Alzheimer's Gut Microbiome Project

阿尔茨海默氏症肠道微生物组项目

• 批准号: 9794999
• 负责人: ROB KNIGHT
• 金额: $ 569.02万
• 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/9794999
• 关键词: 3xTg-AD mouse; Affect; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; 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; Research; Resources; Role; Schizophrenia; Symptoms; Systems Biology; Technology; Translations; Viral; Volatile Fatty Acids; Work; Xenobiotics; autism spectrum disorder; base; biobank; cohort; cytotoxic; deep learning; 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; outcome forecast; 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，情感和认知障碍历史上一直是中枢神经的疾病 系统（CNS）。但是，新兴的数据表明，各种影响该疾病的肠道连接 脑。我们自己的数据和其他人建议在阿尔茨海默氏病（AD）中建立肠道连接 神经退行性疾病是痴呆的主要原因。目前没有疗法可以预防 或慢慢的AD进展，导致巨大的社会经济燃烧并突出我们的不完整知识。 鉴于肠道微生物组的新作用，并假设隐式病毒和细菌对AD的贡献 发病机理，定义大脑与肠道之间的双向生化交流将改善 了解神经退行性和精神疾病。确实，研究大脑不在 隔离，但在外围影响的背景下，包括饮食，生活方式和微生物组。在这个建议中，我们 建立在我们的多学科团队共同建立的大型计划和基础架构的基础上，包括： 美国肠道项目，AD代谢组学联盟，阿尔茨海默氏病研究中心（ADRCS）， 国家中央集中库的阿尔茨海默氏病和相关痴呆症（NCRAD），国家 阿尔茨海默氏症协调中心（NACC）和信息和系统生物学卓越中心。我们 旨在定义肠道微生物组在AD发病机理和生化轴之间的作用 肠和大脑。目标1：检查肠道微生物组和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信的生化轴并识别 有助于AD内表型的代谢产物。目标3：检查 肠道微生物组和AD发病机理的活性，并确定预防AD的新方法 该靶向肠道轴。这些目标将启用由OMICS支持的三个项目， 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 和生物设施基础架构。项目1将定义肠道微生物组和代谢组的变化 广告轨迹；项目2利用受控饮食的三项现有临床试验来检查对饮食的影响 肠道微生物组，代谢组，认知和脑成像；项目3考试机制通过定义肠道 AD动物模型中的大脑通信和基于微生物组的干预措施。在这个U19中，我们将创建 专门为广告研究界的空前，高质量的数据集和资源 这些可在开放科学，公平（可访问，可互操作，可重复使用的）数据原理下可用。和 我们的跨学科临床广告专家团队，肠道微生物组研究，成像，代谢组学， 信息，深度学习和系统生物学，这种努力将产生新颖的生物标志物，以进行广告的发展和 预后和对机制的洞察力为开发AD的变革选择开发了大门。