Project 4: Pesticides and Genes In PD: Studies In Humans

项目 4：PD 中的农药和基因：人类研究

• 批准号: 8377935
• 负责人: Beate R Ritz
• 金额: $ 40.21万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8377935
• 关键词: Affect; Agriculture; Alcohol dehydrogenase; Aldehydes; Basic Science; Benomyl; Biological; Biological Testing; CDK5 gene; California; Candidate Disease Gene; Cellular Assay; Collaborations; County; Data; Data Set; Databases; Diagnosis; Dopamine; Drosophila genus; Drug Metabolic Detoxication; Enrollment; Environment; Environmental Risk Factor; Enzymes; Epidemiologic Studies; Equilibrium; Exposure to; Feedback; France; Funding; Future; Gene Cluster; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genetic screening method; Genotype; Goals; Haplotypes; Human; Individual; Investigation; Laws; Lead; Letters; Methods; Microtubules; Movement Disorders; National Institute of Environmental Health Sciences; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurologist; New Agents; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Pesticides; Pilot Projects; Population; Population Control; Population Study; Principal Investigator; Records; Recruitment Activity; Registries; Reporting; Research Personnel; Resources; Risk; Sample Size; Sampling; Sampling Studies; Single Nucleotide Polymorphism; Study Subject; System; Testing; Toxic Environmental Substances; Toxic effect; Translations; Ubiquitin; Variant; Woman; Work; Ziram; aldehyde dehydrogenases; base; case control; cohort; cost; cost effective; dopaminergic neuron; environmental agent; farmer; gene environment interaction; gene interaction; genetic association; genetic variant; genome wide association study; genome-wide; genotyping technology; human study; improved; multicatalytic endopeptidase complex; novel; parkinson' s disease registry; pesticide exposure; programs; promoter; risk sharing; tool; toxicant; vesicular monoamine transporter

The goal of the UCLA-CGEP is to investigate the hypothesis that the cellular mechanisms of action identified for Putative Environmental Toxicants (PETs) contribute to a significant increase in PD risk; this project will focus on investigations in humans. Our group identified specific cellular mechanisms that are affected by PETs: the proteasome, microtubule integrity, and aldehyde dehydrogenase detoxification. In conjunction with altered VMAT function/expression that influences dopamine balance, these pathways may affect the vulnerability of DA neurons to neurodegeneration. We propose to use our existing data from the Parkinson Environment Gene (PEG) study to test biological candidate genes and PETs for association with PD. We have enrolled nearly 400 PD patients and 400 population controls from California's Central Valley. Each individual has been assessed for pesticide exposure based on records mandated by state law, and patients have been examined by a UCLA Movement Disorder neurologist, thus, we have a unique resource of well characterized PD subjects and controls with exceptional data for exposure to specific agricultural pesticides. To detect associations for rarer pesticides and genetic variants acting in the hypothesized biological pathways and to investigate gene-gene (GxG) and gene-environment (GxE) interactions with sufficient power, we propose to recruit and collect biological (DMA) samples from 400 additional population controls as a quick and cost-effective way to increase sample size and power. Our specific aims are to test the hypotheses that 1) environmental pesticides targeting the same cellular systems as the previously identified PETs also increase PD risk; 2) variants of genes (assessed via putative functional and haplotype tagging SNPs) in cellular pathways affected by PETs increase PD risk. Secondarily, we will a) test GxE and GxG interactions (including VMAT) to determine whether variants of the candidate genes selected interact with PETs and/or other genes to modulate PD risk in humans; b) retest genetic and GxG interaction associations in a replication cohort. Genes selected for initial investigation in this project have been determined by data~ on pathways and genes from our basic science projects (projects 1-3). Genetic investigations in later years of this project will be driven by the initial results of projects 1-3 in this center. In turn, the findings from gene and PET investigations in this human study will feedback and help develop hypotheses to be tested in the other projects.

UCLA-CGEP的目的是研究鉴定出动作的细胞机理的假设 对于推定的环境有毒物质（PET），PD风险显着增加；这个项目将 专注于人类的调查。我们的小组确定了受到受影响的特定细胞机制 宠物：蛋白酶体，微管完整性和醛脱氢酶解毒。结合 随着影响多巴胺平衡的VMAT功能/表达的改变，这些途径可能会影响 DA神经元对神经变性的脆弱性。我们建议使用帕金森森的现有数据 环境基因（PEG）研究以测试生物候选基因和宠物与PD关联。我们 来自加利福尼亚州中央山谷的近400名PD患者和400名人口对照。每个 根据州法律规定的记录，对个人的农药暴露进行了评估，患者 已经由UCLA运动障碍神经科医生进行了检查，因此，我们有一个独特的资源 具有特殊数据的PD受试者和对照表征，以暴露于特定的农业农药。 检测作用于假设生物学的稀有农药和遗传变异的关联 途径并研究基因基因（GXG）和基因环境（GXE）与足够的相互作用 权力，我们建议从400个其他人口控制中招募和收集生物（DMA）样本 一种快速且具有成本效益的方法，以增加样本量和功率。我们的具体目的是测试 假设1）针对与先前鉴定的相同细胞系统的环境农药 宠物还增加了PD风险； 2）基因的变体（通过推定的功能和单倍型标记评估 SNP）在受宠物影响的细胞途径中增加了PD风险。其次，我们将a）测试GXE和GXG 相互作用（包括VMAT）以确定选定的候选基因的变体是否与 宠物和/或其他基因调节人类的PD风险； b）重新遗传和GXG相互作用关联 在复制队列中。在该项目中选择进行初步研究的基因已由数据〜确定 关于我们基础科学项目的途径和基因（项目1-3）。后来的遗传研究 该项目将由该中心的项目1-3的初始结果驱动。反过来，基因的发现 这项人类研究中的宠物调查将反馈并有助于开发假设以在 其他项目。