Interaction of Pyrethroid Exposure and the Microbiome on Parkinson's Disease related Pathologies

拟除虫菊酯暴露与微生物组对帕金森病相关病理的相互作用

基本信息

批准号：
10569042
负责人：
Timothy Robert Sampson
金额：
$ 34.8万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-09 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569042
关键词：
Acceleration Acute Affect Animal Model Architecture Bacterial Genes Brain Pathology Cell Survival Central Nervous System Colon Constipation Data Disease Enteric Nervous System Enteroendocrine Cell Environment Environmental Exposure Epidemiology Etiology Exhibits Experimental Models Exposure to Family Foundations Functional disorder Gastrointestinal tract structure Genes Genetic Risk Germ-Free Gnotobiotic Goals Human Immune Impairment Incidence Indigenous Individual Inflammation Inflammatory Bowel Diseases Inflammatory Response Intestinal Motility Intestinal permeability Intestines Lactobacillus Link Mediating Microbe Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurons Neuropeptides Oral Organ Outcome Pain Parkinson Disease Parkinsonian Disorders Pathology Peripheral Pesticides Physiological Population Primates Production Resistance Risk Risk Factors Rodent Role Rotenone Severity of illness Shapes Signal Transduction Taxonomy Testing Toxic Environmental Substances Toxicant exposure Transgenic Mice Xenobiotic Metabolism alpha synuclein cell motility decamethrin disease diagnosis dopamine system dopaminergic neuron dysbiosis enteric infection gastrointestinal gastrointestinal system gene environment interaction gut inflammation gut microbiome gut microbiota inflammatory modulation insight microbial microbiome microbiome alteration microbiome components microbiome composition monoamine motor disorder mouse model nerve supply neuron loss nigrostriatal system overexpression pesticide exposure pyrethroid sporadic Parkinson&apos s Disease tool

项目摘要

Project Summary Pesticide exposures are a significant risk factor for many neurodegenerative diseases, including Parkinson’s disease (PD). Sporadic PD, with no known etiology accounts for ~90% of disease incidences, as highly penetrant genetic risks are not very prevalent. Experimental models have largely elucidated molecular mechanisms of pesticide exposures directly on those neurons vulnerable during PD. For instance, exposures to rotenone and MPTP are used to induce nigrostriatal neuron loss in rodents. While the effects of these exposures on the central nervous system (CNS) have been explored, outcomes of PD-relevant exposures in peripheral organs, such as the intestine, are largely unknown. Gastrointestinal (GI) dysfunctions, such as constipation and inflammatory bowel disease often precede PD diagnosis, and loss of GI innervation appears prior to CNS pathology in some PD-predisposed populations. It is likely that GI pathologies may signal the onset of CNS dysfunctions in PD. Within the GI tract, alterations to the microbiome (i.e. dysbiosis) are established to arise during PD, and specific alterations to bacterial taxa correlate with disease severity. Dysbiosis is not simply an epiphenomenon, but has physiological impacts on the host, particularly in the context of PD. Intestinal inflammation and dysbiosis are sufficient to exacerbate CNS pathology and motor dysfunctions in animal models of PD. Intriguingly, the PD- derived microbiome is enriched for bacterial genes involved in xenobiotic metabolism, indicating that pesticide exposures shape the GI environment. We therefore predict that dysbiosis, resultant from pesticide exposure, impacts PD-relevant GI and CNS pathologies. Here, we will use germ-free (GF) mice as tool to determine microbiome contributions to pesticide-induced pathologies. Most importantly, we will identify the contributions of dysbiosis to established nigrostriatal dysfunctions that arise following pesticide exposure. Combining microbial effects with relevant toxicant exposure, we will test the interaction of these external influences in a transgenic mouse model of PD. This proposed project will bridge a gap in our understanding of how exposure to environmental toxicants influences neurodegenerative outcomes. We hypothesize intestinal pyrethroid exposure impacts microbiome architecture, which modulates inflammatory responses, and exacerbates PD-relevant outcomes in the GI and nigrostriatal system. This project will provide a foundation for uncovering microbe- environment interactions that modulate risk of neurodegenerative disease.

项目概要接触农药是许多神经退行性疾病的重要危险因素，包括帕金森病病因不明的散发性 PD 占疾病发病率的约 90%，具有高度渗透性。遗传风险并不十分普遍，实验模型已在很大程度上阐明了遗传风险的分子机制。帕金森病期间易受影响的神经元直接接触农药，例如接触鱼藤酮和 MPTP 用于诱导啮齿动物黑质纹状体神经元损失，而这些暴露对中枢神经元的影响。神经系统 (CNS) 已被探索，外周器官中与 PD 相关的暴露的结果，例如胃肠道（GI）功能障碍，例如便秘和炎症，在很大程度上是未知的。肠道疾病通常先于帕金森病诊断，并且在某些情况下，胃肠道神经支配的丧失出现在中枢神经系统病理学之前。帕金森病易感人群。胃肠道病理可能预示着帕金森病中枢神经系统功能障碍的发生。在胃肠道内，微生物组的改变（即菌群失调）在 PD 期间会出现，并且特定的细菌分类群的改变与疾病的严重程度相关，菌群失调不仅仅是一种附带现象，而且还具有相关性。对宿主的生理影响，特别是在肠道炎症和生态失调的情况下。足以加剧 PD 动物模型中的中枢神经系统病理和运动功能障碍。衍生的微生物组富含参与外源代谢的细菌基因，表明农药因此，我们预测农药暴露导致的生态失调，在这里，我们将使用无菌 (GF) 小鼠作为工具来确定。最重要的是，我们将确定微生物组对农药引起的病理的贡献。微生物接触导致的黑质纹状体功能失调。与相关毒物暴露的影响，我们将在转基因中测试这些外部影响的相互作用这个拟议的项目将弥补我们对如何接触PD的理解上的差距。环境毒物会影响神经退行性结果，我们会在肠道中接触拟除虫菊酯。影响微生物组结构，从而调节炎症反应，并加剧与帕金森病相关的疾病该项目将为发现微生物提供基础。调节神经退行性疾病风险的环境相互作用。