Alzheimer's Gut Microbiome Project

摘要--总体 行为、情绪和认知障碍历来被作为中枢神经疾病进行研究 系统(CNS)。然而，新出现的数据表明，肠道和大脑之间的联系在各种疾病中都会影响到 大脑。我们自己的数据和其他人的数据表明，阿尔茨海默病(AD)的肠道和大脑之间存在联系，这是一种进行性的 神经退行性疾病是痴呆症的主要原因。目前还没有可以预防的疗法。 或者减缓AD的进展，造成巨大的社会经济负担，并突显我们知识的不完整。 考虑到肠道微生物群的新兴作用和暗示病毒和细菌对AD的贡献的假设 发病机制，定义大脑和肠道之间的双向生化通讯将得到改善 了解神经退行性疾病和精神疾病。事实上，研究大脑是至关重要的，而不是在 与世隔绝，但在包括饮食、生活方式和微生物群在内的外围影响的背景下。在这份提案中，我们 以我们的跨专业团队共同建立的大型计划和基础设施为基础，包括： 美国肠道计划、AD代谢组学联盟、阿尔茨海默病研究中心(ADRC)、 国家阿尔茨海默病及相关痴呆中央资料库(NCRAD) 阿尔茨海默氏症协调中心(NACC)以及信息学和系统生物学方面的卓越中心。我们 目的明确肠道微生物组在阿尔茨海默病发病机制中的作用及生化轴之间的联系 肠子和大脑。目的1：研究肠道微生物组与AD表型之间的关系。目标2： 确定肠道微生物群和大脑之间的生物化学轴，并确定 有助于AD内表型的代谢物。目标3：检查机构之间的联系 肠道微生物群的活动与AD的发病机制，并寻找预防AD的新方法 以肠道-脑轴为靶点。这些目标将由OMICS和OMICS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 和生物库基础设施。项目1将定义肠道微生物组和代谢组的变化 AD轨迹；项目2利用现有的三个受控饮食的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- 阿尔茨海默病动物模型的脑通讯和基于微生物组的干预。在这部U19中，我们将创造 专为AD研究社区提供的史无前例的高质量数据集和资源， 这些数据是在开放科学、公平(可发现、可访问、可互操作、可重复使用)数据原则下获得的。使用 我们的跨学科专家团队在临床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，这一努力将产生AD进展和 预测，洞察打开AD变革性选择之门的机制。

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.