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

• 批准号: 10364916
• 负责人: Timothy Robert Sampson
• 金额: $ 34.84万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/10364916
• 关键词: Acute; Affect; Animal Model; Architecture; Bacterial Genes; Brain Pathology; Cell Survival; 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; Neuraxis; 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; insight; microbial; microbiome; microbiome alteration; microbiome components; microbiome composition; monoamine; motor disorder; mouse model; nerve supply; neuron loss; nigrostriatal system; overexpression; pesticide exposure; pyrethroid; tool

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.

项目摘要 农药暴露是许多神经退行性疾病的重要风险因素，包括帕金森氏症 疾病（PD）。病因不明的散发性PD占疾病发病率的约90%，是高度渗透性的 遗传风险不是很普遍。实验模型已经在很大程度上阐明了 农药暴露直接影响帕金森病期间脆弱的神经元。例如，接触鱼藤酮和 MPTP用于诱导啮齿动物的黑质纹状体神经元损失。虽然这些暴露对中枢神经系统的影响 神经系统（CNS），外周器官中PD相关暴露的结局，如 肠道，在很大程度上是未知的。胃肠道（GI）功能障碍，如便秘和炎症 肠道疾病通常先于PD诊断，在某些情况下，GI神经支配的丧失出现在CNS病理学之前。 PD易感人群。GI病变可能是PD中CNS功能障碍发作的信号。 在胃肠道内，确定PD期间出现微生物组的改变（即微生态失调），并且特异性 细菌分类群的改变与疾病的严重程度相关。生态失调不仅仅是一种附带现象， 对宿主的生理影响，特别是在PD的背景下。肠道炎症和生态失调是 足以加重PD动物模型中的CNS病理和运动功能障碍。有趣的是，警察局- 衍生的微生物组富含参与异生物质代谢的细菌基因，表明农药 暴露塑造GI环境。因此，我们预测，由于农药暴露， 影响PD相关GI和CNS病理。在这里，我们将使用无菌（GF）小鼠作为工具，以确定 微生物组对农药引起的病理学的贡献。最重要的是，我们将确定 生态失调与农药暴露后产生的黑质纹状体功能障碍有关。结合微生物 影响与相关的毒物暴露，我们将测试这些外部影响的相互作用，在转基因 PD小鼠模型。这个拟议的项目将弥合我们对如何接触到 环境毒物影响神经退行性疾病的结果。我们假设肠道暴露于拟除虫菊酯 影响微生物组结构，从而调节炎症反应，并加重PD相关性 GI和黑质纹状体系统的结果。该项目将为发现微生物提供基础- 环境相互作用调节神经退行性疾病的风险。