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：
8350767
负责人：
Jason R Cannon
金额：
$ 24.9万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-10 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8350767
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 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 meetings neurobehavioral neurochemistry neuron loss novel strategies novel therapeutic intervention overexpression prevent small hairpin RNA synuclein toxicant transgene expression vector

项目摘要

This proposal is for a pathway to independence award. The candidate will learn new techniques and create a divergent research focus from the mentor lab. 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 - ~10% are inherited. The causes of the remaining 'sporadic' ~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. I hypothesize that: 'early-stage' environmental PD modeling is best suited to study gene-environment interactions. I propose to overcome current barriers by: Aim1) 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.

该提案是获得独立奖的途径。候选人将学习新技术并创建一个与导师实验室的研究重点不同。候选人的首要目标是成为一名独立人士研究员并为神经退行性疾病研究领域做出重大科学贡献。一个详细的职业发展计划，包括课程作业、学习新技术、科学会议出席率以及咨询委员会的具体反馈已经建立，以帮助候选人实现这一目标。该提案的研究重点是帕金森病的基因与环境相互作用疾病（PD）。建模此类交互的新方法是该提案的主要焦点。产生的原因大多数 PD 病例未知 - 约 10% 是遗传性的。其余约 90% 的“零星”病例的原因尚不清楚。流行病学证据多次表明环境暴露会增加患帕金森病的风险。然而，尚未确定任何单一毒物是致病因素。大多数情况都可能由这两种情况引起环境和遗传因素。然而，人们对这种相互作用知之甚少。迄今为止的研究基因-环境相互作用通常使用与人类关系不大的毒物模型健康。事实上，当前的 PD 模型存在重大病因学局限性。毒性模型通常使用大型急性不具代表性的暴露途径和遗传模型的剂量通常使用完全寿命敲除的基因或大量转基因表达。我假设：“早期”环境局部放电建模是最好的适合研究基因与环境的相互作用。我建议通过以下方式克服当前障碍：目标 1) 创造两者使用相关环境毒物的“早期”和“晚期”PD 模型。在这里，有毒物质最近与帕金森病有关将用于创建新的啮齿动物模型，重现早期和晚期 PD 的关键特征，使用与环境相关的有毒物质。这一目标将作为识别最佳毒物的“筛选” 模型以推进以后的目标。产生最佳模型的毒物将继续实现以后的目标。目标2) “真实世界”曝光建模。这一目标将通过剂量方案利用有毒物质暴露与人类健康的相关性。目标 3) 创建新的基因-环境相互作用模型。在这里，转基因老鼠表达已知会导致人类帕金森病的突变将暴露于目标 1 中的最佳毒物。因此将创建一个新的基因-环境啮齿动物帕金森病模型，该模型利用与帕金森病相关的环境毒物并表达已知会导致人类帕金森病的突变。将确定并关联脑毒物水平并进行病理观察（目标 1-3）。目标 4) 在这些模型中测试基因治疗方法。体内 PD 基因的调节将作为新创建的毒物模型中的潜在治疗方法进行测试。该项目预计将在基因-环境相互作用建模方面取得重大进展。新创建的模型将用于识别致病途径并测试新的治疗方法。