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

帕金森病肠脑轴的分子和细胞基础

• 批准号: 10284432
• 负责人: Rachel Saunders-Pullman
• 金额: $ 50.68万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284432
• 关键词: AGFG1 gene; Address; Age of Onset; Applications Grants; Biological Markers; Brain; Cancer Center Planning Grant; Cells; Chemicals; Chronic; Chronic Disease; Clinical; Clinical Research; Colitis; Collaborations; Collection; Communication; Communities; Complex; Constipation; Data; Development; Disease; Disease Progression; Disease model; Etiology; Functional disorder; Future; Genetic; Genetic Predisposition to Disease; Goals; Grant; Heterogeneity; Hospitals; Hyperactivity; Immune; Immune response; Immune system; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inherited; Institutes; Intestines; Intramural Research; Investigation; Israel; LRRK2 gene; Leukocyte L1 Antigen Complex; Link; Mediating; Modeling; Molecular; Molecular Disease; Motor; Motor Manifestations; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Office of Administrative Management; Onset of illness; Outcome Study; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Predisposition; Preparation; Protein Kinase; Reporting; Research; Research Activity; Research Personnel; Research Project Grants; Risk; Role; Signal Pathway; Strategic Planning; Substantia nigra structure; Syndrome; Testing; Tissues; Variant; Work; alpha synuclein; base; cell type; comorbidity; disease heterogeneity; disorder subtype; feasibility research; gastrointestinal; gastrointestinal system; gut microbiome; gut microbiota; gut-brain axis; improved; inflammatory disease of the intestine; microbial; molecular marker; motor symptom; mouse model; multidisciplinary; non-motor symptom; novel; novel therapeutics; personalized medicine; protein complex; response; synergism; synucleinopathy; targeted treatment; therapeutic target; transmission process

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.

摘要（总体） 我们的P20应用程序旨在解决帕金森氏病（PD）的挑战，以解决令人难以置信的 疾病病因的复杂性和异质性。我们已经组装了一个拥有多学科的财团 专业知识和强大的协同作用将对PD致病性进行协作和综合研究 机制。结果将导致准备全面的Udall Center Grant应用程序（P50）。 我们的P20和未来P50应用的总体目标是确定与PD相关的亚型 前驱肠道慢性炎症，剖析肠脑轴的致病机制，并识别 PD亚型的分子生物标志物和新型疗法。我们的总体假设是（1）慢性 胃肠道系统中的炎症有助于PD的一部分，这是由致病性介导的 LRRK2和A-核蛋白之间的相互作用； （2）LRRK2充当信号通路的接口 导致PD和IBD，并研究LRRK2病理生理学将有助于阐明分子机制 用于PD发病机理中的肠道轴。为了检验这些假设，我们提出了三个高度 协同项目。这些项目基于强大的科学前提和承诺数据的收集 由所有调查人员生产。我们P20应用的战略计划是建立新的遗传LRK2 疾病模型和A核蛋白传播模型，以测试PD的肠脑轴假设（项目1和2）， 并确定肠道感染在多大程度上有助于PD的发展并确定 PD的亚型基于免疫失调的遗传敏感性水平（项目3）。项目1 使用新型遗传小鼠模型介导PD的肠脑轴的Decipher LRRK2病理生理学；项目 2。阐明LRRK2在PD胃肠道表现中的作用；项目3。了解 PD发病机理中遗传，微生物和肠炎性生物标志物的关系；我们的管理员核心 是为研究，管理，金融和沟通的所有活动提供中心支持 三个可行性研究项目和协作。