Sex Differences in Hypertension: Contribution of DAMPs

高血压的性别差异：DAMP 的贡献

• 批准号: 10094231
• 负责人: Jennifer C Sullivan
• 金额: $ 38万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094231
• 关键词: Address; Adoptive Cell Transfers; Adult; Affect; Age; Animals; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Arteries; Attenuated; Automobile Driving; Basic Science; Biochemical; Blood; Blood Pressure; Cardiovascular Diseases; Cell Death; Cell membrane; Cells; Cessation of life; Chronic Kidney Failure; Data; Dendritic Cells; Dendritic cell activation; Disease Progression; Equilibrium; Exhibits; Female; Foundations; Goals; HMGB1 Protein; Heart failure; Human; Hypertension; Immune; Immune system; In Vitro; Inbred SHR Rats; Inbred WKY Rats; Inflammatory; Inflammatory Response; Kidney; Knowledge; Measures; Membrane; Mission; Molecular; Myelogenous; Myocardial Infarction; Necrosis; Pathway interactions; Patients; Pattern; Peripheral arterial disease; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Predisposition; Process; Regulatory T-Lymphocyte; Research; Risk; Sex Differences; Stroke; T-Cell Activation; T-Lymphocyte; TLR4 gene; Techniques; Testing; United States National Institutes of Health; base; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; cell type; experimental study; improved; insight; kidney medulla; kidney vascular structure; male; men; pre-clinical; premature; prevent; sex; targeted treatment; young woman

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.

项目摘要 P2，沙利文 高血压影响约 33% 的美国成年人，无论性别如何，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。一个关键障碍 改善血压控制率的原因是缺乏关于导致血压升高的分子机制的知识 性别。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 来自心血管疾病。 T 细胞导致实验动物高血压，但其机制 两性中引发炎症反应的问题仍未得到解决。高迁移率族盒 1 蛋白 (HMGB1) 是一种损伤相关分子模式 (DAMP)，当坏死释放时会刺激促炎细胞 免疫细胞通过 Toll 样受体 (TLR)4。相反，细胞凋亡限制 HMGB1 释放并促进 T 调节细胞（Treg）。项目 (P)2 的目标是确定细胞死亡、HMGB1、 TLR4 和树突状细胞 (DC) 与 T 细胞激活、血压控制、高血压中的肾和血管功能有关。 我们的中心假设是细胞死亡通过 HMGB1 驱动 DC 和 T 细胞激活并增加血压 两性中 TLR4 的释放和激活。然而，由于细胞死亡类型的性别差异， 驱动女性免疫性高血压的分子途径有利于更多的 Treg 形成。我们将测试 我们的假设通过三个具体目标：1）检验细胞坏死是促炎和促炎症的假设。 男性 SHR 患有高血压，但女性的细胞凋亡较多，减弱了细胞的促炎作用 死亡，2) 检验 HMGB1 和 TLR4 在男性中促炎症和促高血压的假设，而 女性中的 HMGB1 促进 Treg 形成并减轻血压升高，并且 3) 检验以下假设： 男性 SHR 中的 mDC 促进更大的促炎 T 细胞激活和高血压，同时更大的 女性 SHR 中的浆细胞样 DC 导致更多的 Tregs 和更低的血压。 P2 与其他药物具有高度协同作用 项目并依赖于所有核心来成功完成我们的目标。 P2 的目标 1 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 有关炎症的信息 肾髓质的状态，可以进一步了解性别和血压对肾髓质的影响 功能。拟议的研究整合了生理学、药理学、生化、分子和细胞 技术提供对血压控制的机械洞察。几十年来，基础科学研究一直集中在 几乎只针对男性；对疾病进展和治疗的机制洞察 通过研究女性就被忽视了。我们的结果将为支持提供临床前基础 以性别特异性的方式针对免疫系统的特定组成部分，以提高血压控制率 人类。