Chemokine control of cardiovascular function during hemorrhagic shock

项目总结/摘要 这项研究计划的目标是阐明心血管反应的机制 并为创伤患者确定新的治疗靶点。我们以前的工作和 新的初步数据表明，CXC趋化因子受体（CXCR）7的激活导致血管内皮细胞的凋亡。 儿茶酚胺抵抗和心血管崩溃，而CXCR 4激活维持血管 在失血性休克期间对儿茶酚胺的反应性。这导致了一个主要的假设，即CXCR 4和 CXCR 7是失血性休克期间心血管功能的关键调节因子，其影响血管 调节肾上腺素能受体（AR）信号。为了验证我们的假设，我们提出了 以下目标：1.确定药理学CXCR 4/7调节如何影响血管功能 vivo.利用压力肌造影作为测试平台，我们将回答以下关键问题： CXCR 4/7激动剂对血管反应性的影响，特异于<$1AR激活？是否存在差异 血管床内皮是否有助于观察到的效应？SDF-1对CXCR 4的影响 CXCR 7有什么区别？G蛋白的解偶联如何影响CXCR 4/7调节剂的作用？ 失血性休克是否会引起血管反应性的持续变化？2.为了确定CXCR 4/7 在体内暴露于儿茶酚胺和失血性休克时对心血管功能影响。我们 将利用压力容量回路分析来确定CXCR 4/7调节如何改变心血管 在对肾上腺素能激动剂的反应中以及在随后的液体复苏的失血性休克期间， 此外，我们将确定CXCR 7对正常心血管功能的有害作用是否能 被拯救，测试在其他致死期间CXCR 4激活后存活时间延长的动物 失血性休克可通过液体复苏从心血管性虚脱中抢救出来，并可进行长期评估 休克和复苏期间选择性CXCR 4激活的后果。3.来鉴定 CXCR 4/7血管效应的潜在机制。具体假设是CXCR 4/7控制 1AR信令。为了验证这一假设，我们将确定 CXCR 4/7/1AR，其信号转导串扰的机制，并阐明CXCR 4/7 调节血管平滑肌细胞中AR诱导的血管收缩。 我们提出了一个全面的一系列最先进的体内和体外研究， 生物化学，分子和细胞生物学方法来阐明分子机制， CXCR 4和CXCR 7调节<$1AR信号以控制失血性休克期间的血管张力。新 从该提案中获得的知识将有助于将CXCR 4/7确立为稳定心血管疾病的药物靶点， 功能和增强抗冲击能力。

Project Summary/Abstract 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 affect 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.