Regulation of vascular eicosanoid receptors

血管类二十烷酸受体的调节

基本信息

批准号：
7640891
负责人：
EMER MARIA SMYTH
金额：
$ 35.44万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7640891
关键词：
Address Agonist Anabolism Antioxidants Arachidonic Acids Attenuated Biological Blood Platelets Blood Vessels Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cell membrane Cell surface Cells Complex Coxibs Cultured Cells Dimerization Disease Down-Regulation Eicosanoid Receptor Endoplasmic Reticulum Endothelium Epoprostenol Equilibrium Event Functional disorder G-Protein-Coupled Receptors Generations Golgi Apparatus Health Homeostasis Homo Homodimerization Human Hydrogen Peroxide Injury Maintenance Mediating Mediator of activation protein Membrane Metabolism Mitogens Modeling NADPH Oxidase Oxidants Oxidation-Reduction Pathway interactions Process Prostaglandin-Endoperoxide Synthase Prostaglandins Prostaglandins I Public Health RNA Splicing Reactive Oxygen Species Receptor Signaling Regulation Role Series Signal Transduction System Thromboxanes Up-Regulation Variant Vasoconstrictor Agents Work cardiovascular risk factor cyclooxygenase 1 cyclooxygenase 2 depression design dimer feeding in vivo insight mouse model novel prevent receptor receptor expression response

项目摘要

DESCRIPTION (provided by applicant): Vasoactive prostanoids and redox signaling are integral to cardiovascular physiology and disease. Principal amongst these mediators are prostacyclin (PGI2), predominantly cyclooxygenase (COX)-2-derived, and thromboxane (TxA2), the primary product of platelet COX-1. Opposition of TxA2 by PGI2 appears critical to cardiovascular homeostasis and pathophysiology - depression of PGI2 generation, with unrestricted biosynthesis of TxA2 provides a mechanistic explanation for the cardiovascular risk associated with selective COX-2 inhibitors. Biosynthesis of TxA2 and PGI2, and expression of their receptors, is augmented coincident with elevated reactive oxygen species (ROS) in cardiovascular disease. The dynamic interplay between these prostanoids appears to be mediated by complex interactions of their receptors and signaling events that they transduce. This proposal will investigate novel pathways through which redox signaling modulates the regulation, function and dimeric association of the receptors for TxA2 (the TP) and PGI2 (the IP). These studies will provide novel mechanistic insights into human cardiovascular disease. We will examine the convergence of TP and IP on redox signaling in three specific aims. Specific Aim 1 will define the mechanisms that drive a feed-froward loop, through which TP-derived ROS enhance TP expression, in vascular cells and in a mouse model of vascular injury. In Specific Aim 2, we will examine how IP-dependent modulation of TP can interrupt this loop. Finally, in Specific Aim 3, we propose to examine non-monomeric association of TP and IP, and the role of ROS in this process, as a regulator of receptor expression and function. Relevance to public health: The cardiovascular system has a series of check and balances designed to keep it functioning and prevent disease. This work will investigate one such system, examining novel mechanisms through which one mediator, prostacyclin, works to offsets the actions of another thromboxane, thus contributing to the maintenance of cardiovascular health.

描述（由申请人提供）：血管活性前列腺素和氧化还原信号对于心血管生理学和疾病是不可或缺的。这些介质中主要的是前列环素 (PGI2)（主要源自环氧合酶 (COX)-2）和血栓素 (TxA2)（血小板 COX-1 的主要产物）。 PGI2 对 TxA2 的对抗似乎对心血管稳态和病理生理学至关重要 - PGI2 生成的抑制以及 TxA2 生物合成不受限制，为与选择性 COX-2 抑制剂相关的心血管风险提供了机制解释。 TxA2 和 PGI2 的生物合成及其受体的表达随着心血管疾病中活性氧 (ROS) 的升高而增强。这些前列腺素之间的动态相互作用似乎是由它们的受体和它们转导的信号事件之间的复杂相互作用介导的。该提案将研究氧化还原信号传导调节 TxA2 (TP) 和 PGI2 (IP) 受体的调节、功能和二聚体关联的新途径。这些研究将为人类心血管疾病提供新的机制见解。我们将在三个具体目标中研究 TP 和 IP 在氧化还原信号传导方面的融合。具体目标 1 将定义驱动前馈循环的机制，通过该机制，TP 衍生的 ROS 增强血管细胞和血管损伤小鼠模型中的 TP 表达。在具体目标 2 中，我们将研究 TP 的 IP 相关调制如何中断此循环。最后，在具体目标 3 中，我们建议检查 TP 和 IP 的非单体关联，以及 ROS 作为受体表达和功能调节剂在此过程中的作用。与公共卫生的相关性：心血管系统有一系列旨在保持其功能和预防疾病的制衡。这项工作将研究这样一个系统，检查一种介质前列环素抵消另一种血栓素作用的新机制，从而有助于维持心血管健康。