Genomic markers of environmental toxins for Parkinsonism
DESCRIPTION (provided by applicant): Parkinson's disease is a prevalent and devastating neurodegenerative condition of unknown etiology. One prominent hypothesis holds that the selective loss of the nigrostriatal dopaminergic neurons characteristic of the disease results from damage from environmental neurotoxins in genetically vulnerable individuals. Identifying such environmental contributors to Parkinson s pathogenesis represents a significant public health concern. This project aims to identify the in vivo gene expression changes that occur in the primate brain in response to environmental toxins that have been implicated in the production of Parkinson's and compare these changes with the selective neurotoxin, MPTP, and with the limited knowledge of genetic abnormalities in some Parkinson's patients. Because of the unique vulnerabilities of nonhuman primates and humans to dopamine neurotoxic agents, studies in primates are essential to uncover common genetic markers of toxicity and to reveal the potential toxicity of chemicals of unknown liability. The proposed Phase I studies will test the hypotheses that transcriptional changes that accompany and precede dopamine cell death can be identified using high density gene arrays and bioinformatics in the primate nigrostriatal system in vivo following MPTP exposure. Changes in mRNA initiation of regimen of 3 doses of MPTP over 36 hours that has been established to result in Parkinsonism. Expression changes will also be assessed 6 hours after the administration of a single dose. Changes in nigrostriatal dopamine concentrations and tyrosine hydroxylase immunohistochemistry will be assessed at all time points. Additionally neurobehavioral changes will be assessed in the 20-day animals. Together these data will allow a determination of the sequence of transcriptional changes that parallel or precede histological, biochemical and behavioral events, and allow an assessment of transcriptional events related to acute versus chronic toxicity, with confirmation by quantitative RT-PCR. Defining the chronological and dose dependent gene expression changes induced by MPTP may reveal a transcriptional profile that is predictive of nigrostriatal injury from this toxin. Phase II studies will address whether similar gene expression changes and neuronal injury are seen following exposure to environmentally prevalent compounds that are postulated to be risk factors for the development of Parkinson's disease, and to integrate the resulting transcriptional data into a toxicogenornic database and potentially customized microarrays which may be applied to the assessment of compounds for their possible health risk.
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