Regulation of vascular eicosanoid receptors

描述(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学和疾病不可或缺的。这些介质中的主要是前列环素(PGI2)，主要是环氧合酶(COX)-2衍生的，以及血栓素A2(TXA2)，血小板COX-1的主要产物。PGI2对TXA2的拮抗似乎对心血管内稳态和PGI2生成的病理生理抑制至关重要，TXA2的不受限制的生物合成为选择性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自由基(ROS)的升高而增加。这些前列腺素之间的动态相互作用似乎是通过它们的受体和它们转导的信号事件的复杂相互作用来调节的。这项建议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洞察力。我们将在三个特定的目标中研究TP和IP在氧化还原信号上的融合。具体目标1将确定驱动反馈环的机制，通过该机制，TP衍生的ROS在血管细胞和血管损伤的小鼠模型中增强TP的表达。在特定的目标2中，我们将研究依赖于IP的TP调制如何中断这一循环。最后，在特定的目标3中，我们建议研究TP和IP的非单体结合，以及ROS作为受体表达和功能的调节因子在这一过程中的作用。与公共健康相关：心血管系统有一系列旨在保持其运转和预防疾病的制衡机制。这项工作将研究一个这样的系统，检查一种新的机制，通过这种机制，一种介质前列环素可以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.