Prostaglandin E2, Immunity and hypertension

前列腺素(PGs)是花生四烯酸的氧化代谢产物，调节一系列生理功能 包括炎症和全身血压动态平衡。前列腺素E2(PGE2)是一种主要的调节因子 血压，根据环境的不同，发挥降压或降压作用。 这些生理上相反的效应是由四种PGE2受体介导的，它们被称为E-前列腺素 (EP)受体EP1至EP4。我们小组和其他人之前的工作确定了EP1和EP3主要是 EP2和EP4受体介导降压反应。 前列腺素G具有炎症效应的特征，因此PG作用于炎症的交叉点。 和血压动态平衡，使它们成为高血压病因学的潜在靶点。我们的 假设EP受体调节免疫炎症细胞和强大的T细胞介导的免疫 这种反应会导致高血压。此外，对T细胞反应的多次、重复刺激 面对高血压刺激，如盐负荷，PGs调节产生持续升高的血液 压力。我们假设EP3受体是促进PGE2反应升高的主要受体 血压。为了检验这些相关假设，我们提出了三个具体目标：1)检验假设 EP3调节对反复高血压前刺激的反应，导致记忆T细胞的发展 潜在的持续血压升高；2)检验ROS升高导致 新抗原刺激T细胞形成；3)检验T细胞上EP受体表达的假说 会导致高血压的产生。

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.