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。存在于肠道(肠道)的共生细菌 微生物)可以影响血管张力和调节血压。血压正常的动物 当移植来自高血压动物的肠道微生物区系时，变得高血压，以及 反之亦然。此外，人类的高血压与肠道的特殊变化有关。 微生物多样性，证明了肠道微生物负荷的变化和 多样性(生物失调)导致了高血压的发病。 这一应用位于肠道生物失调和高血压的交汇点。它假定了这种直觉 生物失调是高血压患者血管张力增加的关键驱动因素，它还提出了 血管平滑肌富含microRNA-204(miR-204)传递代谢的假说 来自肠道细菌的信号通过其作用于 肌浆网钙离子释放到细胞质内。 该申请得到了强劲的初步数据的支持。它显示了肠道微生物的变化 社区和微生物衍生的代谢物，在高血压小鼠。这进一步表明， 抗生素诱导的小鼠肠道生物失调下调血管平滑肌miR-204，Leads 与血管的过度收缩有关，与肌醇1，4，5- 三磷酸(IP3)受体(IP3R1)，控制血管平滑肌细胞内钙离子，以及 放松对血管平滑肌细胞内钙动态平衡的调节。 这一应用程序非常新颖、机械性以及潜在的可译性。它将利用 独特的组织靶向转基因小鼠，以及分析这种关系的体外工具 在肠道微生物组miR-204和肌浆网钙离子装置之间 血管平滑肌细胞。此外，它还将使用最先进的方法来评估 活体动物细胞和血管内的钙离子通量。最后，它将探索细菌是否 代谢产物可逆转钙离子稳态失调，减缓高血压的发展。 高血压。 鉴于人们对人类微生物群如何影响健康和疾病的巨大兴趣，这 应用程序提供了一个独特的机会来探索肠道细菌如何调节microRNA 调节血压。这样的信息将为基于microRNA和/或 以微生物群为基础的疗法预防或治疗高血压。

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.