Molecular Mechanism of PGE2 Receptor Pressor Effects

PGE2 受体升压效应的分子机制

基本信息

批准号：
7850083
负责人：
RICHARD M. BREYER
金额：
$ 2.3万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7850083
关键词：
Accounting Acute Angiotensin II Angiotensins Arachidonic Acids Attenuated Blood Pressure Blood Vessels Cells Chronic Kidney Failure Data Development Diabetic Nephropathy Dinoprostone Disodium Salt Nitroprusside Double Effect EP4 receptor Fibrosis Gene Targeting Genetic Hypertension In Vitro Infusion procedures Kidney Kidney Diseases Kidney Failure Knock-out Knockout Mice Mediating Molecular Nephrectomy Phenotype Phenylephrine Physiological Property Prostaglandins Receptor Signaling Receptor, Angiotensin, Type 1 Regulation Renin-Angiotensin System Role Signal Transduction Transgenic Mice Vasoconstrictor Agents Work base blood pressure regulation human WFDC2 protein hypertension treatment in vivo insight mouse model novel pressure prevent prostaglandin EP3 receptor prostanoid receptor EP1 public health relevance receptor response

项目摘要

DESCRIPTION (provided by applicant): Prostaglandin E2 (PGE2) regulates blood pressure, where it can exert either vasopressor or vasodepressor effects. These physiologically opposing effects can be explained in part by the existence of four PGE2 receptors, designated the E-Prostanoid (EP) receptors EP1 through EP4. The EP1 and EP3 receptors primarily mediate the pressor response, while the EP2 and EP4 receptors mediate the depressor response. We will investigate the role of the pressor effects of PGE2 utilizing EP1 and EP3 null mouse models. We will determine the mechanism by which angiotensin II interacts with EP1 activation. We will further investigate the mechanism of action of the EP3 receptor, which appears to have has quite distinct properties and mechanism of pressor action compared to the EP1 receptor. We hypothesize that the two receptors act in distinct manners on disparate targets and may synergize to produce the pressor effect of PGE2. Because the EP1 receptor has been demonstrated to mediate some of the pressor effects of angiotensin II and the renin-angiotensin-system, we hypothesize that EP1 may mediate renin-angiotensin-system evoked effects on renal fibrosis and chronic kidney disease. To investigate these related hypotheses, we will undertake the following three Specific Aims: Specific aim 1. To determine the molecular mechanism of EP1 receptor pressor effects. Specific aim 2: To determine the molecular mechanism of EP3 receptor pressor effects. Specific aim 3: To determine whether EP1 or EP3 receptor blockade will prevent or attenuate the progression of chronic kidney disease. PUBLIC HEALTH RELEVANCE This project will assess the mechanism of action of two PGE2 receptors and their contribution to elevated blood pressure in the development of renal fibrosis. In vitro studies will focus on the downstream receptor signal transduction of AT1 angiotensin receptor and PGE2 EP receptors to investigate evidence of receptor synergy. Studies will include mouse models of diabetic nephropathy, 5/6 nephrectomy and angiotensin induced hypertension to examine potential mechanisms of renal damage.

描述（由申请人提供）：前列腺素 E2 (PGE2) 调节血压，可发挥血管加压或血管抑制作用。这些生理上相反的作用可以部分解释为四种 PGE2 受体的存在，称为 E-前列腺素 (EP) 受体 EP1 至 EP4。 EP1和EP3受体主要介导升压反应，而EP2和EP4受体介导降压反应。我们将利用 EP1 和 EP3 缺失小鼠模型研究 PGE2 升压效应的作用。我们将确定血管紧张素 II 与 EP1 激活相互作用的机制。我们将进一步研究 EP3 受体的作用机制，与 EP1 受体相比，EP3 受体似乎具有截然不同的特性和升压作用机制。我们假设这两种受体以不同的方式作用于不同的靶标，并且可能协同产生 PGE2 的升压作用。由于 EP1 受体已被证明可以介导血管紧张素 II 和肾素血管紧张素系统的一些升压作用，因此我们假设 EP1 可能介导肾素血管紧张素系统对肾纤维化和慢性肾脏疾病的诱发作用。为了研究这些相关的假设，我们将采取以下三个具体目标：具体目标1.确定EP1受体升压作用的分子机制。具体目标2：确定EP3受体升压作用的分子机制。具体目标 3：确定 EP1 或 EP3 受体阻断是否会预防或减轻慢性肾病的进展。公共卫生相关性该项目将评估两种 PGE2 受体的作用机制及其在肾纤维化发展过程中对血压升高的影响。体外研究将重点关注AT1血管紧张素受体和PGE2 EP受体的下游受体信号转导，以研究受体协同作用的证据。研究将包括糖尿病肾病、5/6 肾切除术和血管紧张素诱导的高血压的小鼠模型，以检查肾脏损伤的潜在机制。