Damage-Associated Molecular Patterns in Hypertension

项目摘要 项目总监，WEBB 该计划项目的整合主题和统一假设集中于损害所发挥的作用- 高血压的相关分子模式（DAMP）。 DAMP 是受伤时产生的警报信号 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 假设高血压患者先天免疫系统的持续激活是适应不良的，导致 激活外周循环中的循环中性粒细胞和单核细胞，它们位于血管系统中， 并导致组织破坏增加和低度炎症。这些炎症事件会导致 在起始作用下发生的血管收缩、血管重塑和肾损伤增加 血压升高的因素。项目 1 将检验以下假设：在高血压中，夸大 血管壁中的细胞凋亡和坏死产生线粒体 DNA (mtDNA)，这是一种激活 DAMP Toll 样受体 9 (TLR9) 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（HMGB1）释放和TLR4 激活导致树突状细胞 (DC) 和 T 细胞激活，并导致男女血压升高。 然而，由于细胞死亡类型的性别差异，驱动基于免疫的分子途径 女性高血压有利于 T 调节细胞 (Treg) 的形成。这个假设预测 坏死导致雄性体内 HMGB1 释放增多和 TLR4 激活，从而导致髓样 DC 激活 与女性相比，Th17 细胞的血压和终末器官损伤增加，同时细胞凋亡更大 在女性中限制 HMGB1 释放并激活浆细胞样 DC 以增加 Treg 形成限制增加 与男性相比，血压和损伤程度更高。项目 3 测试了高循环 DAMP 的假设 刺激直肠血管 (VR) 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，因为它会抑制 VR 周细胞的自发节律性收缩， 在这些条件下通常会起到防止红细胞聚集的作用。然后 VR 的 RBC 闭塞 导致周围髓质脉管系统稀疏、压力尿钠受损和高血压。 这些概念上独特的方法与新颖的技术工具相结合将推进我们的 了解血管损伤引发的分子和生理机制 高血压的终末器官损害。所有项目都将使用自发性高血压大鼠作为动物 模型。这三个组成项目的高度集成和协作方法得到了 行政核心（核心 A）、动物使用和仪器核心（核心 B）以及生物炎症 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).