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.

项目总结