Investigating the role of myenteric macrophages in enteric synucleinopathy

项目摘要/摘要：肠源性突触核病的特征是错误折叠的α沉积。 突触核蛋白聚集在肠神经细胞中，并导致长期的胃肠功能障碍。肠源性 联核病也被认为是中枢神经系统联核病的先兆，如帕金森氏病(PD)， PD痴呆和路易体痴呆，这是一组衰弱的神经退行性疾病， 导致运动、认知和自主神经功能障碍。值得注意的是，即使在中枢神经系统合并性核病发展之后 胃肠道症状仍然是这些患者发病的主要原因。然而，一个不太了解的人 在发育和进展的基础上的细胞过程已经排除了任何旨在 防止联核症进展到大脑或缓解胃肠功能障碍。在中枢神经系统中 驻留的巨噬细胞，即小胶质细胞，对突触核病有显著的影响。肠神经细胞- 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， 它们的表型和在肠型联核病中的作用尚不明确。因此，这项提案的目的是寻求 明确肠神经相关巨噬细胞如何促进或缓解神经病理和 肠并核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 肠源性突触核素病小鼠模型的病理学。在这里，我将描述巨噬细胞参与的特征 在肠源性、磷酸化α-突触核蛋白的发展和扩散中的神经病理和免疫定义 与这个州相关的转录景观。我对这一目标的工作假设是，一个亚种群 巨噬细胞最初摄取α-突触核蛋白以减轻病理并采用抗原提呈表型 激活T细胞 目的2：确定肌间巨噬细胞如何调节肠神经网络的功能和功能 肠道突触核病小鼠模型的结构连通性。肌间巨噬细胞的变化 表型和α-突触核蛋白病理已被证明可导致肠神经网络功能障碍和肠道 运动障碍是独立的，但在肠源性突触核病的背景下它们是如何协同工作的仍然存在 未知。更具体地说，肌间巨噬细胞是否介导了α-突触核蛋白对网络的影响 连通性和网络输出尚未进行调查。因此，我对这个目标的工作假设是α- 突触核蛋白病理将促使肌间巨噬细胞过度依赖补体 突触修剪导致肠神经网络活动中断。总之，这些实验将揭示 神经免疫相互作用如何影响联体核病的早期阶段。

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.