Gut Microbiota and Cerebral Vascular Disease

肠道微生物群与脑血管疾病

基本信息

批准号：
10448494
负责人：
Weifei Zhu
金额：
$ 55.14万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448494
关键词：
Accounting Acute Address Adult Animal Model Attenuated Binding Blood Circulation Blood Platelets Blood coagulation Brain Cardiovascular Diseases Cells Cerebral Infarction Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Choline Clinical Clinical Research Data Development Diet Dietary Supplementation Engineering Event Family Flavins Fluorescence-Activated Cell Sorting Fostering Funding Generations Germ-Free Heart Diseases Hematological Disease Hepatic Human In Vitro Infarction Inflammasome Inflammation Injury Interruption Ischemic Stroke Link Lung diseases Lyase Medicine Metabolism Microbe Microglia Motor Mus Myocardial Infarction Myocardial Ischemia Nature Nucleotides Nutrient Pathway interactions Pharmaceutical Preparations Pharmacology Phenotype Plasma Predisposition Prevention Process Production Proteins Recovery of Function Research Research Personnel Risk Role Severities Sleep Disorders Stroke Testing Thrombosis Thrombus Training Transplantation Vascular Diseases adverse outcome brain tissue cell type choline supplementation dietary disability endoplasmic reticulum stress enzyme pathway experimental study fecal transplantation functional disability functional outcomes genetic manipulation gut microbes gut microbiome gut microbiota human subject improved inhibitor insight interest mRNA Expression marenostrin microbial microbial community microbiome mortality neutrophil novel strategies novel therapeutic intervention platelet function post stroke pre-clinical prevent professor protein kinase R receptor small molecule inhibitor stress kinase stroke model stroke recovery stroke risk thrombotic trimethyloxamine western diet

项目摘要

Project Summary: Cerebral vascular disease is one of the leading causes of mortality and disability worldwide. Ischemic stroke, accounting for the majority of all strokes, occurs when a blood clot blocks regional cerebral blood flow. The precipitating pathophysiological process for this catastrophic event is often platelet hyperreactivity, heightening thrombosis potential. Enhanced platelet reactivity increases the susceptibility for acute thrombotic occlusion of vessels, such as during ischemic stroke and heart attack. Over the past few years, we have developed mechanistic links between nutrients in a Western diet, gut microbiota formation of the metabolite trimethylamine N oxide (TMAO), and development of both platelet hyper-responsiveness and cardiovascular diseases. In exciting new unpublished studies, we have obtained substantial evidence indicating that the gut microbial TMAO pathway can directly contribute to the development and severity of ischemic stroke and its downstream adverse outcomes. Our proposal aims to confirm and test the hypothesis that gut microbiota, through the metaorganismal (involving both microbes and host) TMAO pathway, contributes to stroke risks. We will evaluate the role of this pathway in enhancing stroke risks by impacting platelet function, fostering worse functional impairment by augmenting cerebral inflammation via NLRP3 inflammasome activation in brain tissue. We will also examine the role of gut microbes in modulating stroke susceptibility and functional recovery post stroke onset, identify potential mechanisms contributing diet enhanced ischemic stroke risks, and explore novel therapeutic approaches targeting gut microbial contributions for prevention and treatment in cerebrovascular disease. Completion of the proposed studies will not only provide proof of concept, but also provide preclinical evidence that drugging the microbiome may serve as a novel strategy to prevent and treat cerebrovascular diseases.

项目概要：脑血管疾病是全世界死亡和残疾的主要原因之一。缺血性中风，占所有中风的大部分，当血栓阻塞局部脑血流时就会发生这种情况。这促成这种灾难性事件的病理生理过程通常是血小板高反应性，血栓形成潜力。血小板反应性增强会增加急性血栓闭塞的易感性血管，例如在缺血性中风和心脏病发作期间。在过去的几年里，我们开发了西方饮食中的营养素与代谢物三甲胺的肠道微生物群形成之间的机制联系一氧化氮（TMAO），以及血小板高反应性和心血管疾病的发展。在令人兴奋的未发表的新研究，我们已经获得大量证据表明肠道微生物 TMAO 途径可直接导致缺血性中风的发展和严重程度及其下游不良反应结果。我们的建议旨在证实并测试肠道微生物群通过元有机体的假设（涉及微生物和宿主）TMAO 途径会增加中风风险。我们将评估其作用通过影响血小板功能增加中风风险的途径，通过促进更严重的功能损伤通过脑组织中 NLRP3 炎症小体的激活增强脑炎症。我们还将检查肠道微生物在调节中风易感性和中风发作后功能恢复中的作用，确定饮食增加缺血性中风风险的潜在机制，并探索新的治疗方法针对肠道微生物对脑血管疾病预防和治疗的贡献的方法。完成拟议的研究不仅可以提供概念证明，还可以提供临床前证据对微生物组进行药物治疗可能成为预防和治疗脑血管疾病的新策略。