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

主动脉瘤通常是沉默的，而且是致命的，而且没有药物治疗。老兵们， 尤其是那些吸烟(尼古丁)的人，非常容易患上主动脉瘤及其后遗症，如 破裂和夹层。因此，了解这种疾病的基本基础对疾病的发展至关重要。 可以对退伍军人的健康产生积极影响的治疗方法。 在人类队列中的研究表明，非编码的microRNA-204(miR-204)在主动脉中下调 动脉瘤组织与未受影响组织比较。此外，以人口为基础的研究表明 使用广谱抗生素增加了主动脉瘤的患病率和破裂的风险。这些 抗生素在退伍军人健康系统中被广泛(而且经常是不适当的)开出。抗生素改变了 健康肠道微生物群的组成(生物失调)。这个应用程序将检验肠道生物失调的假说 抗生素通过影响主动脉miR-204的表达促进主动脉瘤的形成。 平滑肌细胞从正常收缩表型到功能障碍的去分化 合成的一种，是动脉重塑疾病的核心特征，包括主动脉瘤。合成光滑度 肌肉细胞优先利用脂肪而不是葡萄糖。此应用程序还将探索以下假设 MiR-204下调导致主动脉平滑肌细胞从收缩状态转换为功能障碍状态 通过刺激脂肪酸利用来合成表型。 支持这一应用的假设是基于令人兴奋的数据显示，主动脉miR-204 表达是由肠道微生物群控制的-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，小鼠体内缺少miR-204使它们 易受血管紧张素II诱导的主动脉瘤扩张，并上调脂肪酸中的代谢物 氧化途径。 这一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和尼古丁诱导的主动脉瘤中的作用。会的 确定抗生素诱导的生物失调是否下调主动脉平滑肌miR-204并促进主动脉 动脉瘤性疾病，以及这种疾病是否可以通过miR-204的功能增强而挽救。它将探索 MiR-204在调节血管内皮细胞可塑性中的作用 MIR-204促进动脉瘤性疾病中的主动脉平滑肌细胞去分化。此外，使用 代谢组学和生物能量学工具，它将揭示miR-204在调节平滑肌细胞中的作用 偏爱燃料利用，并调查在主动脉瘤疾病中miR-204缺陷是否增加 平滑肌脂肪酸氧化。 主动脉瘤很常见，对退伍军人来说是一个巨大的健康负担。此应用程序 提供了一个独特的机会来探索由肠道细菌调控的血管microRNA是如何参与 主动脉瘤疾病的发病机制，并可能为患有主动脉瘤疾病的退伍军人提供新的治疗希望 这种病。

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.