Investigating the role of myenteric macrophages in enteric synucleinopathy

研究肌间巨噬细胞在肠突触核蛋白病中的作用

• 批准号: 10678094
• 负责人: Phillip Mackie
• 金额: $ 4.19万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2026-05-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678094
• 关键词: Address; Adopted; Affect; Age; Aging; Antigen Presentation; Atlases; Automobile Driving; Autonomic Dysfunction; Biological Assay; Braak' s hypothesis; Brain; Calcium; Cell physiology; Cells; Central Nervous System; Complement; Dementia; Deposition; Development; Disease; Disease Progression; Enteral; Etiology; Event; Functional disorder; Future; Genetic Transcription; Goals; Image; Immune; Immune response; Immune system; Impaired cognition; Inflammatory; Inflammatory Response; Injections; Intestines; Investigation; Lewy Body Dementia; Macrophage; Mediating; Microglia; Microscopy; Molecular; Morbidity - disease rate; Movement Disorders; Myelogenous; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neuroimmune; Neuronal Dysfunction; Neurons; Outcomes Research; Output; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathology; Patients; Phagocytes; Phenotype; Phosphorylation; Physicians; Population; Prevalence; Prevention; Preventive treatment; Process; Resources; Rest; Risk Factors; Role; Scientist; Sentinel; Source; Synapses; T-Cell Activation; Testing; Time; Training; Translational Research; Vagus nerve structure; Work; alpha synuclein; brain pathway; career; economic cost; experimental study; gastrointestinal; gastrointestinal symptom; motility disorder; motor disorder; mouse model; multi-photon; network dysfunction; neuropathology; neurophysiology; novel; palliate; prevent; response; single-cell RNA sequencing; synaptic pruning; synucleinopathy; therapeutic candidate; therapeutic target

Project Summary/Abstract: Enteric synucleinopathy is characterized by the deposition of misfolded α- synuclein aggregates in enteric neurons and induces long-term gastrointestinal dysfunction. Enteric synucleinopathy is also thought to be a precursor to CNS synucleinopathies, such as Parkinson’s’ Disease (PD), PD-Dementia, and Lewy Body Dementia, a collective group of debilitating neurodegenerative disorders that cause motor, cognitive, and autonomic dysfunction. Notably, even after development of CNS synucleinopathy gastrointestinal symptoms remain as major causes of morbidity in these patients. However, a poor understanding of the cellular processes underlying development and progression has precluded any therapies aimed at preventing synucleinopathy progression into the brain or mitigating GI dysfunction. In the central nervous system resident macrophages, the microglia, can have pronounced impact on synucleinopathy. Enteric neuron- associated macrophages resemble microglia at rest in that they support nearby neurons. But unlike microglia, their phenotype and role in enteric synucleinopathy is undefined. Therefore, the Aims of this proposal seek to define how enteric neuron associated macrophages promote or palliate the neuropathological and neurophysiological aspects of enteric synucleinopathy. Aim 1: Explicate the macrophage subpopulations that influence spread of phosphorylated α-synuclein pathology in a mouse model of enteric synucleinopathy. Herein, I will characterize macrophage involvement in the development and spread of enteric, phosphorylated α-synuclein neuropathology and define the immune transcriptional landscape associated with this state. My working hypothesis for this aim is that a sub-population of macrophages initially take up α-synuclein to mitigate pathology and adopt an antigen-presentation phenotype to activate T-cells Aim 2: Determine how myenteric macrophages modulate enteric neuronal network functional and structural connectivity in a mouse model of enteric synucleinopathy. Alterations in myenteric macrophage phenotype and α-synuclein pathology have been shown to induce enteric neuronal network dysfunction and gut dysmotility independently, but how they work in concert in the setting of enteric synucleinopathy remains unknown. More specifically, whether myenteric macrophages mediate α-synuclein’s effects on network connectivity and network output has not been investigated. Thus, my working hypothesis for this aim is that α- synuclein pathology will prompt myenteric macrophages to engage in excessive, complement-dependent synaptic pruning leading to disrupted enteric neuronal network activity. Together, these experiments will reveal how neuro-immune interactions influence the early stages of synucleinopathies.

项目概要/摘要：肠突触核蛋白病的特征是错误折叠的α- 突触核蛋白在肠神经元中聚集并诱导长期胃肠功能障碍。肠溶 突触核蛋白病也被认为是CNS突触核蛋白病，如帕金森病（PD）， PD-痴呆症和路易体痴呆症，一组衰弱性神经退行性疾病， 导致运动认知和自主神经功能紊乱值得注意的是，即使在发生CNS突触核蛋白病后， 胃肠道症状仍然是这些患者发病的主要原因。然而，一个贫穷的理解 的细胞过程的潜在发展和进展已经排除了任何治疗， 防止突触核蛋白病进展到大脑或减轻GI功能障碍。中枢神经系统中 常驻巨噬细胞，即小胶质细胞，可对突触核蛋白病具有显著影响。肠神经元 相关的巨噬细胞类似于静止的小胶质细胞，因为它们支持附近的神经元。但与小胶质细胞不同， 它们的表型和在肠突触核蛋白病中的作用是不确定的。因此，本建议的目的是 定义肠神经元相关巨噬细胞如何促进或减轻神经病理学和 肠突触核蛋白病的神经生理学方面。 目的1：阐明影响磷酸化α-突触核蛋白扩散的巨噬细胞亚群 在肠突触核蛋白病的小鼠模型中的病理学。在此，我将描述巨噬细胞参与 在肠道，磷酸化α-突触核蛋白神经病理学的发展和传播中， 与这种状态相关的转录景观。我的工作假设是， 的巨噬细胞最初摄取α-突触核蛋白以减轻病理并采用抗原呈递表型 活化t细胞 目的2：确定肌间巨噬细胞如何调节肠神经元网络功能， 肠突触核蛋白病小鼠模型中的结构连接性。肌间巨噬细胞的变化 表型和α-突触核蛋白病理学已显示诱导肠神经元网络功能障碍和肠 运动障碍独立，但如何在肠道突触核蛋白病的背景下协同工作仍然存在 未知更具体地说，肌间巨噬细胞是否介导α-突触核蛋白对网络的影响， 连接性和网络输出尚未被研究。因此，我对这一目标的工作假设是α- 突触核蛋白病理学将促使肌间巨噬细胞参与过度的补体依赖性免疫反应， 突触修剪导致肠神经元网络活动中断。这些实验将揭示 神经免疫相互作用如何影响突触核蛋白病的早期阶段。