Microbiome, Environment, and Parkinsons disease (MEP) PESTICIDE EXPOSURES AND THE GUT MICROBIOME IN PARKINSONS DISEASE

微生物组、环境和帕金森病 (MEP) 农药暴露以及帕金森病中的肠道微生物组

基本信息

批准号：
10053242
负责人：
Beate R Ritz
金额：
$ 66.16万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10053242
关键词：
Address Affect Age Air Pollution Animals Area Assessment tool Behavior Biological Biological Models Blood Blood specimen Brain Brain Pathology California Chronic Clinical Clinical Data Cognitive Communities Complement Constipation Cross-Sectional Studies Data Development Diet Digestive System Disorders Disease Disease Progression Elderly Enrollment Enteric Nervous System Environment Environmental Exposure Environmental Impact Environmental Risk Factor Etiology Exposure to Feces Funding Gastroparesis Genes Genetic Geographic Information Systems Health Personnel Household Human Human Microbiome Immune system Inflammation Intervention Lewy Bodies Life Style Longitudinal Studies Measures Mediating Medical Metabolic Pathway Metagenomics Metals Microbe Motor Nerve Degeneration Nervous System Physiology Neurodegenerative Disorders Nutrient Onset of illness Parkinson Disease Participant Pathologic Pathway interactions Patients Pesticides Pharmaceutical Preparations Phenotype Physiology Play Population Population Study Prevention Process Public Policy RNA, Ribosomal, 16S Records Regulation Reporting Research Resources Role Sampling Serum Shotguns Specificity Susceptibility Gene System Testing Time Toxin agricultural pesticide alpha synuclein base cell motility cohort disease diagnosis experience experimental study follow-up gastrointestinal gastrointestinal symptom gene environment interaction gut microbiome gut microbiota gut-brain axis human microbiota inflammatory disease of the intestine insight member metabolomics metagenome microbiome microbiome composition microbiome research microbiota motor impairment non-motor symptom novel parkinson&apos s disease registry pesticide exposure prevent protein aggregation recruit rural environment rural health network sex time use tool uptake

项目摘要

Abstract. The human microbiome has a major role in the uptake and handling of nutrients, medications, and toxins; and is of great immune system relevance. Evidence is mounting that it can affect aspects of neurologic function, brain activity, and behavior via the ‘gut-brain-axis’. New propositions are that environmental exposures such as pesticides, metals, and air pollution influence the microbiome and the human immune system and that the microbiome plays a role in Parkinson’s disease (PD). Here we propose the novel hypothesis that a) the microbiome is affected by chronic environmental exposures, specifically pesticides; and b) an altered gut microbiome composition or function contributes to the progression of neurodegeneration in PD. PD - a progressive neurodegenerative disease – has various non-motor symptoms including gastro-intestinal (GI) features such as constipation and gastroparesis. Its pathologic hallmarks, namely Lewy bodies and α-synuclein aggregates, have been found in the gut’s enteric nervous system of PD patients along with inflammation. The role of the gut microbiome in PD is underexplored and no study has addressed whether toxins influence neurodegeneration via the microbiome. We previously developed a resource to investigate long-term exposure to pesticides in humans, i.e. a geographic information system (GIS) model based on records from the California state pesticide use reporting (PUR) system. Capitalizing on our unique PUR exposure assessment tool and the Parkinson's Disease Susceptibility Genes and Pesticides Study (PEG; R01 ES-010544) resources, we have joined forces with Drs. Mayer and Jacob (UCLA Division of Digestive Diseases) - experts in brain-gut connection microbiome research - and propose to analyze the gut microbiome of 400 PD patients and 600 (200 age-matched household & 400 age-sex matched community) controls using 16S ribosomal RNA to assess relative abundance of microbiota. Specifically, we will assess composition and function (using the predicted metagenome) in pesticide exposed vs. non-exposed controls and PD patients of different progression phenotypes. We will newly enroll 200 new-onset, of these 100 medication naïve (MN) PD patients, to collect data on exposures, gut motility indicators, and fecal samples for metabolomics and culture based experiments (before and after starting PD medications); assess differences in relative abundances of microbes over time using 16S ribosomal RNA and shotgun metagenomics and conduct metabolomics (blood or stool) analyses for new onset PD patients (twice, longitudinally) and their household controls. We combine for this research our extensive expertise in pesticide exposure assessment and studying PD progression in community-based patients, an exceptionally well-characterized population living in a heavily pesticide exposed region, with the expertise of our UCLA GI team in brain-gut axis research and the resources of the UCLA microbiome core. Our resources provide a strong and efficient platform for addressing chronic environmental exposure to pesticides and their impacts on the gut microbiome and on neurodegeneration. This research will suggest novel pathways and prevention options for a growing elderly population with chronic environmental exposures.

抽象的。人体微生物组在营养物质、药物和毒素的吸收和处理中发挥着重要作用，并且具有重要作用。越来越多的证据表明它可以影响神经功能、大脑活动和免疫系统的各个方面。新的主张是通过“肠-脑轴”来控制行为。空气污染影响微生物组和人体免疫系统，微生物组在在此，我们提出了一个新假设：a) 微生物群受到慢性疾病的影响。环境暴露，特别是农药；b) 肠道微生物组组成或功能的改变有助于 PD 是一种进行性神经退行性疾病，其神经退行性疾病的进展具有多种非运动功能。症状包括胃肠（GI）特征，例如便秘和胃轻瘫其病理特征，即路易体和α-突触核蛋白聚集体，已在PD患者的肠道肠神经系统中发现肠道微生物组在帕金森病中的作用尚未得到充分探索，也没有研究涉及。毒素是否通过微生物组影响神经退行性疾病我们之前开发了一种资源来研究。人类长期接触农药，即基于记录的地理信息系统（GIS）模型加利福尼亚州农药使用报告 (PUR) 系统利用我们独特的 PUR 暴露评估工具和帕金森病易感基因和农药研究（PEG；R01 ES-010544）资源，我们联手与 Mayer 和 Jacob 博士（加州大学洛杉矶分校消化疾病部） - 脑肠连接微生物组研究专家 - 并建议分析 400 名 PD 患者和 600 名（200 名年龄匹配的家庭和 400 名年龄性别具体来说，我们将使用 16S 核糖体 RNA 来评估微生物群的相对丰度。评估暴露农药与未暴露对照的组成和功能（使用预测的宏基因组），我们将新招募 200 名新发的 PD 患者，其中 100 名未接受过药物治疗。 (MN) PD 患者，收集有关暴露、肠道动力指标和粪便样本的数据，用于代谢组学和培养基于实验（在开始帕金森病药物治疗之前和之后）；评估微生物相对丰度的差异随着时间的推移，使用 16S 核糖体 RNA 和鸟枪法宏基因组学并进行代谢组学（血液或粪便）分析新发帕金森病患者（两次，纵向）及其家庭对照我们在这项研究中结合了我们广泛的研究。农药暴露评估和研究社区患者帕金森病进展方面的专业知识，生活在农药严重暴露地区的具有明确特征的人群，凭借我们加州大学洛杉矶分校 GI 团队的专业知识脑肠轴研究和加州大学洛杉矶分校微生物组核心资源我们的资源提供了强大而高效的支持。解决长期环境接触农药及其对肠道微生物组和环境影响的平台这项研究将为不断增长的老年人口提出新的途径和预防方案。长期暴露在环境中。