Prostaglandin E2, Immunity and hypertension

前列腺素 E2、免疫与高血压

基本信息

批准号：
10077572
负责人：
RICHARD M. BREYER
金额：
$ 39.5万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10077572
关键词：
Adoptive Transfer American Angiotensin II Antigens Antihypertensive Agents Antiinflammatory Effect Arachidonic Acids Blood Pressure Cause of Death Cell Transplantation Cells Chronic Congestive Heart Failure Data Dendritic Cells Development Dietary Sodium Dinoprostone Disease Drug usage EP4 receptor Enzymes Essential Hypertension Etiology Experimental Models Exposure to Generations Heart Diseases Hypertension Immune Immunity Inflammation Inflammatory Inflammatory Response Knockout Mice Lead Ligands Link Lymphocyte Mediating Molecular Mouse Strains Mus NG-Nitroarginine Methyl Ester Non-Steroidal Anti-Inflammatory Agents Oxidative Stress Pain management Physiological Prostaglandin-Endoperoxide Synthase Prostaglandins Proteins Rag1 Mouse Reactive Oxygen Species Regulation Research Personnel Resistance Risk Factors Role Signal Pathway Sodium Chloride Stimulus Stroke Systemic blood pressure T cell response T memory cell T-Cell Activation T-Lymphocyte Testing United States Universities WFDC2 gene Work adaptive immune response adduct blood pressure regulation cell mediated immune response cyclooxygenase 1 cyclooxygenase 2 high salt diet hypertension treatment mouse model neoantigens novel physiologic stressor prostanoid receptor EP1 receptor receptor expression response side effect small molecule

项目摘要

Prostaglandins (PGs), oxidative metabolites of arachidonic acid, mediate an array of physiologic functions including inflammation and systemic blood pressure homeostasis. Prostaglandin E2 (PGE2) is a major regulator of blood pressure, where it exerts pro-hypertensive or anti-hypertensive effects depending upon the setting. These physiologically opposing effects are mediated by four PGE2 receptors, designated the E-Prostanoid (EP) receptors EP1 to EP4. Previous work by our group and others determined that EP1 and EP3 primarily mediate the pro-hypertensive response, while EP2 and EP4 receptors mediate the anti-hypertensive response. PGs are well characterized to be effectors of inflammation, and thus PGs act at the intersection of inflammation and blood pressure homeostasis, making them potential targets in the etiology of essential hypertension. Our hypothesis is that EP receptors regulate immune-inflammatory cells and a robust T-cell mediated immune response contributes to hypertension. Moreover, multiple, repeated stimulation of the T-cell response in the face of hypertensive stimuli such as salt loading is modulated by PGs to generate sustained elevated blood pressure. We hypothesize that the EP3 receptor is the principal receptor facilitating the PGE2 response to raise blood pressure. To test these related hypotheses we propose three Specific Aims: 1) Test the hypothesis that EP3 regulates the response to repeated pro-hypertensive stimuli leading to the development of memory T-cells underlying sustained elevation of blood pressure; 2) Test the hypothesis that elevated ROS leads to neoantigen stimulated T-cell formation; 3) Test the hypothesis that EP receptor expression on T-cells contributes to the generation of hypertension.

前列腺素（PGS），蛛网膜酸的氧化代谢产物，介导一系列生理功能包括炎症和全身性血压稳态。 Prostaglandin E2（PGE2）是主要的调节器血压，在情况下会根据环境发挥促甲状管拉力或抗高血压作用。这些在生理上相反的作用是由四个PGE2受体介导的，称为电子肉食素（EP）受体EP1至EP4。我们小组和其他人的先前工作确定EP1和EP3主要是介导促氧化反应，而EP2和EP4受体则介导抗高血压反应。 PG被很好地表征为炎症的效应因子，因此PG在炎症的交集处起作用和血压稳态，使其成为基本高血压病因的潜在靶标。我们的假设是EP受体调节免疫炎性细胞和强大的T细胞介导的免疫反应有助于高血压。此外，多次反复刺激T细胞响应 PGS调节诸如盐负荷之类的高血压刺激，以产生持续的血液压力。我们假设EP3受体是促进PGE2响应以升高的主要受体血压。为了检验这些相关假设，我们提出了三个具体目的：1）检验以下假设。 EP3调节对重复的促甲状腺重复刺激的反应，导致记忆T细胞的发展持续的血压升高； 2）检验升高ROS导致的假设新抗原刺激T细胞的形成； 3）检验了T细胞上EP受体表达的假设有助于产生高血压。