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

• 批准号: 8610308
• 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
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-10 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610308
• 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; 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; screening; small hairpin RNA; synuclein; toxicant; transgene expression; vector

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.

这一提议是为了获得独立奖的途径。候选人将学习新技术并创建一个 与导师实验室不同的研究重点。 这位候选人的主要目标是成为一名无党派人士 研究者，并作出重大的科学贡献，神经退行性疾病的研究领域。 一 详细的职业发展计划，包括课程，学习新技术，科学会议 出席率，以及咨询委员会的具体反馈，以帮助候选人 以实现这一目标。 该提案的研究重点是帕金森氏症的基因-环境相互作用 疾病（PD）。新的方法来模拟这种相互作用是本提案的一个主要重点。的原因 大多数PD病例是未知的-约10%是遗传的。其余的“散发性”的原因约90%是未知的。 流行病学证据一再表明，环境暴露会增加PD的风险。 然而，没有一种毒物被确定为致病因子。 大多数情况下，可能是由这两种原因引起的。 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-环境相互作用通常利用与人类几乎无关的毒物模型， 健康事实上，目前的PD模型具有主要的病因学局限性。毒性模型通常使用大急性 非代表性暴露途径的剂量和遗传模型通常使用完全寿命敲除 基因或大量转基因表达。 我假设：“早期”环境PD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目前的障碍：目标1） 使用相关环境毒物的“早期”和“晚期"PD模型。在这里，最近与帕金森病有关的毒物 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， 使用与环境有关的有毒物质。这一目标将作为一个“屏幕”，以确定最佳的毒物 以达到后来的目标。产生最佳模型的毒物将向后来的目标前进。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。目的3）建立新的基因-环境相互作用模型。这里，转基因老鼠 表达已知在人类中引起PD的突变的人将暴露于来自目的1的最佳毒物。因此 一种新的基因-环境啮齿动物PD模型将被创建，该模型利用与PD相关的环境毒物 并表达一种已知会导致人类帕金森病的突变大脑毒物水平将被确定和关联 病理学观察（目标1-3）。目的4）在这些模型中测试基因治疗方法。体内 PD基因的调节将在新创建的毒物模型中作为潜在的治疗方法进行测试。 该项目有望在基因-环境相互作用建模方面取得重大进展。新创建 模型将被用来确定致病途径和测试新的治疗方法。

项目成果

Novel dose-dependent alterations in excitatory GABA during embryonic development associated with lead (Pb) neurotoxicity.

• DOI: 10.1016/j.toxlet.2014.05.016
• 发表时间: 2014-08-17
• 期刊: TOXICOLOGY LETTERS
• 影响因子: 3.5
• 作者: Wirbisky, Sara E.;Weber, Gregory J.;Lee, Jang-Won;Cannon, Jason R.;Freeman, Jennifer L.
• 通讯作者: Freeman, Jennifer L.