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会影响大脑活动，并有助于塑造心理或 身体反应。胃肠道（GI）区域代表了我们周围分子世界的最大门户 我们，并发送信号传播到影响其功能（包括大脑）的身体的所有器官。 用于肠道通信的导管包括肠道中产生的代谢物，可能 通过迷走神经激活肠神经系统（ENS）和信号，或者分子甚至可能到达 大脑通过全身循环。但是，关于细胞和分子的知之甚少 将肠道连接到大脑的机制。此外，如果确实确实是肠道的复杂信号的流动 调节大脑活动，也许由于环境改变而导致的变化可能导致脑离开 健康。人类与众多居民微生物物种有亲密而终身的联系， 被称为微生物组，它代表了可能的疾病中潜在强大的环境因素。肠 细菌调节营养和代谢，并策划免疫的发育和功能 系统。有趣的是，肠道微生物组的社区结构和组成在神经系统中发生了变化 焦虑，抑郁，自闭症谱系障碍（ASD），精神分裂症，帕金森氏病等疾病 （PD）和阿尔茨海默氏病（AD）。这些变化是疾病的结果还是贡献者 保持完全未知。区分相关性与因果关系的研究既是挑战，又是 人类不合理。这，我们建议研究人类微生物组在 AD的新型小鼠模型，以测试从肠道传播到大脑的微生物信号的假设 促进神经免疫性激活，病理和神经退行性的症状。虽然基本和临床 研究正在迅速定义AD的病理生理学，大多数病例的原因仍然未知。那， 即使是相对无效或具有严重副作用的最好的药物，也只能解决症状 并且不是调整疾病。我们提供了第二个证据，表明肠道微生物组是造成的关键因素 使用小鼠模型的AD病理学，将疾病病因的完全新颖的观点提供给。解开 肠道 - 微生物组 - 脑连接有望改变神经科学并揭示 阿尔茨海默氏病的潜在革命性诊断和治疗方法。