Damage-Associated Molecular Patterns in Hypertension

项目摘要项目总监，韦伯 该项目的整合主题和统一假设围绕着损伤所起的作用-- 高血压中的相关分子模式(DAMP)。湿气是由受伤产生的警报信号 宿主细胞、受损组织或代谢应激，并由先天免疫系统识别。我们 假设高血压患者先天免疫系统的持续激活是不适应的，导致 激活外周循环中循环中的中性粒细胞和单核细胞，这是血管系统的归宿， 并导致更多的组织破坏和低度炎症。这些炎症性事件导致 在启动作用下发生的血管收缩、血管重塑和肾脏损伤增加 导致血压升高的因素。项目1将测试这一假设，即在高血压中，夸大 血管壁中的细胞凋亡和坏死导致线粒体DNA(MtDNA)，这是一种激活的潮湿物质 Toll样受体9(TLR9)引起血管炎症、血管收缩和内皮功能障碍。在……里面 方案2，假设细胞死亡诱导高迁移率族蛋白1(HMGB1)释放和TLR4 激活导致树突状细胞(DC)和T细胞的激活，并使两性的血压升高。 然而，由于细胞死亡类型的性别差异，驱动免疫的分子途径基于 女性高血压患者更倾向于T调节细胞(Treg)的形成。这一假说预言 坏死导致男性HMGB1释放和TLR4激活，导致髓系DC激活 Th17细胞和血压的增加以及相对于女性的终末器官损害，同时更大的细胞凋亡 女性限制HMGB1的释放并激活浆细胞样树突状细胞以增加Treg的形成限制增加 与男性相比，在血压和伤害方面。项目3验证了高循环阻尼力的假设 刺激直肠血管内皮细胞在低剪切状态下产生不适当的一氧化氮(NO)。 这种NO的产生是有害的，因为它抑制了VR周细胞的自发节律性收缩， 在这些情况下，正常情况下可以防止红细胞聚集。然后VR的RBC闭塞 导致周围髓血管稀疏，血压-钠尿受损和高血压。 这些概念上独特的方法，与新的技术工具相结合，将推动我们的 了解血管损伤发生的分子和生理机制 终结高血压的器官损害。所有项目都将使用自发性高血压大鼠作为动物 模特。这三个组成部分项目的这种高度整合和协作的方法得到了 行政核心(核心A)、动物使用和器械核心(核心B)和生物炎症 核心(核心C)。

PROGRAM SUMMARY PROGRAM DIRECTOR, WEBB The integrating theme and unifying hypothesis of this program project centers on the role played by damage- associated-molecular patterns (DAMPs) in hypertension. DAMPs are alarm signals generated from injured host cells, damaged tissues or metabolic stress and are recognized by the innate immune system. We hypothesize that sustained activation of the innate immune system in hypertension is maladaptive, leading to activation of circulating neutrophils and monocytes in the peripheral circulation, which home to the vasculature, and cause increased tissue destruction and low-grade inflammation. These inflammatory events contribute to increased vasoconstriction, vascular remodeling, and renal injury that occur under the action of initiating factors to increase blood pressure. Project 1 will test the hypothesis that in hypertension, exaggerated apoptosis and necrosis in the vascular wall give rise to mitochondrial DNA (mtDNA), a DAMP that activates Toll-like receptor 9 (TLR9) causing vascular inflammation, vasoconstriction and endothelial dysfunction. In Project 2, it is hypothesized that cell death induces high mobility group box 1 (HMGB1) release and TLR4 activation resulting in dentritic cell (DC) and T cell activation and increases in blood pressure in both sexes. However, due to a sex difference in the type of cell death, the molecular pathway driving immune-based hypertension in females favors greater T regulatory cell (Treg) formation. This hypothesis predicts that necrosis results in greater HMGB1 release and TLR4 activation in males leading to myeloid DC activation of Th17 cells and increases in blood pressure and end-organ damage relative to females, while greater apoptosis in females limits HMGB1 release and activates plasmacytoid DC to increase Treg formation limiting increases in blood pressure and injury relative to males. Project 3 tests the hypothesis that high circulating DAMPs stimulate inappropriate nitric oxide (NO) production by vasa recta (VR) endothelial cells in low sheer states. This NO production is detrimental as it inhibits spontaneous rhythmic contractions of VR pericytes that normally act to prevent red blood cell aggregations under these conditions. RBC occlusion of the VR then leads to rarefaction of the surrounding medullary vasculature, impaired pressure-natriuresis and hypertension. These conceptually unique approaches, combined with novel technological tools will advance our understanding of the molecular and physiological mechanisms underlying the initiation of vascular injury and end organ damage of hypertension. All projects will use the spontaneously hypertensive rat as an animal model. This highly integrative and collaborative approach of the three component projects is supported by an Administrative Core (Core A), the Animal Use and Instrumentation Core (Core B) and the Bioinflammation Core (Core C).