Molecular and Cellular Basis of the Gut-Brain Axis in Parkinsons Disease

摘要(总体) 我们的P20应用程序试图通过解决令人难以置信的问题来解决帕金森病(PD)尚未满足的挑战 疾病病因的复杂性和异质性。我们已经组建了一个由多学科组成的联盟 专业知识和强大的协同能力，将对帕金森病的致病机理进行协作和综合研究 机械装置。结果将导致准备一份全面的Udall中心赠款申请(P50)。这个 我们P20和未来P50应用的总体目标是确定与以下相关的PD亚型 前驱肠道慢性炎症，解剖支持肠脑轴的致病机制，并鉴定 分子生物标记物与帕金森病亚型的新疗法。我们的总体假设是：(1)慢性 胃肠道系统的炎症导致帕金森病的一部分，这是由致病因素介导的。 LRRK2与α-突触核蛋白的相互作用；(2)LRRK2作为信号通路的接口 导致PD和IBD，研究LRRK2的病理生理学有助于阐明其分子机制 为肠-脑轴在帕金森病发病机制中的作用。为了检验这些假设，我们提出了三个非常重要的假设 协同项目。这些项目基于强大的科学前提和对有希望的数据的收集 由所有调查人员出具。我们P20应用的战略计划是建立新的基因LRRK2 疾病模型和α-突触核蛋白传递模型，以检验帕金森病的肠道-脑轴假说(项目1和2)， 确定肠道炎症在多大程度上促进了帕金森病的发展，并确定了 基于免疫失调遗传易感性水平的帕金森病亚型(项目3)。项目1.至 利用新的遗传小鼠模型破译LRRK2在介导帕金森病肠道-脑轴中的病理生理学 2.阐明LRRK2在PD的胃肠道表现中的作用；方案3。了解LRRK2在PD的胃肠道表现中的作用 遗传、微生物和肠道炎症生物标志物在帕金森病发病机制中的关系 是为所有的研究、管理、财务和通信活动提供中央支持 三个可行性研究项目和协作。

Summary (Overall) Our P20 application seeks to address unmet challenges of Parkinson’s disease (PD) by addressing the incredible complexity and heterogeneity in the disease etiology. We have assembled a consortium with multidisciplinary expertise and strong synergy that will perform collaborative and integrated research on PD pathogenic mechanisms. The result will lead to the preparation of a full-scale Udall Center grant application (P50). The overarching goal of our P20 and future P50 application is to determine the subtypes of PD associated with prodromal gut chronic inflammation, dissect the pathogenic mechanism underpinning gut-brain axis, and identify molecular biomarkers and novel therapeutics for subtypes of PD. Our overall hypotheses are that (1) chronic inflammation in the gastrointestinal system contributes to a subset of PD, and this is mediated by pathogenic interaction between LRRK2 and a-synuclein; (2) LRRK2 acts as an interface for the signaling pathways that leads to PD and IBD, and investigation of LRRK2 pathophysiology will help elucidate the molecular mechanisms for the gut-brain axis in the pathogenesis of PD. To test these hypotheses, we have proposed three highly synergistic projects. These projects are based on strong scientific premise and collection of promising data produced by all investigators. The strategic plan for our P20 application is to establish novel genetic LRRK2 disease models and a-synuclein transmission models to test gut-brain axis hypothesis for PD (Project 1 and 2), and to determine to what extent intestinal inflammation contributes to the development of PD and identify subtypes of PD based on the levels of genetic susceptibility to immune dysregulation (Project 3). Project 1. To decipher LRRK2 pathophysiology in mediating gut-brain axis of PD using novel genetic mouse models; Project 2. To elucidate the role of LRRK2 in the gastrointestinal manifestation of PD; Project 3. To understand the relationship of genetic, microbial, and intestinal inflammatory biomarkers in PD pathogenesis; our Admin Core is to provide central support to all activities of research, administration, finance, and communications among the three feasibility research projects and collaboration.