Nexus between miR-204, gut microbiome, and aortic aneurysmal disease

miR-204、肠道微生物组和主动脉瘤疾病之间的关系

• 批准号: 10201510
• 负责人: Kaikobad J. Irani
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201510
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Age-Years; Aneurysm; Angiotensin II; Antibiotics; Aorta; Aortic Aneurysm; Aortitis; Architecture; Bacteria; Bioenergetics; Blood; Blood Vessels; Caliber; Cellular Metabolic Process; Clinic; Cross-Sectional Studies; Data; Detection; Development; Dilatation - action; Disease; Dissection; Down-Regulation; Epigenetic Process; Fatty Acids; Fatty acid glycerol esters; Gap Junctions; Genes; Germ-Free; Glucose; Goals; Health; Health system; Healthcare Systems; Heart; Human; Incidence; Medial; Mediating; Medical; Metabolic; MicroRNAs; Molecular; Morbidity - disease rate; Mus; Nicotine; Observational Study; Oral cavity; Pathogenesis; Pathway interactions; Phenotype; Plasma; Play; Population; Population Study; Prevalence; Primary Health Care; Recording of previous events; Risk; Role; Running; Rupture; Severities; Skin; Smoke; Smooth Muscle; Smooth Muscle Myocytes; Symptoms; Testing; Tissues; United States Department of Veterans Affairs; Untranslated RNA; Vascular Smooth Muscle; Veterans; Work; acylcarnitine; aged; arterial remodeling; cohort; cooperative study; differential expression; dysbiosis; fatty acid elongases; fatty acid oxidation; fecal transplantation; gain of function; gut bacteria; gut dysbiosis; gut microbiome; gut microbiota; human disease; long chain fatty acid; loss of function; male; metabolomics; microbiome; microorganism; military veteran; mortality; novel therapeutics; oxidation; preference; prevent; tool; trait

Aortic aneurysms are often silent and deadly, and there is no medical therapy for them. Veterans, especially those who smoke (nicotine), are highly vulnerable to aortic aneurysms and their sequelae such as ruptures and dissections. Thus, understanding the fundamental basis for the disease is central to developing cures that can have a positive impact on health of veterans. Studies in human cohorts show that the non-coding microRNA-204 (miR-204) is downregulated in aortic aneurysmal tissue compared to non-affected tissue. In addition, human population-based studies have shown increased prevalence of aortic aneurysms and risk of their rupture with use of broad-spectrum antibiotics. These antibiotics are widely (and often inappropriately) prescribed in the VA Health System. Antibiotics change the composition of the healthy gut microbiome (dysbiosis). This application will test the hypothesis that gut dysbiosis caused by antibiotics promotes aortic aneurysms via its effect on aortic miR-204 expression. Dedifferentiation of smooth muscle cells from a normal contractile phenotype to a dysfunctional synthetic one, is a core feature in diseases of arterial remodeling, including aortic aneurysms. Synthetic smooth muscle cells preferentially utilize fat over glucose. This application will also explore the hypothesis that downregulation of miR-204 causes switching of aortic smooth muscle cells from a contractile to a dysfunctional synthetic phenotype by stimulating fatty acid utilization. The hypotheses underlying this application are grounded in exciting data showing that aortic miR-204 expression is governed by the gut microbiome – dysbiosis caused by broad-spectrum antibiotics leads to profound decrease in aortic miR-204 expression. In addition, absence of miR-204 in mice makes them susceptible to Angiotensin II-induced aortic aneurysmal dilatation and upregulates metabolites in the fatty acid oxidation pathway. This application will leverage state-of-the-art molecular tools and genetically modified mice to examine the role of smooth muscle miR-204 in Angiotensin II-induced and nicotine-induced aortic aneurysms. It will determine if antibiotic-induced dysbiosis down-regulates aortic smooth muscle miR-204 and promotes aortic aneurysmal disease, and whether this disease can be rescued by gain-of-function of miR-204. It will explore the role of miR-204 in regulating the plasticity of smooth muscle cells and investigate whether loss of function of miR-204 promotes dedifferentiation of aortic smooth muscle cells in aneurysmal disease. Additionally, using metabolomics and bioenergetic tools, it will uncover the role of miR-204 in regulating smooth muscle cell preference for fuel utilization, and investigate if deficiency of miR-204 in aortic aneurysmal disease increases smooth muscle fatty acid oxidation. Aortic aneurysms are common and represent a significant health burden in veterans. This application offers a unique opportunity to explore how a vascular microRNA regulated by gut bacteria is involved in the pathogenesis of aortic aneurysmal disease and could offer hope for new therapies for veterans who suffer from this disease.

主动脉瘤通常是无声的和致命的，没有药物治疗。退伍军人， 尤其是那些吸烟者（尼古丁），非常容易患主动脉瘤及其后遗症， 破裂和夹层因此，了解这种疾病的基本基础是发展 可以对退伍军人的健康产生积极影响的治疗方法。 人类队列研究显示，主动脉瘤中非编码microRNA-204（miR-204）下调， 与未受影响的组织相比，囊肿组织。此外，基于人群的研究表明， 使用广谱抗生素会增加主动脉瘤的患病率及其破裂风险。这些 抗生素在VA卫生系统中被广泛使用（并且通常是不适当的）。抗生素改变了 健康肠道微生物组的组成（生态失调）。这个应用程序将测试肠道生态失调的假设， 抗生素引起的动脉瘤通过影响主动脉miR-204表达而促进主动脉瘤。 平滑肌细胞从正常收缩表型去分化为功能障碍 合成的一种，是动脉重塑疾病的核心特征，包括主动脉瘤。合成光滑 肌肉细胞优先利用脂肪而不是葡萄糖。本应用程序还将探讨假设， miR-204的下调导致主动脉平滑肌细胞从收缩性转变为功能障碍性。 通过刺激脂肪酸利用合成表型。 该应用的基础假设基于令人兴奋的数据，该数据显示主动脉miR-204 表达受肠道微生物组控制-广谱抗生素引起的生态失调导致 主动脉miR-204表达显著降低。此外，小鼠中miR-204的缺乏使它们 易受血管紧张素II诱导的主动脉瘤扩张的影响，并上调脂肪酸代谢产物 氧化途径 该应用程序将利用最先进的分子工具和转基因小鼠来检查 平滑肌miR-204在血管紧张素II诱导和尼古丁诱导的主动脉瘤中的作用。它将 确定缺氧诱导的微生态失调是否下调主动脉平滑肌miR-204并促进主动脉平滑肌miR-204的表达。 肿瘤性疾病，以及这种疾病是否可以通过miR-204的功能获得来挽救。将探索 miR-204在调节平滑肌细胞可塑性中的作用，并研究 miR-204促进血管平滑肌细胞的去分化此外，使用 利用代谢组学和生物能量学工具，将揭示miR-204在调节平滑肌细胞中的作用， 燃料利用的偏好，并研究主动脉瘤样疾病中miR-204的缺乏是否增加 平滑肌脂肪酸氧化。 主动脉瘤很常见，是退伍军人的一个重大健康负担。本申请 提供了一个独特的机会来探索肠道细菌调控的血管microRNA如何参与了 主动脉瘤性疾病的发病机制，并可能为患有糖尿病的退伍军人提供新的治疗方法 这种疾病。