Gut Microbiota and Cerebral Vascular Disease

肠道微生物群与脑血管疾病

• 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
• 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

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.

项目摘要： 脑血管疾病是全球死亡率和残疾的主要原因之一。缺血性中风， 当血块阻止区域大脑血流时，所有中风中的大部分时间都会发生。这 在这种灾难性事件的促进病理生理过程通常是血小板过度反应性，增强 血栓形成潜力。增强的血小板反应性增加了急性血栓性闭塞的敏感性 船只，例如缺血性中风和心脏病发作。在过去的几年中，我们已经发展 西方饮食中的营养物质之间的机械联系，代谢产物三甲胺的肠道菌群形成 n氧化物（TMAO），以及血小板高反应性和心血管疾病的发展。在 令人兴奋的新的未发表的研究，我们获得了大量证据，表明肠道微生物TMAO 途径可以直接有助于缺血性中风的发展和严重性及其下游不利 结果。我们的建议旨在确认和检验肠道微生物群，通过元有机体的假设 （涉及微生物和宿主）TMAO途径有助于中风风险。我们将评估这一角色 通过影响血小板功能来增强中风风险的途径，通过 通过NLRP3炎症体激活脑组织中的大脑炎症。我们还将检查 肠道微生物在调节中风敏感性和中风后功能恢复性的作用，识别 促进饮食的潜在机制增强了缺血性中风风险，并探索新型治疗 针对肠道疾病预防和治疗的肠道微生物贡献的方法。 拟议研究的完成不仅将提供概念证明，而且还提供临床前证据 吸毒微生物组可以作为预防和治疗脑血管疾病的新型策略。