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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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