Sex Differences in Hypertension: Contribution of DAMPs

项目摘要P2，沙利文 在美国，约33%的成年人患有高血压，不分性别，只有不到40%的高血压患者 服用药物的患者将血压(BP)控制在推荐水平。一个严重的障碍 提高血压控制率缺乏关于推动血压升高的分子机制的知识 性。针对高血压病因的治疗将提高血压控制率并防止过早死亡 死于心血管疾病。T细胞在实验动物高血压中的作用及其机制(S) 无论男女，引发炎症反应的问题仍未解决。高迁移率族蛋白1(HMGB1) 是一种损伤相关的分子模式(DAMP)，当坏死释放时，会刺激促炎反应 免疫细胞通过Toll样受体(TLR)4。相反，细胞凋亡限制HMGB1的释放并促进T细胞 调节细胞(Treg)。项目(P)2的目标是确定细胞死亡、HMGB1、 TLR4、树突状细胞(DC)对T细胞的激活、血压控制、肾脏和血管功能在高血压中的作用。 我们的中心假设是，细胞死亡通过HMGB1驱动DC和T细胞的激活并增加血压 释放和TLR4激活在两性中都存在。然而，由于细胞死亡类型的性别差异， 在女性中，驱动免疫性高血压的分子途径有利于更大的Treg形成。我们将测试 我们的假设通过三个特定的目的：1)检验细胞坏死是促炎和促炎症的假设 男性自发性高血压，但女性更多的细胞凋亡减弱了细胞的促炎作用 死亡，2)检验HMGB1和TLR4在男性中是促炎和促高血压的假设，而 女性体内的HMGB1促进Treg的形成并减缓血压的增加，3)验证了以下假设 男性自发性高血压患者的MDCS促进更大的促炎T细胞激活和高血压，而更大的 在女性SHR中，浆细胞样树突状细胞导致更多的树突状细胞和更低的血压。P2与另一个具有很强的协同性 项目，并依赖于所有核心的成功完成我们的目标。P2的目标1是高度 与P1的目标1和P3的目标3合作，P2中生成的数据将告知P3炎症 肾髓质状况，进一步了解性别和血压对肾髓质的影响 功能。拟议的研究包括生理、药理、生化、分子和细胞 提供对BP控制的机械性见解的技术。几十年来，基础科学研究一直专注于 几乎只针对男性；对疾病进展和可以获得的治疗的机械性洞察 对女性的研究一直被忽视。我们的结果将为临床前支持提供基础 以特定性别的免疫系统特定组件为靶点，以提高血压控制率 人类。

PROJECT SUMMARY P2, SULLIVAN Hypertension affects ~33% of adults in the U.S. and regardless of sex, fewer than 40% of hypertensive patients taking medication achieve blood pressure (BP) control to recommended levels. A critical barrier to improving BP control rates is lack of knowledge regarding molecular mechanisms driving elevated BP in either sex. Therapies targeting the cause of hypertension will improve BP control rates and prevent premature death from cardiovascular disease. T cells contribute to hypertension in experimental animals, yet the mechanism(s) initiating inflammatory responses in either sex remains unresolved. High mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) that when released by necrosis stimulates pro-inflammatory immune cells via toll-like receptor (TLR)4. In contrast, apoptosis limits HMGB1 release and promotes T regulatory cells (Treg). The objective of Project (P)2 is to determine the contributions of cell death, HMGB1, TLR4, and dendritic cells (DCs) to T cell activation, BP control, renal and vascular function in hypertension. Our central hypothesis is that cell death drives DC and T cell activation and increases in BP via HMGB1 release and TLR4 activation 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 Treg formation. We will test our hypothesis via three specific aims: 1) test the hypothesis that cellular necrosis is pro-inflammatory and pro- hypertensive in male SHR, yet greater apoptosis in females attenuates the pro-inflammatory impact of cell death, 2) test the hypothesis that HMGB1 and TLR4 are pro-inflammatory and pro-hypertensive in males, while HMGB1 in females promotes Treg formation and mitigates increases in BP, and 3) test the hypothesis that mDCs in male SHR promote greater pro-inflammatory T cell activation and hypertension, while greater plasmacytoid DCs in female SHR result in more Tregs and lower BP. P2 is highly synergistic with the other projects and is dependent on all cores for the successful completion of our aims. Aim 1 of P2 is highly collaborative with aim 1 of P1 and aim 3 of P3, and data generated in P2 will inform P3 as to the inflammatory status of the renal medulla, allowing for further insight into the impact of sex and BP on renal medullary function. Proposed studies integrate physiological, pharmacological, biochemical, molecular and cellular techniques to provide mechanistic insight into BP control. For decades, basic science research has focused almost exclusively on males; mechanistic insight into disease progression and treatment that could be gained by studying females has been ignored. Our results will provide the pre-clinical foundation to support targeting specific components of the immune system in a sex-specific manner to improve BP control rates in humans.