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Development of in vivo quantitative stable isotope probing to quantify microbiome dynamics in Alzheimers Disease

开发体内定量稳定同位素探测以量化阿尔茨海默病微生物组动态

基本信息

批准号：
10473765
负责人：
Emily K Cope
金额：
$ 19万
依托单位：
NORTHERN ARIZONA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473765
关键词：
16S ribosomal RNA sequencing 3xTg-AD mouse AD transgenic mice Address Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Amyloidosis Bacteria Blood - brain barrier anatomy Brain Cardiovascular system Cessation of life Communities DNA DNA sequencing Data Death Rate Dementia Density Gradient Centrifugation Deposition Development Disease Progression Ecology Ecosystem Elderly Enteric Nervous System Etiology Exhibits Gastrointestinal tract structure Goals Growth Health Human Human Microbiome Human body Immune Immune system Individual Inflammatory Isotope Labeling Isotopes Label Longitudinal Studies Measures Methods Microbe Mouse Strains Mus Nature Nerve Degeneration Neurofibrillary Tangles Neurologic Neurotransmitters Nucleic Acids Pathogenesis Pathologic Pathology Patients Phase III Clinical Trials Population Population Dynamics Process Production Proteins Quality of life RNA Research Research Personnel Role Senile Plaques Severities Shotguns Soil Structure Tauopathies Taxon Techniques Technology Time Transgenic Organisms Vagus nerve structure Volatile Fatty Acids Water Wild Type Mouse abeta accumulation aging population base beta pleated sheet blood-brain barrier crossing cognitive function density disorder prevention disorder risk gut microbiome gut microbiota gut-brain axis host microbiome host-associated microbial communities human disease human microbiota in vivo innovation insight interest member metagenomic sequencing microbial microbial community microbial host microbiome microbiome composition microbiome research microbiome sequencing microbiota microorganism mouse model neuroinflammation neuropathology new technology novel pathogenic microbe stable isotope tool vagus nerve stimulation β-amyloid burden

项目摘要

ABSTRACT Alzheimer’s Disease (AD) is the leading cause of dementia in the aging population and severely impacts patient’s and caretaker’s quality of life. Despite decades of research, the underlying etiology of AD is incompletely understood. The prevailing hypothesis for AD pathology is the amyloid cascade hypothesis, which posits that the causative agent of AD is the accumulation of amyloid-β (Aβ, the main component of plaques) in the brain. However, recent Phase III clinical trials that target Aβ have not led to significant improvements in cognitive function, despite reducing overall brain Aβ burden. There has been a growing interest in understanding additional pathological features of AD that may impact disease progression. Recent studies in humans and in mice have suggested a role for pathogenic microbes or altered microbiota in neuroinflammation and AD. Microbiota in the GI tract can influence neurological health through microbial production of neurotransmitter precursors, immune-modulatory metabolites (e.g. short chain fatty acids), or interaction with the vagus nerve or enteric nervous system. Gut microbiota can also produce amyloids (aggregated, insoluble proteins exhibiting β-pleated sheet structures) that may cross the blood-brain barrier. Despite growing efforts to understand the gut microbiome-brain axis, current technologies using DNA or RNA amplicon sequencing are unable to address fundamental ecological questions, such as quantifying taxon-specific growth rates of host- associated microbiota. Understanding microbial ecosystem dynamics has large implications for human disease; quantifying growth or turnover of species in terms of absolute abundance change over time in an ecosystem can enable predictions of interspecies competition or trajectories of microbial succession in early and late life, which are associated with host health or disease risk. In this study, we will adapt an innovative technique widely used in soil microbial ecology to study host-microbiome dynamics in AD. We will use quantitative stable isotope probing (qSIP), a technique that uses an isotopically enriched substrate (e.g. 18O-water) to measure gut microbiome dynamics in triple transgenic (3xTg-AD) and wild- type mice. Since H2O is a universal substrate, labeled 18O will incorporate into microbial and host biomolecules, including nucleic acids; this feature allows a researcher to separate extracted DNA by density to quantify taxon-specific growth rates. Completion of this study will lead to the development of a novel tool that can be widely used in the AD community to better understand the contribution of host- associated microbiota to AD progression and neuroinflammation.

摘要