Immune Modulation of Hypertension

高血压的免疫调节

基本信息

批准号：
9223751
负责人：
Kathryn L Sandberg
金额：
$ 48.06万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9223751
关键词：
Adoptive Transfer Age Age of Onset Angiotensin II Angiotensins Animal Model Anti-Inflammatory Agents Anti-inflammatory Attenuated B-Lymphocytes Blood Pressure CD3 Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cardiovascular Diseases Cell physiology Development Equilibrium Estradiol Estrogens Female Genetic Gonadal structure Hormonal Hypertension Immune Immune system Immunity Inflammatory Infusion procedures Injury to Kidney Interleukin-10 Interleukin-17 Kidney Diseases Lead Leukocytes Link Mediating Mesentery Modeling Mus Organ Ovarian hormone Phenotype Play Predisposition Premenopause Rag1 Mouse Regulation Research Resistance Role Sex Characteristics Sex Chromosomes T cell response T-Lymphocyte T-Lymphocyte Subsets TNF gene Testicular Hormones Testing Testosterone Woman arteriole cardiovascular risk factor cytokine immunoregulation male men novel therapeutic intervention pressure prevent public health relevance receptor response sex

项目摘要

DESCRIPTION (provided by applicant): Recent studies indicate that T cells can modulate arterial pressure. We found that adoptive transfer of male but not female CD3+, CD4+ and CD8+ T cells can mediate Ang II-dependent hypertension in male Rag1 deficient mice. These observations indicate sex specific ations of T cells determine resistance and vulnerability in the regulation of hypertension by the immune system. In aim 1, we will determine if T cell-mediated susceptibility and resistance to hypertension induced by Ang II infusion in the male Rag1-/- host is due to gonad-dependent or gonad-independent effects of the sex chromosomes (XX vs XY) on the T cell donor and how these effects link to end organ damage and T cell responses. In aim 2, we will determine if sex-specific T cell subset responses to Ang II infusion in the male Rag1-/- host are due to sex differences in T cell angiotensin type 1 and type 2 receptors (AT1R and AT2R) and how these receptor- mediated T cell effects link to blood pressure, end organ damage and T cell function. Aim 3 will determine the role of pro- and anti-inflammatory cytokines in CD4+ and CD8+- mediated susceptibility and resistance to Ang II-induced hypertension and link these findings to end organ damage. Defining the mechanisms by which T cell sub- specification and T cell function are regulated by sex in a model of Ang II-dependent hypertension may provide an explanation for the delayed onset of hypertension in premenopausal women compared with age-matched men. Furthermore, discovering immune regulatory phenotypes associated with resistance and susceptibility to hypertension induced by Ang II could uncover T cell subset specific targets and strategies for treating hypertension in both sexes.

描述（由申请人提供）：最近的研究表明 T 细胞可以调节动脉压。我们发现，雄性而非雌性 CD3+、CD4+ 和 CD8+ T 细胞的过继转移可以在雄性 Rag1 缺陷小鼠中介导 Ang II 依赖性高血压。这些观察结果表明，T 细胞的性别特异性决定了免疫系统对高血压调节的抵抗力和脆弱性。在目标 1 中，我们将确定男性 Rag1-/- 宿主中 Ang II 输注诱导的 T 细胞介导的高血压易感性和抵抗力是否归因于性染色体的性腺依赖性或性腺非依赖性效应（XX 与 XY） T 细胞供体以及这些效应如何与终末器官损伤和 T 细胞反应联系起来。在目标 2 中，我们将确定男性 Rag1-/- 宿主中对 Ang II 输注的性别特异性 T 细胞亚群反应是否是由于 T 细胞血管紧张素 1 型和 2 型受体（AT1R 和 AT2R）的性别差异造成的，以及这些差异如何引起的。受体介导的 T 细胞效应与血压、终末器官损伤和 T 细胞功能有关。目标 3 将确定促炎和抗炎细胞因子在 CD4+ 和 CD8+- 介导的对 Ang II 诱导的高血压的易感性和抵抗性中的作用，并将这些发现与终末器官损伤联系起来。在Ang II依赖性高血压模型中定义T细胞亚规格和T细胞功能受性别调节的机制可能为绝经前女性与年龄匹配男性相比高血压的延迟发作提供解释。此外，发现与 Ang II 诱导的高血压抵抗和易感性相关的免疫调节表型可以揭示治疗两性高血压的 T 细胞亚群特异性靶点和策略。