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New Approaches to Gene-environment Interaction Modeling in Parkinson's Disease

帕金森病基因-环境相互作用建模的新方法

基本信息

批准号：
8089751
负责人：
Jason R Cannon
金额：
$ 9万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2012-02-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8089751
关键词：
Acute Address Advisory Committees Affect American Animal Model Award Behavioral Brain Brain region Catecholamines Cells Chlorpyrifos Corpus striatum structure Data Development Development Plans Disease model Dopamine Dose Environment Environmental Exposure Epidemiology Feedback Genes Genetic Genetic Models Goals Health Herbicides Human Inherited Insecticides Iron Knock-out LRRK2 gene Laboratories Lead Learning Link Longevity Mentors Modeling Mutation Neurodegenerative Disorders Oxidation-Reduction Paraquat Parkinson Disease Pathology Pathway interactions Play Proteins Rattus Regimen Relative (related person)Research Research Personnel Risk Rodent Rodent Model Role Route Screening procedure Solvents Staging System Techniques Testing Therapeutic Toxic Environmental Substances Toxicant exposure Training Transgenes Transgenic Organisms Trichloroethylene Ursidae Family Viral Work alpha synuclein career development design dopaminergic neuron exposed human population expression vector gene environment interaction gene therapy in vivo Model meetings neurobehavioral neurochemistry neuron loss novel strategies novel therapeutic intervention overexpression prevent public health relevance small hairpin RNA synuclein toxicant transgene expression vector

项目摘要

DESCRIPTION (provided by applicant) This proposal is for a pathway to independence award. The candidate will learn new techniques and create a divergent research focus from the mentor laboratory. The candidate's primary goal is to become an independent investigator and make major scientific contributions to the neurodegenerative disease research field. A detailed Career Development Plan that includes coursework, learning new techniques, scientific meeting attendance, and specific feedback from an advisory committee has been constructed to help the candidate achieve this goal. The research focus of this proposal is on gene-environment interactions in Parkinson's disease (PD). New approaches to modeling such interactions are a major focus of this proposal. The causes of most PD cases are unknown, about 10% are inherited. The causes of the remaining "sporadic", about 90% are unknown. Epidemiological evidence has repeatedly suggested that environmental exposures increase the risk for PD. However, no single toxicant has been identified as a causative agent. Most cases may arise from both environmental and genetic factors. However, such interactions are poorly understood. Research to date on gene-environment interactions has typically utilized toxicant models that have little relevance to human health. Indeed, current PD models have major etiological limitations. Toxicant models typically use large acute doses by unrepresentative routes of exposure and genetic models often use complete life-span knockout of a gene or massive transgene expression. The candidate hypothesizes that: "early-stage" environmental PD modeling is best suited to study gene-environment interactions. He proposes to overcome current barriers by: Aim 1) Creating both "early" and "late" stage PD models using relevant environmental toxicants. Here, toxicants recently linked to PD will be used to create new rodent models that reproduce the key features of both early and late-stage PD and utilize environmentally relevant toxicants. This aim will serve as a "screen" to identify the optimal toxicant model to advance to later aims. The toxicant producing the best model will move forward to later aims. Aim 2) "Real-world" exposure modeling: This aim will utilize toxicant exposure through dosing regimens that bear relevance to human health. Aim 3) Creating new gene-environment interaction models: Here, transgenic rats expressing mutations known to cause PD in humans will be exposed to the optimal toxicant from aim 1. Thus a new gene-environment rodent PD model will be created that utilizes an environmental toxicant linked to PD and expresses a mutation known to cause human PD. Brain toxicant levels will be determined and correlated with pathological observations (Aims 1-3). Aim 4) Testing gene therapy approaches in these models: In vivo modulation of PD genes will be tested as a potential therapeutic approach in newly created toxicant models. This project is expected to produce major advances in gene-environment interaction modeling. Newly created models will be used to identify pathogenic pathways and test new therapeutic approaches. Public Health Relevance: Parkinson's disease (PD) affects roughly 1 million Americans and the causes are largely unknown, although much data suggests that environmental exposures play a role. The proposed work will focus on the development of new models using compounds that have been linked to PD. These newly developed models will be used to test interactions between environmental and genetic factors and also to test potential treatments.

描述（由申请人提供）