The long-term objectives of this project are to use clinical metabolomics to understand environmentalcontributions to Parkinson's Disease and develop novel interventional strategies to reduce risk and manageoutcome. PD is a debilitating disease affecting elderly which is of growing concern because of the aging ofthe American population. PD appears to have multiple causes with environmental exposures, such aspesticides, being of particular concern. These agents induce oxidative stress and inhibit mitochondrialrespiratory complex I, thereby contributing to two biochemical processes associated with PD risk. We haveassembled a team of experts in analytical biochemistry, neurodegenerative disease and bioinformatics touse a new high-throughput metabolic profiling method coupled to bioinformatics to identify unique metabolicsignatures of pesticide exposures and PD development. This powerful methodology is coupled withcapabilities for precise analytical determinations of pesticide contents and oxidative stress so that metabolicsignatures can provide a direct link between exposure and disease symptoms. Identification of suchmetabolic signatures could have considerable impact in providing a means for early detection of risk andsuggesting novel targets for intervention to prevent or manage disease progression. The metabolomicsplatform allows detection of 2000 metabolic features in a 10 min analysis of human plasma.
Specific Aims are to use this assay to 1) profile the metabolic changes in plasma, cerebrospinal fluid and substantia nigraof mouse models of PD in which chemicals (MPTP, dieldrin) are used to elicit symptoms in wildtype mice, asensitive mouse line with reduced ability to properly store dopamine (VMAT2-deficient), and a resistantmouse line with increased content of mitochondrial thioredoxin-2; 2) identify metabolic features associatedwith PD and with pesticide levels in PD and non-PD controls; and 3) develop standardization procedures toallow creation of a cumulative data library for human metabolomic data. Successful completion of theseaims will provide key new information concerning the hypothesis that exposure to environmental chemicalscreate a metabolic platform for PD risk which can be evaluated by clinical metabolomics and used as a basisfor early interventions to prevent disease and therapeutic approaches to delay progression.
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