Project 3 - Mechanistic studies on role of gut microbiome in models for Alzheimer's disease

项目 3 - 肠道微生物组在阿尔茨海默病模型中作用的机制研究

• 批准号: 10017880
• 负责人: Rima F Kaddurah-Daouk
• 金额: $ 43.02万
• 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/10017880
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Anxiety; Basic Science; Behavior; Behavior Disorders; Biological; Blood Circulation; Brain; Brain region; Cells; Clinical Data; Clinical Research; Cognition Disorders; Communication; Communities; Complex; Data; Data Set; Deposition; Development; Diagnostic; Disease; Disease Progression; Emotional disorder; Enteric Nervous System; Environment; Environmental Risk Factor; Etiology; Functional disorder; Gastrointestinal tract structure; Generations; Germ-Free; Gnotobiotic; Goals; Health; Human; Human Microbiome; Immune; Immunology; Impaired cognition; Inflammatory; Inheritance Patterns; Late Onset Alzheimer Disease; Lead; Life; Measures; Medical; Medicine; Memory Loss; Mental Depression; Metabolism; Microbe; Microbiology; Microglia; Molecular; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroimmune; Neurologic; Neuronal Dysfunction; Neurons; Neurosciences; Nociception; Organ; Outcome; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Patients; Peripheral; Pharmacotherapy; Play; Pre-Clinical Model; Research; Resources; Risk; Role; Sampling; Schizophrenia; Seminal; Sensory; Shapes; Signal Transduction; Site; Structure; Symptoms; Synapses; Testing; Transplantation; Travel; Treatment Efficacy; Vagus nerve structure; Validation; abeta accumulation; autism spectrum disorder; brain health; functional disability; gut bacteria; gut microbiome; gut-brain axis; immune system function; innovation; microbial; microbiome; microbiota transplantation; mouse model; nervous system disorder; neuroinflammation; neuron loss; novel; nutrition; pre-clinical research; psychologic; response; side effect

ABSTRACT – PROJECT 3 Sensory and molecular signals from the environment influence brain activity and help shape psychological or physical responses. The gastrointestinal (GI) tract represents our largest portal to the molecular world around us, and sends signals that travel to all organs of the body that impact their function, including the brain. Conduits used for gut-to-brain communication include, among others, metabolites produced in the gut that may activate the enteric nervous system (ENS) and signal via the vagus nerve, or molecules may even reach the brain through systemic circulation. However, there is remarkably little known about the cellular and molecular mechanisms that connect the gut to the brain. Further, if indeed the flow of complex signals from the gut modulates brain activity, perhaps changes due to altered environments may result in deviations from brain health. Humans share an intimate and life-long association with multitudes of resident microbial species, known as the microbiome, which represents a potentially strong environmental factor in may diseases. Gut bacteria regulate nutrition and metabolism, and orchestrate the development and function of the immune system. Intriguingly, the community structure and composition of the gut microbiome is altered in neurologic conditions such as anxiety, depression, autism spectrum disorder (ASD), schizophrenia, Parkinson’s disease (PD) and Alzheimer’s disease (AD). Whether these changes are a consequence of disease or a contributor remain entirely unknown. Studies that distinguish correlation from causation are both challenging and unjustified in humans. Thus, we propose to study the functional contributions of the human microbiome in novel mouse models of AD to test the hypothesis that microbial signals that travel from the gut to the brain promote neuroimmune activation, pathology, and symptoms of neurodegeneration. While basic and clinical research is rapidly defining the pathophysiology of AD, the cause(s) of most cases remain unknown. Thus, even the best medicines, which are relatively ineffective or have severe side effects, only address symptoms and are not disease-modifying. We provide seminal evidence that the gut microbiome is a key contributor to the pathology of AD using mouse models, offering entirely novel perspectives into disease etiology. Unraveling gut-microbiome-brain connections holds the promise of transforming the neurosciences and revealing potentially revolutionary diagnostics and treatments for Alzheimer’s disease.

摘要--项目3 来自环境的感觉和分子信号影响大脑活动，并帮助形成心理或 身体反应。胃肠道(GI)代表着我们通往分子世界的最大门户 并将信号传递到影响其功能的身体所有器官，包括大脑。 用于肠脑交流的管道包括在肠道中产生的代谢物 激活肠道神经系统(ENS)并通过迷走神经发出信号，或者分子甚至可能到达 大脑通过全身循环。然而，关于细胞和分子的研究却知之甚少 连接肠道和大脑的机制。此外，如果真的是来自肠道的复杂信号流 调节大脑活动，也许环境变化引起的变化可能导致偏离大脑 健康。人类与大量栖息的微生物物种有着密切的、终身的联系， 被称为微生物组，它代表了可能导致疾病的一个潜在的强大环境因素。肠 细菌调节营养和新陈代谢，协调免疫的发展和功能。 系统。有趣的是，肠道微生物群的群落结构和组成在神经学中发生了变化。 焦虑、抑郁、自闭症谱系障碍(ASD)、精神分裂症、帕金森氏症等 (PD)和阿尔茨海默病(AD)。无论这些变化是疾病的结果还是促成因素 完全不为人所知。区分相关性和因果关系的研究既具有挑战性，又具有挑战性 在人类身上是不合理的。因此，我们建议研究人类微生物组在功能上的贡献 新型阿尔茨海默病小鼠模型，以测试微生物信号从肠道传播到大脑的假设 促进神经免疫激活，改善病理，改善神经退行性变症状。虽然基础和临床 研究正在迅速明确AD的病理生理机制，但大多数病例的病因(S)尚不清楚。因此， 即使是最好的药物，相对无效或有严重的副作用，也只能治疗症状。 而且不能治疗疾病。我们提供了开创性的证据，证明肠道微生物群是 使用小鼠模型的AD的病理学，为疾病病因学提供了全新的视角。拆解 肠道-微生物-大脑连接有望改变神经科学并揭示 阿尔茨海默病的潜在革命性诊断和治疗。