a member of the Scientific Advisory Board of the National Alliance for Autism Research (NAAR), a community family advocacy organization, they provide targeted basic and clinical research support. This current proposal represents a new direction for basic research in the investigators laboratory, which has focused on defining mechanisms that control generation of distinct neuronal populations from dividing precursors. Previously, they examined both positive and negative regulators of precursor proliferation in the developing nervous system, defining growth factor and neuropeptide effects in culture and in vivo. Further, they employed neuronal populations in forebrain and hindbrain regions involved in learning, memory and motor functions in the fetus as well as the developing postnatal animal. Based on extensive studies, the investigators now turn attention to the effects of well-characterized neurotoxicants, including lead and mercury, and model teratogen, valproic acid, on neurogenesis in the embryo and the newborn, defining mediating mitogenic and cell cycle pathways and designing new model systems.
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