Grant: $248,630 - Department of Health and Human Services - May. 19, 2009
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Award Description: Aim 1: Test the hypothesis that human LRRK2 mutant and overexpressing mice are more vulnerable to nigrostriatal toxicity induced by environmental exposure and/or aging. In this aim, we will test the interactive effects of gene alteration, toxicant exposure and/or aging on the nigrostriatal pathway. Aim 2: Test the hypothesis that interactions between neurotoxicants and LRRK2 trigger the formation of abnormal tau and ?-synuclein in brain. In LRRK2 parkinsonism, there is variable tau and ?-syn pathology. To understand the molecular basis for this heterogeneity, we will evaluate whether protein alterations occur in the overexpressors and G2019S mutants vs. respective control mice, and if the effects are modified with toxicant exposure and/or aging. Aim 3: Determine specific mechanisms underlying LRRK2-related toxicity in the context of aging and toxicant exposure. Accumulating evidence suggests that the multi-domain organization of LRRK2 may allow for its interaction with multiple pathways involved in neurodegeneration. To determine the mechanisms relevant to LRRK2-mediated toxicity, we will investigate the effects of LRRK2 overexpression and the G2019S mutation on the following pathogenic mechanisms: mitochondrial dysfunction (e.g., cytochrome c distribution and caspase activation), oxidative stress (e.g., 4-HNE production), impaired protein quality control (i.e. ubiquitin and insoluble protein accumulation) and altered intracellular trafficking (e.g., cleaved neurofilaments).
Project Description: Have screened candidates for Research Assistant position; candidate selected and ready to hire. Work will begin in mid-October; collaborator on studies--and provider of mouse model-- (Consultant Dr. Heather Melrose) was on maternity leave during first 3 months of grant.
Jobs Summary: Potential Jobs saved: 1; Principal Investigator who will lead studies and be responsible for overall execution an d communication of studies at scientific meetings. Jobs created: 1; Research Assistant who will assist in laboratory experiments and in animal handling. (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on May. 19, 2009. Help expand these official descriptions using the wiki below.