MiR-204 regulates type 1 IP3R/Ca2+ axis to control vascular smooth muscle cell contractility and blood pressure: Potential role of the gut microbiome

项目摘要 高血压是一种多系统疾病。肠道共生菌（gut） 微生物组）可以影响血管张力并调节血压。血压正常动物 当移植来自高血压动物的肠道微生物群时变得高血压，并且 反之亦然此外，人类的高血压与肠道的特定改变有关。 微生物的多样性，贷款的前提下，在肠道微生物负荷的变化， 多样性（生态失调）有助于高血压的发病机制。 这种应用处于肠道生态失调和高血压的交叉点。它假定肠道 微生态失调是高血压血管张力增加的关键驱动因素。 血管平滑肌富集microRNA-204（miR-204）传递代谢的假说 来自肠道细菌的信号，通过其对平滑肌收缩的影响来控制平滑肌收缩。 肌浆网Ca ~（2+）释放到细胞质中。 该申请得到了强有力的初步数据的支持。它显示了肠道微生物的变化 群落和微生物衍生的代谢产物。它进一步表明， 在小鼠中，禁食诱导的肠道生态失调下调血管平滑肌miR-204，导致 血管收缩过度，与肌醇1，4，5- 三磷酸（IP 3）受体（IP 3R 1），其控制血管平滑肌细胞溶质Ca 2+，和 解除血管平滑肌细胞内Ca 2+稳态。 这种应用是非常新颖的，机械的，以及潜在的可翻译。它将利用 独特的组织靶向转基因小鼠，以及体外工具，来剖析这种关系。 miR-204、肠道微生物组和肌浆网Ca 2+装置之间的关系， 血管平滑肌细胞此外，它将使用最先进的方法来评估 活动物细胞和血管中的Ca 2+通量。最后，它将探讨细菌是否 代谢产物可以逆转Ca 2+稳态的失调，并减轻 高血压 鉴于对人类微生物组如何影响健康和疾病的巨大兴趣， 应用程序提供了一个独特的机会，探索肠道细菌如何调节microRNA 调节血压。这些信息将为基于microRNA和/或 微生物群为基础的治疗，以预防或治疗高血压。

Project Summary Hypertension is a multi-system disease. Commensal bacteria that inhabit the gut (gut microbiome) can affect vascular tone and modulate blood pressure. Normotensive animals become hypertensive when transplanted with gut microbiota from hypertensive animals, and vice versa. Furthermore, hypertension in humans is associated with specific alterations in gut microbial diversity, lending credence to the premise that a change in gut microbial load and diversity (dysbiosis) contributes to the pathogenesis of hypertension. This application lies at the intersection of gut dysbiosis and hypertension. It posits that gut dysbiosis is a key driver of increased vascular tone in hypertension It also puts forth the hypothesis that vascular smooth muscle-enriched microRNA-204 (miR-204) relays metabolic signals originating from gut bacteria to control smooth muscle contraction via its effects on sarcoplasmic reticulum Ca2+ release into the cytoplasm. The application is supported by strong preliminary data. It shows a change in the gut microbial community, and microbe-derived metabolites, in hypertensive mice. It further shows that antibiotic-induced gut dysbiosis in mice downregulates vascular smooth muscle miR-204, leads to hypercontractility of blood vessels, is associated with upregulation of Inositol 1,4,5- trisphosphate (IP3) receptor (IP3R1) which controls vascular smooth muscle cytosolic Ca2+, and deregulates vascular smooth muscle intracellular Ca2+ homeostasis. This application is highly novel, mechanistic as well as potentially translatable. It will leverage unique tissue-targeted genetically modified mice, and in vitro tools, to dissect the relationship between miR-204, the gut microbiome, and the sarcoplasmic reticulum Ca2+ apparatus in vascular smooth muscle cells. In addition, it will use state-of-the-art methodologies to assess Ca2+ flux in cells and in vessels of live animals. Finally, it will explore whether bacterial metabolites can reverse deregulation of Ca2+ homeostasis and mitigate the development of hypertension. Given the enormous interest in how the human microbiome impacts health and disease, this application provides a unique opportunity to explore how a microRNA regulated by gut bacteria modulates blood pressure. Such information will open the door for microRNA-based and/or microbiota-based therapeutics to prevent or treat hypertension.