Alzheimer's Gut Microbiome Project

阿尔茨海默氏症肠道微生物组项目

• 批准号: 10251258
• 负责人: ROB KNIGHT
• 金额: $ 532.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251258
• 关键词: 3xTg-AD mouse; Affect; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; American; Amines; Animal Model; Bacteria; Behavior Disorders; Bile Acids; Biochemical; Biological Models; Blood; Brain; Brain imaging; Cells; Central Nervous System Diseases; Chemicals; Clinical; Cognition; Cognition Disorders; Cognitive; Communication; Communities; Computational Biology; Controlled Clinical Trials; Data; Data Analyses; Data Set; Dementia; Depressed mood; Development; Diet; Disease; Disease Progression; Emotional disorder; Environmental Exposure; Etiology; FAIR principles; Failure; Food; Generations; Genetic; Goals; Health; Heterogeneity; Human; Human Microbiome; Image; Immune system; Immunologics; Informatics; Infrastructure; Intervention; Knowledge; Lead; Life Style; Link; Lipids; Manipulative Therapies; Mediating; Mental Depression; Mental disorders; Metabolic; Metabolism; Metagenomics; Methodology; Microbe; Multiple Sclerosis; Mus; Nervous system structure; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurotransmitters; Parkinson Disease; Pathogenesis; Pathology; Patients; Peripheral; Persons; Pharmacology; Phenotype; Play; Pre-Clinical Model; Process; Prognosis; Research; Resources; Role; Schizophrenia; Symptoms; Systems Biology; Technology; Translations; Viral; Volatile Fatty Acids; Work; Xenobiotics; autism spectrum disorder; base; biobank; cohort; cytotoxic; deep learning; dietary; disease heterogeneity; disease phenotype; drug development; endophenotype; fecal metabolome; gut bacteria; gut microbiome; gut-brain axis; improved; insight; metabolome; metabolomics; microbiome; microbiome alteration; microbiome composition; microbiome research; multidisciplinary; nervous system disorder; neuropsychiatric disorder; neuropsychiatric symptom; new therapeutic target; novel marker; novel strategies; novel therapeutics; open data; phenotypic biomarker; pre-clinical; precision medicine; prevent; programs; public health relevance; repository; response; socioeconomics; symposium

ABSTRACT – Overall Behavioral, emotional and cognitive disorders have been historically studied as diseases of the central nervous system (CNS). However, emerging data suggests a gut-brain connection in a variety of diseases that affect the brain. Our own data and others’ suggests a gut-brain connection in Alzheimer’s disease (AD), a progressive neurodegenerative disorder that is the leading cause of dementia. There are currently no therapies to prevent or slow AD progression, causing a huge socioeconomic burden and highlighting our incomplete knowledge. Given an emerging role for gut microbiome and hypotheses implicating viral and bacterial contributions to AD pathogenesis, defining the bidirectional biochemical communication between the brain and the gut will improve understanding of neurodegenerative and psychiatric diseases. Indeed, it is crucial to study the brain not in isolation, but in the context of peripheral influences including diet, lifestyle, and microbiome. In this proposal we build on large initiatives and infrastructures co-established by our multi-disciplinary team including: The American Gut Project, The AD Metabolomics Consortium, Alzheimer’s Disease Research Centers (ADRCs), National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), The National Alzheimer’s Coordinating Center (NACC) and centers of excellence in informatics and systems biology. We aim to define the role of gut microbiome in AD pathogenesis and biochemical axis of communication between gut and brain. Aim 1: Examine the association between the gut microbiome and AD phenotypes. Aim 2: Define the biochemical axis of communication between the gut microbiome and the brain and identify metabolites that contribute to AD endophenotypes. Aim 3: Examine mechanistic links between the activity of the gut microbiome and AD pathogenesis, and identify new approaches for AD prevention that target the gut-brain axis. These aims will be enabled three projects supported by an Omics and Technology Core, a Computational and Systems Biology Core, and an Administrative Core that provides data and biorepository infrastructure. Project 1 will define changes in gut microbiome and metabolome across the AD trajectory; Project 2 leverages three existing clinical trials of controlled diets to examine dietary effects on gut microbiome, metabolome, cognition and brain imaging; Project 3 examines mechanism by defining gut- brain communication and microbiome-based interventions in animal models of AD. In this U19 we will create an unprecedented, high-quality dataset and resources specifically for the AD research community, and make these available under open science, FAIR (findable, accessible, interoperable, reusable) data principles. With our cross-disciplinary team of experts in clinical AD, gut microbiome research, imaging, metabolomics, informatics, deep learning and systems biology, this effort will yield novel biomarkers for AD progression and prognosis, and insight into mechanisms opening the door to development of transformative options for AD.

摘要——总体 行为、情绪和认知障碍历来被视为中枢神经疾病进行研究 系统（中枢神经系统）。然而，新出现的数据表明，影响肠道菌群的多种疾病都存在肠脑联系。 脑。我们自己的数据和其他人的数据表明，阿尔茨海默病 (AD) 中存在肠脑联系，这是一种进行性的疾病 神经退行性疾病是痴呆症的主要原因。目前尚无治疗方法可以预防 或者缓慢的 AD 进展，造成巨大的社会经济负担并凸显我们的知识不完整。 鉴于肠道微生物组的新兴作用以及病毒和细菌对 AD 影响的假设 发病机制，定义大脑和肠道之间的双向生化通讯将改善 了解神经退行性疾病和精神疾病。事实上，研究大脑至关重要，而不是在 隔离，但在饮食、生活方式和微生物组等外围影响的背景下。在这个提案中我们 以我们的多学科团队共同建立的大型举措和基础设施为基础，包括： 美国肠道项目、AD 代谢组学联盟、阿尔茨海默病研究中心 (ADRC)、 国家阿尔茨海默病和相关痴呆症中央存储库 (NCRAD) 阿尔茨海默病协调中心 (NACC) 以及信息学和系统生物学卓越中心。我们 旨在明确肠道微生物组在 AD 发病机制中的作用以及 AD 之间通讯的生化轴 肠道和大脑。目标 1：检查肠道微生物组与 AD 表型之间的关联。目标 2： 定义肠道微生物组和大脑之间通讯的生化轴并识别 有助于 AD 内表型的代谢物。目标 3：检查各因素之间的机制联系 肠道微生物组的活性和 AD 发病机制，并确定预防 AD 的新方法 以肠脑轴为目标。这些目标将由组学支持的三个项目实现， 技术核心、计算和系统生物学核心以及提供数据的管理核心 和生物样本库基础设施。项目 1 将定义整个肠道微生物组和代谢组的变化 AD轨迹；项目 2 利用三项现有的控制饮食临床试验来检查饮食对 肠道微生物组、代谢组、认知和脑成像；项目 3 通过定义肠道来检查机制 AD 动物模型中的大脑通讯和基于微生物组的干预措施。在这个U19中我们将创造 专门针对 AD 研究界的前所未有的高质量数据集和资源，并使得 这些都是根据开放科学、公平（可查找、可访问、可互操作、可重用）数据原则提供的。和 我们的跨学科专家团队涵盖临床 AD、肠道微生物组研究、成像、代谢组学、 信息学、深度学习和系统生物学，这项工作将产生 AD 进展的新型生物标志物， 预后，以及对机制的深入了解，为开发 AD 变革性选择打开了大门。