Mechanisms of T Cell-Mediated Hypertension In Females and Males

女性和男性 T 细胞介导的高血压机制

• 批准号: 9198049
• 负责人: Jennifer C Sullivan
• 金额: $ 42.41万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198049
• 关键词: Address; Adoptive Transfer; Adult; Affect; Age; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Aorta; Arteries; Attenuated; Automobile Driving; Biological Availability; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cells; Cessation of life; Chronic; Chronic Kidney Failure; Data; Development; Endothelial Cells; Environment; Equilibrium; Exhibits; Female; Foundations; Goals; Heart failure; Hypertension; Immune; In Vitro; Inbred SHR Rats; Interleukin-10; Kidney; Kidney Transplantation; Knowledge; Literature; Maintenance; Measures; Mediating; Mesenteric Arteries; Mission; Molecular; Morbidity - disease rate; Myocardial Infarction; Natriuresis; Nitric Oxide; Nitric Oxide Synthase; Patients; Peripheral arterial disease; Pharmaceutical Preparations; Pharmacology; Production; Proteinuria; Publishing; Regulatory T-Lymphocyte; Renal function; Reporting; Risk; Role; Severities; Sex Characteristics; Stroke; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Testing; United States National Institutes of Health; Vasodilation; Woman; age related; attenuation; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; cytokine; improved; inhibitor/antagonist; interleukin-10 receptor; kidney vascular structure; male; men; mortality; novel; pre-clinical; premature; pressure; prevent; public health relevance; receptor expression; response; sex; targeted treatment; young woman

 DESCRIPTION (provided by applicant): Hypertension affects ~33% of adults in the U.S. and is a risk factor for cardiovascular disease. Fewer than 40% of hypertensive patients control their blood pressure (BP) with current medication, leaving 60% at heightened risk for cardiovascular morbidity and mortality. Although both sexes develop hypertension, young women are protected from hypertension relative to age-matched men. The identification of mechanisms by which females delay increases in BP is an underutilized approach that can be exploited to develop improved treatment options for both sexes. A critical barrier to improving BP control rates is the lack of knowledge regarding the molecular mechanisms driving elevated BP in either sex. Our goal is to address these gaps by advancing our understanding of the role of T cells in BP control in males and females. There is growing support for a causal role for effector T cells in hypertension in male animal models. Data in females are largely lacking, however, we reported that female spontaneously hypertensive rats (SHR) have more regulatory T cells (Tregs) than males. Tregs limit increases in BP in males and our preliminary data shows that Treg expansion decreases BP in female SHR. Our central hypothesis is that although effector T cells cause hypertension in both sexes, greater Tregs in females mitigate T cell-mediated hypertension via increased interleukin (IL)-10 induced nitric oxide (NO) production. Treg-mediated attenuation hypertension in male animals is associated with increased NO-dependent vasodilation, and preliminary data indicates NOS activity increases concomitant with increases in Tregs only in female SHR. Two Specific Aims will test our hypothesis. Aim 1 will test the hypothesis that greater Tregs in females limit increases in BP relative to males. We will determine the impact of sex on renal and vascular T cell activation and function and measure BP responses, proteinuria, and vascular function following total T cell depletion and Treg depletion/expansion. Adoptive transfer studies will determine if T cells from males vs. females have innate differences impacting differentiation, or if the local environment is more critical in defining the immune profile. Renal transplant studies will determine of the role of the kidney vs. circulating factors n defining T cell profiles. Aim 2 will test the hypothesis that females have greater Treg-mediated increase in NO bioavailability via IL-10 resulting in improved vascular endothelial and renal function. We will measure NO bioavailability following Treg depletion/expansion in the absence and presence of IL-10 blockers. We will measure the contribution of Treg and IL-10-mediated NO release on the pressure natriuresis curve and vascular function. We will assess the contribution of Treg-mediated NO production on BP control during chronic NOS inhibition. Results will provide necessary pre-clinical foundation to support the development of novel, more refined approaches to target specific immune components in a sex- specific manner to improve BP control rates. Therapies targeting the pathophysiological cause of hypertension will undoubtedly improve BP control rates and prevent premature death from cardiovascular disease.

 描述（由申请人提供）：高血压影响美国约33%的成年人，是心血管疾病的危险因素。只有不到40%的高血压患者通过目前的药物治疗控制了血压（BP），使60%的高血压患者面临心血管发病率和死亡率的高风险。虽然男女都有高血压，但相对于年龄相当的男性，年轻女性不会患高血压。女性延迟血压升高的机制的确定是一种未充分利用的方法，可以用来为两性开发更好的治疗方案。提高血压控制率的一个关键障碍是缺乏关于在任何性别中驱动血压升高的分子机制的知识。我们的目标是通过推进我们对T细胞在男性和女性血压控制中的作用的理解来解决这些差距。在雄性动物模型中，效应T细胞在高血压中的因果作用得到越来越多的支持。在女性的数据很大程度上是缺乏的，然而，我们报道，女性自发性高血压大鼠（SHR）比男性有更多的调节性T细胞（Tcells）。Treg限制男性血压升高，我们的初步数据显示Treg扩增降低了女性SHR的血压。我们的中心假设是，虽然效应T细胞引起高血压在两种性别，更大的Tcells在女性减轻T细胞介导的高血压通过增加白细胞介素（IL）-10诱导的一氧化氮（NO）的生产。雄性动物Treg介导的衰减性高血压与NO依赖性血管舒张增加相关，初步数据表明，NOS活性增加伴随着雌性SHR中TdR的增加。两个具体目标将检验我们的假设。目标1将检验女性TbR值大于男性限制BP升高的假设。我们将确定性别对肾脏和血管T细胞活化和功能的影响，并测量总T细胞耗竭和Treg耗竭/扩增后的血压反应、蛋白尿和血管功能。连续转移研究将确定来自男性与女性的T细胞是否具有影响分化的先天差异，或者局部环境是否在定义免疫特征方面更关键。肾移植研究将确定肾脏与循环因子在定义T细胞谱中的作用。目的2将检验以下假设：女性具有更大的Treg介导的通过IL-10增加NO生物利用度，从而改善血管内皮和肾功能。我们将在不存在和存在IL-10阻断剂的情况下测量Treg耗竭/扩增后的NO生物利用度。我们将测量Treg和IL-10介导的NO释放对压力尿钠排泄曲线和血管功能的贡献。我们将评估慢性NOS抑制期间Treg介导的NO产生对血压控制的贡献。结果将提供必要的临床前基础，以支持开发新的、更精细的方法，以性别特异性方式靶向特定免疫组分，以提高BP控制率。针对高血压病理生理原因的治疗无疑将提高血压控制率，防止心血管疾病导致的过早死亡。