Investigating environmental and gene-environment contributors to Parkinson's disease risk by coupling quantitative environmental exposure data to iPSC modeling

通过将定量环境暴露数据与 iPSC 建模相结合，调查帕金森病风险的环境和基因环境因素

• 批准号: 10572740
• 负责人: Richard Carl Krolewski
• 金额: $ 19.72万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572740
• 关键词: Academic Medical Centers; Affect; Astrocytes; Binding; Biology; Blood - brain barrier anatomy; Brain; Calcium Signaling; California; Cell Line; Cells; Censuses; Central Nervous System; Chairperson; Clinic; Collaborations; Complex; Computing Methodologies; Coupled; Coupling; Cytokine Signaling; Cytoskeleton; Data; Detection; Development; Development Plans; Disease; Disparate; Dropout; Ensure; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Etiology; Evaluation; Exposure to; Gene Dosage; Genes; Genetic; Genetic Transcription; Goals; Grouping; Growth; Health; Hospitals; Idiopathic Parkinson Disease; In Vitro; Industrialization; Inflammation Mediators; Influentials; Institution; Link; Mentorship; Metabolism; Methods; Microglia; Midbrain structure; Mitochondria; Modeling; Mutation; Nerve Degeneration; Neuroglia; Neuroimmune; Neurology; Neurons; Organelles; Paracrine Communication; Paraquat; Parkinson Disease; Pathologic; Pathology; Patients; Penetrance; Pesticides; Phenotype; Physicians; Population; Positioning Attribute; Predisposition; Process; Production; Public Health; Quality Control; Reporter; Reporting; Research; Research Personnel; Research Training; Resources; Risk; Risk Factors; Role; Sampling; Scientist; Signaling Molecule; System; Testing; Toxic effect; Trifluralin; Tyrosine 3-Monooxygenase; Universities; Woman; Work; alpha Tubulin; alpha synuclein; career; career development; cell type; cohort; design; disease phenotype; disease-in-a-dish; disorder risk; dopaminergic neuron; endophenotype; gene environment interaction; genetic risk factor; induced pluripotent stem cell; man; member; mutation correction; neuron loss; neuronal survival; neuroprotection; neurotoxicity; pandemic disease; pesticide exposure; pesticide interaction; prevent; progression marker; response; screening; sporadic Parkinson' s Disease; stem cells; success; synergism; toxicant; translational neuroscience

PROJECT SUMMARY Parkinson's Disease (PD) is considered a “man-made” pandemic, triggered in part by industrialization that has entailed increased production needs and exposure to toxicants resulting from that growth. Despite the discovery of important genetic risk factors, a substantial amount of etiologic risk for idiopathic PD is environmental, with pesticide exposure being a clear and documented risk factor. As a result, understanding the interaction between genetic drivers and environmental risk factors has significant potential to inform etiology and treatment of PD. This project will investigate how environmental factors, specifically pesticides, influence the development of PD at the level of effects on midbrain dopaminergic (mDA) neurons, a cell type whose loss is the hallmark of PD pathology. The work is informed by a paradigm in which highly quantitative pesticide exposure data from a large PD cohort in California is linked to a screening platform using patient stem cell (iPSC)-derived mDA neurons. Fifty-three pesticides were linked to PD with this method and ten proved directly toxic to mDA neurons. The proposed work will: (1) deeply dissect mechanisms of mDA neuron toxicity for top hits with a focus on mitochondrial and cytoskeletal consequences of trifluralin exposure; (2) explore the role of glia in modulating toxicity using a triculture approach to ask how other PD-associated pesticides alter astrocyte and microglial biology to influence mDA neuron pathology; and (3) use population-level modeling of sporadic PD in a dish to build a platform that will stratify cells from ~100 donors functionally based on responses to pesticides and then use computational methods to reconstruct which cell lines are disproportionately affected. This will identify shared phenotypes among genetically disparate samples. The career development plan is designed to support the candidate's goal of becoming an independent investigator at an academic medical center, treating PD patients in clinic while concurrently leading a research team studying their disease. A strong mentorship and collaborative team in a vibrant research environment is led by a supportive neurology chairperson (Batchelor), outstanding physician scientists with expertise spanning from neurodegeneration (Khurana, Selkoe) to public health and epidemiology (Ritz) to translational neuroscience (Rubin, Studer, Powell). This mentorship team, along with extensive research training and relevant coursework, will position the candidate for success. The institutional resources available through Brigham and Women's Hospital, and Harvard University will support the candidate's career in an environment that makes high impact contributions and collaborative endeavors achievable. The successful execution of this proposal will position the candidate along a path for an independent career as a physician scientist studying the interplay of gene-environment interactions in PD to better treat and prevent this disease.

项目摘要 帕金森氏病（PD）被认为是“人造”大流行，部分是由工业化触发的 这需要增加生产需求和由于这种增长而导致的有毒物质。尽管有 发现重要的遗传危险因素，特发性PD的大量病因学风险是 环境，农药暴露是明显且有记录的危险因素。结果，理解 遗传驱动因素与环境风险因素之间的相互作用具有巨大的潜力来告知 PD的病因和治疗。 该项目将调查环境因素（特别是农药）如何影响 在对中脑多巴胺能（MDA）神经元的影响水平上开发PD，一种细胞类型的损失是 PD病理学的标志。这项工作以高度定量的农药为范式来告知 来自加利福尼亚大型PD队列的暴露数据与使用患者干细胞的筛查平台有关 （IPSC）衍生的MDA神经元。使用这种方法将五十三个农药与PD联系在一起，而十种直接证明 对MDA神经元有毒。拟议的工作将：（1）深度剖析了MDA神经元毒性的机制 命中率关注三氟酸酯暴露的线粒体和细胞骨架后果； （2）探索 胶质在调节毒性中使用三栽培方法询问其他与PD相关的农药如何改变星形胶质细胞 和小胶质细胞生物学影响MDA神经元病理； （3）使用零星的种群级建模 菜肴中的PD建立一个平台，该平台将根据对的响应从功能上从〜100个供体中分类的平台 农药，然后使用计算方法来重建哪些细胞系受到不成比例的影响。 这将确定遗传上不同样本之间的共享表型。 职业发展计划旨在支持候选人成为独立的目标 学术医学中心的研究人员，治疗诊所的PD患者，同时领导研究 研究他们的疾病的团队。在充满活力的研究环境中的强烈心态和协作团队是 由支持神经病学主席（Batchelor）领导，具有专业知识的杰出物理科学家 从神经变性（Khurana，Selkoe）到公共卫生和流行病学（RITZ）到转化 神经科学（Rubin，Studer，Powell）。这支训练团队，以及广泛的研究培训和 相关课程将使候选人取得成功。可通过 Brigham and妇女医院和哈佛大学将在环境中支持候选人的职业 这使得可以实现高影响力的贡献和协作努力。成功执行 提案将把候选人定位为独立职业作为物理科学家研究的道路 PD中基因环境相互作用的相互作用，以更好地治疗和预防这种疾病。