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.

项目摘要农药暴露是许多神经退行性疾病的重要危险因素，包括帕金森氏症疾病（PD）。散发性PD，没有已知病因的占疾病事件的约90％，因为高度渗透率遗传风险不是很普遍。实验模型在很大程度上阐明了分子机制在PD期间，农药直接暴露于那些易受伤害的神经元。例如，暴露于鱼藤酮和 MPTP用于诱导啮齿动物中的黑质神经元丧失。而这些暴露对中央的影响神经系统（CNS）已经探索，PD相关的外围器官中的暴露结果，例如肠子在很大程度上未知。胃肠道（GI）功能障碍，例如便秘和炎症肠道疾病通常是在PD诊断之前的，并且在某些CNS病理学之前出现GI神经的丧失 PD誉人群。胃肠道病理可能会在PD中表明CNS功能障碍的发作。在胃肠道中，在PD期间建立了对微生物组（即营养不良）的改变，并具体发生。细菌分类群的改变与疾病严重程度相关。营养不良不仅是epiphenomenon，而且有生理上对宿主的影响，特别是在PD的背景下。肠道注射和营养不良是足以加剧PD动物模型中的病理和运动功能障碍。有趣的是，PD- 衍生的微生物组富含参与异种生物代谢的细菌基因，表明农药暴露塑造GI环境。因此，我们预测，农药暴露导致的营养不良，影响与PD相关的GI和CNS病理。在这里，我们将使用无细菌（GF）小鼠作为工具来确定微生物组对农药诱导的病理的贡献。最重要的是，我们将确定营养不良的染色体功能障碍是农药暴露后出现的。结合微生物与相关毒物暴露的影响，我们将测试这些外部影响在转基因中的相互作用 PD的鼠标模型。这个拟议的项目将弥合我们对暴露如何接触的差距环境有毒物质会影响神经退行性结果。我们假设肠道拟除虫菊酯暴露影响微生物组体系结构，该体系结构调节炎症反应，并加剧PD相关性 gi和nigrostriatal系统的结果。该项目将为发现微生物 - 调节神经退行性疾病风险的环境相互作用。