Sex Differences in Hypertension: Contribution of DAMPs

项目总结P2，Sullivan 在美国，高血压影响约33%的成年人，不分性别， 服用药物的患者实现血压（BP）控制到推荐水平。一个关键的障碍， 提高血压控制率是缺乏知识的分子机制驱动血压升高， 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 心血管疾病T细胞导致实验动物的高血压，但其机制 在任何性别中引发炎症反应仍然没有解决。高迁移率族蛋白1 是一种损伤相关分子模式（DAMP），当坏死释放时， 免疫细胞通过Toll样受体（TLR）4.相反，细胞凋亡限制HMGB 1的释放，促进T 调节细胞（Treg）。项目（P）2的目的是确定细胞死亡、HMGB 1、 TLR 4和树突状细胞（DCs）对高血压患者T细胞活化、血压控制、肾和血管功能的影响。 我们的中心假设是，细胞死亡驱动DC和T细胞活化，并通过HMGB 1增加血压 释放和TLR 4活化。然而，由于细胞死亡类型的性别差异， 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）测试细胞坏死是促炎性和促炎性的假设， 高血压在男性SHR，但更大的凋亡在女性减弱促炎性细胞的影响， 死亡，2）检验HMGB 1和TLR 4在男性中是促炎症和促高血压的假设， 女性中的HMGB 1促进Treg形成并减轻BP的增加，以及3）检验以下假设： 雄性SHR的mDCs促进更大的促炎性T细胞活化和高血压，而雄性SHR的mDCs促进更大的促炎性T细胞活化和高血压。 雌性SHR中浆细胞样DCs可导致高血压和低血压。P2与另一个具有高度协同作用 项目，并依赖于所有的核心，以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协作，并且在P2中生成的数据将告知P3关于炎性 肾髓质的状态，允许进一步了解性别和BP对肾髓质的影响。 功能建议的研究整合生理学，药理学，生物化学，分子和细胞 技术，以提供对BP控制的机械见解。几十年来，基础科学研究一直专注于 几乎仅在男性中;可以获得对疾病进展和治疗的机制性见解 一直被忽视我们的研究结果将提供临床前基础， 以性别特异性方式靶向免疫系统的特定成分，以提高 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.