Chemokine control of cardiovascular function during hemorrhagic shock

失血性休克期间趋化因子对心血管功能的控制

• 批准号: 9701546
• 负责人: Matthias Majetschak
• 金额: $ 14.32万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9701546
• 关键词: Chemokine; control; cardiovascular; function; during

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 α1AR activation? Are there differences among vascular beds? Does the endothelium contribute to the observed effects? Can effects of SDF-1α on CXCR4 and CXCR7 be differentiated? How does uncoupling of Gαi 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 α1AR signaling. To test this hypothesis, we will determine the mechanism of cross-talk between CXCR4/7/α1AR, the mechanism of their signaling crosstalk and elucidate the pathway by which CXCR4/7 modulate α1AR-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 α1AR 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.

项目概要/摘要 该研究计划的目标是阐明控制心血管反应的机制 我们之前的工作和失血性休克期间的研究以及为创伤患者确定新的治疗目标。 新的初步数据表明，CXC 趋化因子受体 (CXCR) 7 的激活会导致血管 儿茶酚胺抵抗和心血管衰竭，而 CXCR4 激活则维持血管 失血性休克期间对儿茶酚胺的反应性这导致了 CXCR4 和 CXCR4 的主要假设。 CXCR7 是失血性休克期间心血管功能的关键调节因子，可影响血管 为了检验我们的假设，我们提出了通过调节肾上腺素能受体（AR）信号来调节音调。 以下目标： 1. 确定药理学 CXCR4/7 调节如何影响血管功能 利用压力肌动描记图作为测试平台，我们将回答以下关键问题： CXCR4/7 激动剂对 α1AR 激活特异性血管反应的影响 之间是否存在差异？ 血管床是否有助于观察到 SDF-1α 对 CXCR4 的影响？ Gαi 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变化？ 2. 如何确定 CXCR4/7？ 儿茶酚胺暴露和体内失血性休克期间影响心血管功能。 将利用压力容量环分析来确定 CXCR4/7 调节如何改变心血管 肾上腺素能激动剂的反应以及失血性休克和随后的液体复苏期间的功能。 此外，我们将确定 CXCR7 对正常心血管功能的有害影响是否可以 被营救，测试动物在 CXCR4 激活后是否能延长生存期，否则会致命 失血性休克可以通过液体复苏从心血管衰竭中挽救出来并进行长期评估 休克和复苏过程中选择性 CXCR4 激活的后果 3. 鉴定分子。 CXCR4/7 血管作用的机制具体假设是 CXCR4/7 控制。 为了验证这一假设，我们将确定α1AR信号之间的串扰机制。 CXCR4/7/α1AR，它们的信号串扰机制并阐明CXCR4/7的信号通路 调节血管平滑肌细胞中 α1AR 诱导的血管收缩。 我们提出了一系列最先进的体内和离体研究，并辅以 生物化学、分子和细胞生物学方法来阐明其分子机制 CXCR4 和 CXCR7 调节 α1AR 信号传导以控制失血性休克期间的血管张力。 从该提案中获得的知识将有助于将 CXCR4/7 确立为稳定心血管的药物靶点 功能并增强抗震能力。

项目成果

Characterization of heteromeric complexes between chemokine (C-X-C motif) receptor 4 and α1-adrenergic receptors utilizing intermolecular bioluminescence resonance energy transfer assays.

利用分子间生物发光共振能量转移测定来表征趋化因子（C-X-C 基序）受体 4 和 α1-肾上腺素受体之间的异聚复合物。

• 发表时间: 2020
• 影响因子: 3.1
• 作者: Gao, Xianlong;Enten, Garrett A;DeSantis, Anthony J;Volkman, Brian F;Gaponenko, Vadim;Majetschak, Matthias
• 通讯作者: Majetschak, Matthias

Regulation of the thrombin/protease-activated receptor 1 axis by chemokine (CXC motif) receptor 4.

趋化因子（CXC 基序）受体 4 对凝血酶/蛋白酶激活受体 1 轴的调节。

• 发表时间: 2020
• 作者: Gao, Xianlong;Cheng, You;Enten, Garrett A;DeSantis, Anthony J;Gaponenko, Vadim;Majetschak, Matthias
• 通讯作者: Majetschak, Matthias