T Cell-Mediated Regulation of Blood pressure In Postmenopausal Hypertension

T 细胞介导的绝经后高血压血压调节

• 批准号: 9239751
• 负责人: HEDDWEN L BROOKS
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239751
• 关键词: Ablation; Adaptive Immune System; Adoptive Transfer; Adrenergic beta-Antagonists; Androgens; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Anti-inflammatory; Antihypertensive Agents; Area; Attenuated; B-Lymphocytes; Blood Pressure; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cells; Clinical; Data; Dependence; Development; Disease; Estrogen Receptor Modulators; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen Replacements; Estrogens; Female; Fibrosis; Genes; Goals; Gonadal Steroid Hormones; Human; Hypertension; Immune; Immune response; Impairment; Infiltration; Inflammation; Inflammatory; Infusion procedures; Injury; Interleukin-10; Kidney; Lead; Mediating; Menopause; Modeling; Molecular; Mus; Organ; Outcome; Ovarian; Ovarian Tissue; Ovarian hormone; Ovariectomy; Pathogenicity; Pathway interactions; Perimenopause; Pharmaceutical Preparations; Pharmacology; Play; Postmenopause; Predisposition; Premenopause; Production; Rag1 Mouse; Regulatory T-Lymphocyte; Research; Residual state; Resistance; Risk Factors; Rodent Model; Role; Severities; Signal Transduction; Sodium Chloride; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Woman; blood pressure regulation; cardiovascular risk factor; coronary fibrosis; cytokine; hormone therapy; in vivo; inflammatory milieu; male; men; novel; novel therapeutics; ovarian failure; prevent; receptor; reconstitution; response; transcriptome; translational study

Cardiovascular disease is the leading cause of death in the U.S., and hypertension is its number one risk factor. In postmenopausal women, the loss of estrogen after menopause dramatically increases both of these conditions. While estrogen is known to be the major protective factor against hypertension and cardiovascular disease in premenopausal females, the mechanisms through which it is capable of exerting its protection remains ill-defined and impairs our ability to adequately treat or prevent its progression and severity. Postmenopausal women do not respond well to current anti- hypertensives; 64% of women do not have their blood pressure controlled when in menopause. We recently demonstrated that premenopausal females are protected against T cell mediated hypertension. We now show that postmenopausal females are not protected, and T cell mediated hypertension progresses rapidly in the absence of ovarian hormones. Determining the cellular mechanisms through which estrogen regulates T cell function would identify a novel and important anti-hypertensive pathway that would aid in the development of new therapeutic treatments for cardiovascular disease in women. As detailed below, there is evidence to support the notion that this protection is mediated through estrogen-induced signaling in T-regulatory cells, increasing their production of anti-inflammatory and anti-hypertensive genes, and repressing the function of opposing pro-inflammatory and pro-hypertensive types of T cells. The studies outlined in this proposal will investigate central hypothesis that sex hormones attenuate the hypertensive effects of angiotensin II by preventing T cell infiltration/activation, thus protecting against T cell mediated hypertension and renal injury. We propose that by studying the transition from perimenopause to postmenopause, so moving from hypertension resistance to hypertension sensitivity, we are likely to uncover the pathogenic mechanisms leading to postmenopausal hypertension. We will test these hypotheses via the following specific aims 1) Determine the estrogen receptor (ER) dependence of T cell mediated hypertension in postmenopausal females. We will determine if postmenopausal hypertension and renal injury are mediated via ER receptors on T cells versus the host kidney 2) Determine if modulation of T cell subtypes impacts postmenopausal hypertension and renal injury. Estrogen can increase anti-inflammatory T cells (Tregs) and anti-inflammatory cytokine production (IL-10) thus we will use the VCD model of menopause to determine loss of estrogen is associated with an increase in susceptibility to pro-inflammatory cytokine production and renal injury. Translational potential of our studies is high: by studying the onset of T cell-mediated hypertension in postmenopausal females, the pathogenic mechanisms uncovered may lead to novel treatments in decreasing hypertension-related complications in postmenopausal females.

心血管疾病是美国人死亡的主要原因，高血压是 头号危险因素在绝经后妇女中， 更年期会显著增加这两种情况。虽然雌激素已知 是预防高血压和心血管疾病的主要保护因素， 绝经前女性，通过它能够发挥其 保护仍然不明确，损害了我们充分治疗或预防其 进展和严重程度。绝经后妇女对目前的抗- 高血压; 64%的女性在怀孕期间血压没有得到控制。 绝经我们最近证明，绝经前女性受到保护， 抗T细胞介导的高血压。我们现在发现绝经后女性 不受保护，T细胞介导的高血压在缺乏 卵巢激素确定雌激素通过细胞机制 调节T细胞功能将确定一种新的和重要的抗高血压药物 这将有助于开发新的治疗方法， 女性的心血管疾病如下文所述，有证据支持 这种保护作用是通过雌激素诱导的T细胞调节信号传导介导的， 细胞，增加其抗炎和抗高血压基因的产生， 抑制对抗促炎和促高血压类型T细胞的功能， 细胞这项建议中概述的研究将调查中心假设， 激素通过阻止T细胞增殖来减弱血管紧张素II的高血压效应， 浸润/活化，从而保护免受T细胞介导的高血压和肾损害。 损伤我们建议，通过研究从围绝经期过渡到 绝经后，所以从高血压抵抗性到高血压敏感性，我们 有可能揭示导致绝经后 高血压我们将通过以下具体目标来测试这些假设1）确定 T细胞介导高血压对雌激素受体依赖性 绝经后女性我们将确定绝经后高血压和肾性高血压 损伤是通过T细胞上的ER受体介导的，而不是宿主肾脏。 调节T细胞亚型影响绝经后高血压和肾功能 损伤雌激素可以增加抗炎性T细胞（TCLs）和抗炎性T细胞（TCLs）。 因此，我们将使用绝经的VCD模型来确定 雌激素的损失与促炎性反应的易感性增加有关 细胞因子产生和肾损伤。我们研究的翻译潜力很高： 研究绝经后女性T细胞介导的高血压的发病， 发现的致病机制可能导致新的治疗方法， 绝经后女性的高血压相关并发症。