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

基本信息

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
项目类别：
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

项目摘要

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的首要死因，而高血压是其中最常见的疾病第一个风险因素。对于绝经后女性来说，绝经后雌激素的流失更年期会急剧增加这两种情况。虽然众所周知雌激素是预防高血压和心血管疾病的主要保护因素绝经前女性，它能够发挥其作用的机制保护仍然不明确，并损害了我们充分治疗或预防其的能力进展和严重程度。绝经后妇女对当前的抗药物反应不佳高血压； 64% 的女性在工作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对抗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保护的情况下迅速进展卵巢激素。确定雌激素的细胞机制调节 T 细胞功能将鉴定出一种新型且重要的抗高血压药物途径将有助于开发新的治疗方法女性心血管疾病。如下详述，有证据支持这种保护作用是通过雌激素诱导的 T 调节信号介导的细胞，增加抗炎和抗高血压基因的产生，以及抑制对抗促炎和促高血压类型 T 细胞的功能细胞。本提案中概述的研究将调查性的中心假设激素通过阻止 T 细胞减弱血管紧张素 II 的高血压作用浸润/激活，从而防止 T 细胞介导的高血压和肾病受伤。我们建议通过研究从围绝经期到绝经期的过渡绝经后，因此从高血压抵抗转向高血压敏感性，我们有可能揭示导致绝经后的致病机制高血压。我们将通过以下具体目标来检验这些假设 1) 确定 T细胞介导的高血压的雌激素受体（ER）依赖性绝经后女性。我们将确定绝经后高血压和肾病是否损伤是通过 T 细胞与宿主肾脏上的 ER 受体介导的 2) 确定是否 T 细胞亚型的调节影响绝经后高血压和肾病受伤。雌激素可以增加抗炎 T 细胞 (Treg) 并具有抗炎作用细胞因子的产生（IL-10）因此我们将使用更年期的VCD模型来确定雌激素的丧失与促炎性物质的易感性增加有关细胞因子的产生和肾损伤。我们的研究的转化潜力很高：研究绝经后女性 T 细胞介导的高血压的发病情况揭示的致病机制可能会导致新的治疗方法减少绝经后女性高血压相关并发症。