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

这项提议是为了获得独立之路奖。候选人将学习新技术，并创造一个 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无党派人士 研究人员，并在神经退行性疾病研究领域做出了重大科学贡献。一个 详细的职业发展计划，包括课程学习、学习新技术、科学会议 出席，并建立了一个咨询委员会的具体反馈，以帮助候选人 实现这一目标。这项建议的研究重点是帕金森氏症患者的基因-环境相互作用 疾病(PD)。对这种互动进行建模的新方法是本提案的主要重点。原因是什么？ 大多数帕金森病患者是未知的--~10%是遗传性的。剩下的“零星”的~90%的原因不明。 流行病学证据一再表明，环境暴露会增加帕金森病的风险。 然而，没有一种毒物被确定为致病因素。大多数病例可能同时由这两种原因引起 环境和遗传因素。然而，人们对这种相互作用知之甚少。到目前为止对 基因-环境相互作用通常使用与人类几乎没有相关性的毒物模型 健康。事实上，目前的帕金森病模型存在主要的病因学局限性。中毒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所致的剂量通常使用完全寿命的基因敲除 基因或大量转基因表达。我假设：‘早期’环境PD模型是最好的 适合于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的障碍：1)创造两者 “早期”和“晚期”帕金森病模型使用相关的环境毒物。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，再现早期和晚期PD和 使用与环境有关的毒物。这一目标将成为确定最佳毒物的“屏障”。 前进到后来的目标的模式。产生最好模型的毒剂将前进到更晚的目标。目标2) “真实世界”曝光模型。这一目标将通过给药方案利用毒物暴露 与人类健康相关。目的3)建立新的基因-环境相互作用模型。在这里，转基因老鼠 表达已知导致人类帕金森病的突变将暴露于来自Aim 1的最佳毒物。 一种新的基因-环境啮齿动物帕金森病模型将被创建，该模型利用一种与帕金森病有关的环境毒物 并表达一种已知可导致人类帕金森病的突变。脑部毒物水平将被测定和关联 并进行病理观察(目标1-3)。目的4)在这些模型中测试基因治疗方法。活体内 PD基因的调节将作为一种潜在的治疗方法在新创建的毒物模型中进行测试。 该项目有望在基因-环境相互作用模型方面取得重大进展。新创建的 模型将用于确定致病途径和测试新的治疗方法。

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.