Damage-Associated Molecular Patterns in Hypertension

Webb董事 本项目的综合主题和统一假设集中在损害所起的作用上- 相关分子模式（DAMPs）。DAMP是由受伤人员产生的警报信号 宿主细胞、受损组织或代谢应激，并被先天免疫系统识别。我们 假设先天免疫系统在高血压中持续激活是不适应的，导致 激活外周循环中的循环中性粒细胞和单核细胞，它们归巢于脉管系统， 导致组织破坏和轻度炎症这些炎症事件有助于 血管收缩、血管重塑和肾损伤的增加，这些都是在引发 增加血压的因素。项目1将测试假设，在高血压，夸大 血管壁中的凋亡和坏死引起线粒体DNA（mtDNA），一种激活 Toll样受体9（TLR 9）引起血管炎症、血管收缩和内皮功能障碍。在 项目2，假设细胞死亡诱导高迁移率族蛋白1（HMGB 1）释放和TLR 4 激活导致树突状细胞（DC）和T细胞激活，并增加两种性别的血压。 然而，由于细胞死亡类型的性别差异， 女性中的高血压有利于更大的T调节细胞（Treg）形成。这一假说预测， 坏死导致男性中HMGB 1释放和TLR 4活化增加，导致骨髓DC活化， Th 17细胞和增加血压和终末器官损伤相对于女性，而更大的细胞凋亡 在女性中限制HMGB 1释放并激活浆细胞样DC以增加Treg形成限制性增加 与男性相比，血压和受伤的几率更高。项目3测试了高循环DAMP的假设， 刺激低剪切状态下直小血管（VR）内皮细胞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， 通常在这些条件下起到防止红细胞聚集的作用。红细胞阻塞VR， 导致周围髓血管的稀疏、压力-尿钠排泄受损和高血压。 这些概念上独特的方法，结合新的技术工具，将推动我们的 了解血管损伤启动的分子和生理机制， 高血压终末器官损害所有项目都将使用自发性高血压大鼠作为动物 模型这三个组成部分项目的高度整合和协作方法得到了 管理核心（核心A）、动物使用和工具核心（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).