Understanding the role of LRRK2 G2019S-mediated gut-brain axis in the pathogenesis of Parkinson's disease

了解 LRRK2 G2019S 介导的肠脑轴在帕金森病发病机制中的作用

• 批准号: 10584197
• 负责人: Zizhen Kang
• 金额: $ 42.49万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10584197
• 关键词: Acute; American; Animal Model; Bacterial Infections; Brain; Cells; Chemicals; Chronic; Cohort Studies; Colitis; DNA Sequence Alteration; Development; Disease; Disease model; Enteral; Environment; Environmental Risk Factor; Ethnic group; Etiology; Exhibits; Gastrointestinal tract structure; Genetic; Goals; Human; Immune; Immune response; Impairment; Incidence; Individual; Infection; Inflammasome; Inflammation; Inflammatory Bowel Diseases; Interleukin-1 beta; Investigation; Kidney; Knock-in; Knock-in Mouse; LRRK2 gene; Lung; Mediating; Modeling; Mus; Mutation; Neurodegenerative Disorders; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Patients; Penetrance; Persons; Pharmaceutical Preparations; Phosphotransferases; Play; Population Study; Production; Proteins; Reporting; Research; Risk; Role; Salmonella typhimurium; Serum; Signal Transduction; Symptoms; System; Testing; Translations; Variant; autoinflammatory; cilium biogenesis; dysbiosis; exome sequencing; gain of function; gastrointestinal infection; genetic variant; genome wide association study; gut dysbiosis; gut inflammation; gut-brain axis; high risk; human old age (65+); motor symptom; mutant; novel; pathogen; population based

Project Summary: Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world, with over 1 million Americans currently suffering from PD. The risk of PD increases greatly in people over the age of 65 years. Both genetic and environmental factors are known to contribute to the pathogenesis of PD. Among these, LRRK2-G2019S is the most prevalent, being found in a wide range of ethnic groups and in 1-3% of sporadic and 4-8% of familial PD cases. However, how LRRK2-G2019S promotes the pathogenesis of PD remains largely unknown. Surprisingly, G2019S knockin(KI) mice only develop pre-symptoms of PD, suggesting other triggers are needed for the pathogenesis. We recently reported a crucial role for LRRK2 in the activation of NLRC4 inflammasome and subsequent production of IL-1β. A recent study showed that increased serum levels of IL-1β effectively identified asymptomatic LRRK2-G2019S carriers from noncarriers in humans and higher IL-1β concentration in the serum predicted increased risk for developing PD among the asymptomatic carriers, suggesting that inflammasome activation might play critical roles in PD pathogenesis. Of note, numerous studies have identified pathophysiological changes in the gastrointestinal tract in PD patients preceding the development of motor symptoms. PD patients have higher incidence of gut dysbiosis, and gut dysbiosis promotes PD pathogenesis in animal models. Furthermore, IBD patients have 20–90% higher risk of developing PD. Intriguingly, a recent finding unraveled novel pathogenic LRRK2 variants shared by both IBD and PD, suggesting LRRK2 might bridge the gut-brain axis in PD pathogenesis. We thus hypothesize that second hit-induced LRRK2-mediated intestinal inflammation promotes the PD penetrance in the predisposed LRRK2-G2019S KI model. The objective of our study is to test the “two-hit” model for PD etiology in LRRK2-G2019S KI mice and establish novel PD models through gut-brain axis. Our long-term goal is to understand the underlying mechanisms of the LRRK2-mediated gut-brain axis in the pathogenesis of PD. We will test our hypothesis with two specific aims: Aim 1, Establish a model for investigation of the role of LRRK2-mediated enteric NLRC4 inflammasome activation in the pathogenesis of PD; Aim 2, Establish a model for investigation of the role of LRRK2-mediated colitis in the pathogenesis of PD. Completion of this project will provide novel PD models through gut-brain axis for further understanding of the role of LRRK2- mediated gut-brain axis in the pathogenesis of PD.

项目概要： 帕金森病（Parkinson's disease，PD）是世界上第二常见的神经退行性疾病， 目前，美国有100万人患有PD。65岁以上的人患PD的风险大大增加 年已知遗传和环境因素均有助于PD的发病机制。之间 其中，LRRK 2-G2019 S是最普遍的，在广泛的种族群体中发现， 散发和4-8%的家族性PD病例。然而，LRRK 2-G2019 S如何促进PD的发病机制， 仍然是未知的。令人惊讶的是，G2019 S敲入（KI）小鼠仅发展PD的前症状， 这表明发病机制还需要其他诱因。我们最近报道了LRRK 2在 NLRC 4炎性体的激活和随后IL-1β的产生。最近的一项研究表明， 血清IL-1β水平升高可有效鉴别无症状LRRK 2-G2019 S携带者和非携带者 在人类中，血清中较高的IL-1β浓度预测了PD发生的风险增加， 无症状携带者，表明炎性小体激活可能在PD发病机制中起关键作用。 值得注意的是，许多研究已经确定了PD患者胃肠道的病理生理学变化， 运动症状出现前的患者。PD患者的肠道生态失调发生率较高， 并且肠道生态失调促进动物模型中的PD发病。此外，IBD患者有20-90% 发展PD的风险更高。有趣的是，最近的一项发现揭示了新的致病性LRRK 2变体， 提示LRRK 2可能在PD发病机制中起桥梁作用。我们因此 假设第二次打击诱导的LRRK 2介导的肠道炎症促进了PD发病率， LRRK 2-G2019 S KI型号。本研究的目的是检验帕金森病的“二次打击”模型 在LRRK 2-G2019 S KI小鼠中进行病因学研究，并通过肠-脑轴建立新的PD模型。我们的长期 目的是了解LRRK 2介导的肠-脑轴在发病机制中的潜在机制 的PD。我们将从两个具体的目标来检验我们的假设：目标1，建立一个调查角色的模型 LRRK 2介导的肠道NLRC 4炎性小体激活在PD发病机制中的作用;目的2，建立一个 用于研究LRRK 2介导的结肠炎在PD发病机制中的作用的模型。完成本 该项目将通过肠-脑轴提供新的PD模型，以进一步了解LRRK 2- 介导的肠-脑轴在PD发病机制中的作用。