Chemokine control of cardiovascular function during hemorrhagic shock

描述（由申请人提供）：本研究项目旨在阐明失血性休克期间心血管反应的机制，并为创伤患者寻找新的治疗靶点。我们之前的工作和新的初步数据表明，CXC趋化因子受体（CXCR） 7的激活导致血管儿茶酚胺抵抗和心血管衰竭，而CXCR4的激活在失血性休克期间维持血管对儿茶酚胺的反应性。这导致了主要假设，即CXCR4和CXCR7是失血性休克期间心血管功能的关键调节因子，通过调节肾上腺素能受体（AR）信号通路影响血管张力。为了验证我们的假设，我们提出以下目标：1。以确定体外CXCR4/7的药理调节如何影响血管功能。利用压力肌图作为测试平台，我们将回答以下关键问题：CXCR4/7激动剂对血管反应性的影响是否对1AR激活具有特异性？血管床之间有区别吗？内皮对观察到的效果有贡献吗？SDF-1对CXCR4和CXCR7的影响是否可以区分？G i蛋白的解偶联如何影响CXCR4/7调节剂的作用？失血性休克是否会引起血管反应性的持续改变？2. 研究体内暴露于儿茶酚胺和失血性休克时CXCR4/7对心血管功能的影响。我们将利用压力-体积环分析来确定CXCR4/7调节如何在肾上腺素能激动剂和随后的液体复苏失血性休克期间改变心血管功能。此外，我们将确定是否可以挽救CXCR7对正常心血管功能的有害影响，测试在致命的失血性休克中激活CXCR4后存活时间延长的动物是否可以通过液体复苏从心血管衰竭中拯救出来，并评估在休克和复苏期间选择性激活CXCR4的长期后果。3. 探讨CXCR4/7对血管作用的分子机制。具体假设是CXCR4/7控制1AR信号。为了验证这一假设，我们将确定CXCR4/7/ 1AR之间的串扰机制，它们的信号串扰机制，并阐明CXCR4/7调节血管平滑肌细胞中1AR诱导的血管收缩的途径。我们提出了一系列最先进的体内和离体研究，并辅以生化、分子和细胞生物学方法来阐明CXCR4和CXCR7在失血性休克期间通过调节α - 1AR信号来控制血管张力的分子机制。从该提案中获得的新知识将有助于确定CXCR4/7作为稳定心血管功能和增强休克耐受性的药物靶点。

DESCRIPTION (provided by applicant): The goals of this research program are to elucidate the mechanisms that govern the cardiovascular response during hemorrhagic shock and to identify new therapeutic targets for trauma patients. Our previous work and new preliminary data suggest that activation of CXC chemokine receptor (CXCR) 7 results in vascular catecholamine resistance and cardiovascular collapse, whereas CXCR4 activation maintains vascular reactivity to catecholamines during hemorrhagic shock. This leads to the main hypothesis that CXCR4 and CXCR7 are critical regulators of cardiovascular function during hemorrhagic shock, which influence vascular tone through modulation of adrenergic receptor (AR) signaling. To test our hypothesis, we propose the following aims: 1. to determine how pharmacological CXCR4/7 modulation affects vascular function ex vivo. Utilizing pressure myography as a test platform, we will answer the following key questions: Are the effects of CXCR4/7 agonists on vascular reactivity specific for �1AR activation? Are there differences among vascular beds? Does the endothelium contribute to the observed effects? Can effects of SDF-1� on CXCR4 and CXCR7 be differentiated? How does uncoupling of G�i protein affect the actions of CXCR4/7 modulators? Does hemorrhagic shock induce persistent changes in vascular reactivity? 2. To determine how CXCR4/7 influence cardiovascular function during catecholamine exposure and hemorrhagic shock in vivo. We will utilize pressure volume loop analyses to determine how CXCR4/7 modulation alters cardiovascular function in response to adrenergic agonists and during hemorrhagic shock with subsequent fluid resuscitation. Furthermore, we will determine whether deleterious effects of CXCR7 on normal cardiovascular function can be rescued, test whether animals with prolonged survival after CXCR4 activation during otherwise lethal hemorrhagic shock can be rescued from cardiovascular collapse with fluid resuscitation and evaluate long term consequences of selective CXCR4 activation during shock and resuscitation. 3. To identify the molecular mechanisms underlying vascular effects of CXCR4/7. The specific hypothesis is that CXCR4/7 control �1AR signaling. To test this hypothesis, we will determine the mechanism of cross-talk between CXCR4/7/�1AR, the mechanism of their signaling crosstalk and elucidate the pathway by which CXCR4/7 modulate �1AR-induced vasoconstriction in vascular smooth muscle cells. We propose a comprehensive series of state-of-the-art in vivo and ex vivo studies complemented with biochemical, molecular and cellular biology approaches to elucidate the molecular mechanisms by which CXCR4 and CXCR7 modulate �1AR signaling to control vascular tone during hemorrhagic shock. New knowledge gained from this proposal will help to establish CXCR4/7 as drug targets to stabilize cardiovascular function and enhance shock tolerance.