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

项目摘要 接触杀虫剂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)。散发性帕金森病，原因不明，约占疾病发病率的90%，是高度渗透性的 遗传风险并不是很普遍。实验模型已在很大程度上阐明了分子机制。 农药直接暴露在帕金森病易受伤害的神经元上。例如，接触鱼藤酮和 MPTP被用来诱导啮齿动物黑质纹状体神经元的丢失。虽然这些暴露对中央动脉的影响 神经系统(CNS)已被探索，与PD相关的暴露在外围器官的结果，如 肠道，在很大程度上是未知的。胃肠(GI)功能障碍，如便秘和炎症 肠道疾病通常先于帕金森病的诊断，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之前 易患帕金森病的人群。胃肠道病理可能是帕金森病患者中枢神经系统功能障碍发生的信号。 在胃肠道内，微生物群的改变(即生物失调)在PD期间被确定为出现，并且特定的 细菌分类群的改变与疾病的严重程度相关。生物失调不只是一种附生现象，而是 对寄主的生理影响，特别是在帕金森病的背景下。肠道炎症和生物失调是 足以加重帕金森病动物模型的中枢神经系统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物代谢的细菌基因，表明农药 暴露塑造了胃肠道环境。因此，我们预测，由于接触杀虫剂而导致的生物失调， 影响与PD相关的胃肠道和中枢神经系统的病理。在这里，我们将使用无菌(GF)小鼠作为工具来确定 微生物组在农药致病中的作用。最重要的是，我们将确定 因接触杀虫剂而引起的已确定的黑质纹状体功能障碍的生物失调。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的相互作用在转基因 帕金森病小鼠模型。这项拟议的项目将弥合我们对如何接触到 环境毒物会影响神经退化的结果。我们假设肠道接触拟除虫菊酯 影响微生物群结构，后者调节炎症反应，并加剧与PD相关的 胃肠道和黑质纹状体系统的转归。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。

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.