Regulation of vascular eicosanoid receptors

描述（由申请人提供）：血管活性前列腺素和氧化还原信号是心血管生理和疾病的组成部分。这些介质中主要有环氧化酶(COX)-2衍生的环环素（PGI2）和血小板COX-1的主要产物血栓素（TxA2）。PGI2对TxA2的拮抗似乎对心血管稳态和病理生理至关重要——PGI2生成的抑制，不受限制的TxA2生物合成为选择性COX-2抑制剂相关的心血管风险提供了机制解释。在心血管疾病中，TxA2和PGI2的生物合成及其受体的表达随着活性氧（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的复杂相互作用介导的。该提案将研究氧化还原信号调节TxA2 （TP）和PGI2 （IP）受体的调节、功能和二聚体结合的新途径。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中的收敛性。Specific Aim 1将定义在血管细胞和血管损伤小鼠模型中驱动一个前馈循环的机制，通过这个前馈循环，TP衍生的ROS增强TP的表达。在具体目标2中，我们将研究TP的ip依赖调制如何中断该环路。最后，在Specific Aim 3中，我们建议研究TP和IP的非单体关联，以及ROS在这一过程中的作用，作为受体表达和功能的调节剂。与公共卫生的相关性：心血管系统有一系列的检查和平衡，旨在保持其功能和预防疾病。这项工作将研究一个这样的系统，检查新的机制，通过一种介质，前列环素，抵消另一种血栓素的作用，从而有助于维持心血管健康。

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.