The basic research goal of the Neurotoxicology Core is to understand the nature of the effects of environmental chemicals on nervous system function, their consequences over the life span, the mechanisms by which these effects are produced, and the risks they pose to human health. A key element in this goal is to understand the contribution of combined effects of genetic predisposition and environmental chemical exposures on neurological dysfunctions, particularly as it relates to neurodegenerative diseases. The research within this Core involves both basic neuroscience research and neurotoxicology and explores the age spectrum from development to aging. The general theme of the Core is that both early and late stages of life represent periods of potentially enhanced vulnerability to neurotoxic effects. Embedded within this theme is the emerging concept that neurological effects of toxic exposures may not manifest themselves until years after exposure, and that toxicants interact in complex ways with the genetic composition of the human to influence the nature and severity of functional outcomes. The Core consists of seven members of which five are continuing members and two are new members, drawn from the Departments of Neurology, Environmental Medicine, and Obstetrics-Gynecology. The members have been chosen on the basis of their productivity, commitment to multidisciplinary neuroscience research, and experience in areas of thematic interest to the Center. In the past funding period, the Core was called the Neurobehavioral Toxicology Research Core to reflect its focus on behavioral toxicology. The present Core, now named the Neurotoxicology Core, has expanded its focus to include a broader spectrum of issues, ranging from mechanisms, genetic predispositions and contributions to human diseases, and human risk assessment, while maintaining strengths in behavioral toxicology. Of particular note are the inclusions of sophisticated molecular biology and neurochemistry into the battery of Core skills. The present proposal continues to advance the traditional strengths in metal neurotoxicology, while venturing into several new initiatives as well. A major change is the plan to recruit a new faculty to replace Dr. Cory-Slechta as Core Director. The individual will be selected to further integrate the neurotoxicology and basic neuroscience. Another change is the new initiative into molecular neuroscience and genetic-toxicant interactions, which has been developed through the addition of Drs. Federoff and Gelbard to the Core. This group will focus particularly on toxicant contributions to the development of neurodegenerative disorders. The major thematic areas of the Neurotoxicology Core are the following: 1) Neurochemical mechanism of lead-induced behavioral toxicology (Cory-Slechta). This project examines the neurochemical and neuroanatomical sites through which lead alters neural functions. Work had identified neurotransmitter alterations, neural pathways and behavioral deficits in animal models of lead exposure. 2) Environmental neurotoxicant genetic interaction: murine model (Federoff). This work would test the hypothesis that neurotoxicants interact with yet uncharacterized genetic determinants to produce selective vulnerability. Focusing on the dopamine transporter (DAT), the principal investigator will engineer a population of dopaminergic neurons overexpressing DAT by means of a somatic mosaic approach and directed gene expression to compare the responses of expressing and non-expressing neurons in the same animal. 3) A murine model of genetic and environmental neurotoxicant action (Richfield). This project would look at the role of the alpha-synuclein gene and gene product in Parkinson?s disease using the somatic mosaic approach. Studies will determine whether mice overexpressing alpha-synuclein show an enhanced dopaminerigic vulnerability when exposed to low does of paraquat. 4) Genotype and phenotype of autism spectrum disorders (Rodier). This project will continue the investigator?s work linking injury during early development (as early as neural tube fusion) and specific genes with the development of the autism disorders. Work will continue to examine the valproic acid model of brain injury (which phenocopies some aspects of autism spectrum disorders), and the toxicant involves the HOX family of genes. 5) The role of inflammation and oxidative stress in human immunodeficiency virus type 1- associated neurologic disease (Gelbard). This project has been investigating how HIV type 1 results in neurotoxicity. In the proposed research, the principal investigator would examine the role of tumor necrosis factor alpha (TNF-a) and platelet activating factor (PAF) in the pathogenesis of neurotoxicity. Future plans include the development of TNF-overexpressing mice by somatic mosaic methods, and subsequent examination of neuronal death under various challenges. 6) Neurobehavioral and developmental effects of methylmercury exposure (Clarkson). This represents a continuation of the large human study of methylmercury exposure via fish and its consequences on development. This is one of two definitive epidemiological studies of human methylmercury exposure, which will continue and expand during the next funding period. In addition, the project director will continue his involvement in a prospective study of mercury exposure via dental amalgams. 7) Persisting functional consequences of neurotoxicant exposure during early development (Weiss). This work will continue studies of developmental exposure to several classes of toxicants. These will include solvents in addition to ongoing work in metals, endocrine disruptors (e.g., TCDD), and drugs (e.g., cocaine).
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