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

总结（总体） 我们的P20应用程序旨在通过解决令人难以置信的问题来解决帕金森病（PD）的未满足挑战。 疾病病因的复杂性和异质性。我们已经组建了一个多学科的财团， 专业知识和强大的协同作用，将执行合作和综合研究PD致病 机制等结果将导致一个全面的尤德尔中心赠款申请（P50）的准备。的 我们的P20和未来P50应用的首要目标是确定与以下疾病相关的PD亚型： 前驱期肠道慢性炎症，剖析肠-脑轴的致病机制， 分子生物标志物和新的治疗方法。我们的总体假设是：（1）慢性 胃肠系统中的炎症导致PD的一个子集，并且这是由致病性炎症介导的。 LRRK 2和α-突触核蛋白之间的相互作用;（2）LRRK 2作为信号通路的界面， 导致PD和IBD，对LRRK 2病理生理学的研究将有助于阐明其分子机制 肠-脑轴在PD发病机制中的作用。为了验证这些假设，我们提出了三个高度 协同项目。这些项目是基于强有力的科学前提和收集有希望的数据 由所有调查人员制作。我们的P20应用的战略计划是建立新的遗传LRRK 2 疾病模型和α-突触核蛋白传递模型以测试PD的肠-脑轴假设（项目1和2）， 并确定肠道炎症在多大程度上有助于PD的发展， 基于免疫失调的遗传易感性水平的PD亚型（项目3）。项目1。到 使用新型遗传小鼠模型解读LRRK 2在介导PD肠-脑轴中的病理生理学;项目 2.阐明LRRK 2在PD胃肠道表现中的作用;项目3。了解 PD发病机制中遗传、微生物和肠道炎症生物标志物的关系;我们的管理核心 是提供中央支持的所有活动的研究，行政，财务和通信之间的 三个可行性研究项目和合作。

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.