Microbiota-targeted approaches to resolve dysbiosis-induced AD neuropathology following brain injury.

以微生物群为目标的方法来解决脑损伤后生态失调引起的 AD 神经病理学问题。

基本信息

批准号：
10910348
负责人：
Sonia Villapol
金额：
$ 64.26万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10910348
关键词：
APP-PS1 Ablation Acceleration Acute Affect Aftercare Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Antibiotics Anxiety Bacteria Behavior Brain Brain Injuries Chronic Cognitive deficits Communication Computer Analysis DNA sequencing Data Dementia Deposition Disease Progression Elderly Encephalitis Engraftment Environmental Risk Factor Event Flow Cytometry Foundations Functional disorder Gastrointestinal Physiology Germ-Free Hip region structure Hospitals Immune Immune system Impaired cognition Inflammation Inflammatory Inflammatory Response Intervention Lactobacillus Mediating Mental Depression Metabolic Microglia Mus Nerve Degeneration Neurodegenerative Disorders Neurological outcome Neuromodulator Outcome Pathogenesis Pathologic Pathology Pathway interactions Persons Phase Play Probiotics Process Production Proteins Recovery Rehabilitation therapy Research Proposals Role Severities Signal Transduction Testing Tg2576 Therapeutic Traumatic Brain Injury Traumatic Brain Injury recovery Traumatic CNS injury Vulnerable Populations abeta accumulation bacteriome behavior test bone cognitive function design dysbiosis experimental study extracellular fall risk falls fecal transplantation global health gut bacteria gut microbiome gut microbiota gut-brain axis high risk immune activation improved injured metabolomics metaproteomics microbial microbiome microbiome composition microbiota microbiota-gut-brain axis motor deficit mouse model multidisciplinary nervous system disorder neuroinflammation neuropathology next generation patient population preservation response restoration tau Proteins tau aggregation tau-1

APP-PS1 Ablation Acceleration Acute Affect Aftercare Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Antibiotics Anxiety Bacteria Behavior Brain Brain Injuries Chronic Cognitive deficits Communication Computer Analysis DNA sequencing Data Dementia Deposition Disease Progression Elderly Encephalitis Engraftment Environmental Risk Factor Event Flow Cytometry Foundations Functional disorder Gastrointestinal Physiology Germ-Free Hip region structure Hospitals Immune Immune system Impaired cognition Inflammation Inflammatory Inflammatory Response Intervention Lactobacillus Mediating Mental Depression Metabolic Microglia Mus Nerve Degeneration Neurodegenerative Disorders Neurological outcome Neuromodulator Outcome Pathogenesis Pathologic Pathology Pathway interactions Persons Phase Play Probiotics Process Production Proteins Recovery Rehabilitation therapy Research Proposals Role Severities Signal Transduction Testing Tg2576 Therapeutic Traumatic Brain Injury Traumatic Brain Injury recovery Traumatic CNS injury Vulnerable Populations abeta accumulation bacteriome behavior test bone cognitive function design dysbiosis experimental study extracellular fall risk falls fecal transplantation global health gut bacteria gut microbiome gut microbiota gut-brain axis high risk immune activation improved injured metabolomics metaproteomics microbial microbiome microbiome composition microbiota microbiota-gut-brain axis motor deficit mouse model multidisciplinary nervous system disorder neuroinflammation neuropathology next generation patient population preservation response restoration tau Proteins tau aggregation tau-1

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项目摘要

PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative disease that results in cognitive decline. The neuroinflammatory events that are associated with the pathology of AD exacerbate neurodegeneration. Elderly people with dementia or AD have a higher risk of falling because their cognitive function is affected. They lose their orientation and are very prone to breaking their hips, other bones, or even more severe falls that can cause brain trauma. Although they are treated in the hospitals with subsequent rehabilitation, their weakened immune state typically affects their recovery phases. We need to develop new treatments for AD patients who have had a traumatic brain injury (TBI). This vulnerable population could be particularly amenable to precision-microbiota therapy. Although not fully understood, the brain-gut-microbiota axis plays a major role in the onset and severity of many neurological diseases. We plan to develop precision-microbiota therapy to protect against neurodegeneration and functional behavior in AD mice after TBI. The gut microbiome is emerging as an essential neuromodulator of brain-gut axis signaling. It can significantly impact brain inflammation and outcome after CNS trauma and alter anxiety- and depression-like behaviors. This research proposal is based on the scientific premise that gut bacteria can impact behavior and that brain injury can disrupt diversity in a healthy gut microbiome. The overarching hypothesis is that the gut microbiota dysfunction caused by brain trauma contributes directly to neuroinflammation and neurodegeneration responses in AD mice, and the microbiota modulation will delay the progression of AD neuropathology. Our preliminary data indicate how the microbiota of AD mice affected adversely to TBI outcomes and how probiotics help brain recovery in C57B6/J young mice. This proposal investigates the mechanistic linkage between gut microbiota and AD progression following TBI and explores potential intervention strategies. We will test this premise with the following three Specific Aims: we 1) will determine if the gut microbiome plays a role in accelerating AD pathology and cognitive decline induced by TBI, and 2) will investigate the impact of fecal transplants on AD pathology and cognitive decline after TBI, and 3) will assess the ability of multi-strain probiotics to reduce AD pathology after TBI. We expect to identify a particularly vulnerable patient population by defining which inflammatory responses associated with brain trauma accelerate AD pathogenesis and are regulated by brain-gut-microbiome signals. Our approach is significant because we will establish a “translatable” foundation for the potential of therapeutic approaches for AD after TBI by using the gut as a non-CNS target of precision-microbiota therapy.

项目摘要 /摘要阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，导致认知能力下降。这与AD恶化神经变性有关的神经炎症事件。老年患有痴呆症或AD的人会因其认知功能受到影响而有更高的跌倒风险。他们输了它们的方向非常容易打破臀部，其他骨头，甚至可能引起更严重的跌落脑创伤。尽管他们在医院接受了随后的康复治疗，但其免疫力减弱状态通常会影响其恢复阶段。我们需要为已有的广告患者开发新的治疗方法创伤性脑损伤（TBI）。这个脆弱的人群可能特别适合精确菌花菌治疗。尽管尚未完全理解，但脑螺旋菌轴轴在发作和严重程度中起着重要作用在许多神经系统疾病中。我们计划开发精确的菌菌疗法，以防止 TBI后AD小鼠的神经变性和功能行为。肠道微生物组正在成为必不可少的脑形轴轴信号传导的神经调节剂。 CNS后它可能会显着影响大脑感染和结局创伤和改变焦虑和抑郁症的行为。该研究建议基于科学肠道细菌会影响行为的前提，脑损伤会破坏健康的肠道多样性微生物组。总体假设是脑创伤引起的肠道微生物群功能障碍直接促进AD小鼠的神经炎症和神经变性反应，而微生物群调节将延迟AD神经病理学的进展。我们的初步数据表明了微生物群是如何 AD小鼠对TBI的结果不利，以及益生菌如何帮助C57B6/J Young小鼠的大脑恢复。该提案研究了TBI后肠道菌群与AD进展之间的机械联系并探讨潜在的干预策略。我们将以以下三个特定目的测试此前提：我们1）确定肠道微生物组是否在加速AD病理学和认知下降中起作用 TBI和2）将研究粪便移植对TBI后AD病理学和认知下降的影响， 3）将评估多应变益生菌减少TBI后AD病理的能力。我们希望确定一个通过定义哪些与脑创伤相关的炎症反应，特别是脆弱的患者人群加速AD发病机理，并由脑肠球菌信号调节。我们的方法很重要因为我们将建立一个“可翻译”的基础，以实现TBI后的AD治疗方法的潜力通过将肠道用作精确 - 微生物疗法的非CNS靶标。