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: 8693520
• 负责人: Matthias Majetschak
• 金额: $ 26.91万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693520
• 关键词: AMD3100; Accidental Injury; Accounting; Adrenergic Agonists; Adrenergic Receptor; Affect; Agonist; Animals; Biochemical; Blood Vessels; CC chemokine receptor 7; CXC Chemokines; CXCR4 gene; Cardiovascular Physiology; Cardiovascular system; Catecholamines; Cause of Death; Cessation of life; Characteristics; Clinical; Complement; Complex; Data; Disease; Drug Targeting; Endocytosis; Endothelium; Functional disorder; Goals; Hemorrhage; Hemorrhagic Shock; Hospitals; Hour; Human; Injury; Knowledge; Lead; Liquid substance; Mediating; Modeling; Molecular; Molecular and Cellular Biology; Multiple Trauma; Myography; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Population; Process; Proteins; Rattus; Receptor Signaling; Regulation; Reporting; Research; Resistance; Resuscitation; Series; Shock; Signal Transduction; Smooth Muscle Myocytes; Stromal Cell-Derived Factor 1; Testing; Time; Trauma; Ubiquitin; United States; Work; aged; biological adaptation to stress; chemokine; chemokine receptor; hemodynamics; improved; in vivo; insight; new therapeutic target; pressure; programs; public health relevance; receptor; response; treatment strategy; vascular bed; vasoconstriction

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.

项目摘要/摘要 该研究计划的目标是阐明控制心血管反应的机制。 在失血性休克期间，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 儿茶酚胺抵抗和心血管衰竭，而CXCR4激活维持血管 失血性休克时对儿茶酚胺的反应性。这导致了主要的假设，即CXCR4和 CXCR7是失血性休克时心血管功能的重要调节因子，影响血管 通过调节肾上腺素能受体(AR)信号来调节音调。为了检验我们的假设，我们提出了 目的如下：1.确定CXCR4/7的药理调节对血管功能的影响 活着。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激动剂对受体特异性血管反应性的影响？他们之间有区别吗？ 血管床？内皮细胞对观察到的效应有贡献吗？SDF-1对CXCR4的CaN作用 CXCR7和CXCR7有什么区别？G？I蛋白的解偶联如何影响CXCR4/7调节剂的作用？ 失血性休克是否导致血管反应性的持续变化？2.确定CXCR4/7是如何 儿茶酚胺暴露和失血性休克对心血管功能的影响。我们 将利用压力-容量环路分析来确定CXCR4/7调制如何改变心血管 对肾上腺素能激动剂的反应和随后液体复苏的失血性休克时的功能。 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 获救，测试CXCR4激活后存活时间延长的动物是否在其他情况下死亡 失血性休克可通过液体复苏从心血管衰竭中抢救并进行长期评估 休克和复苏过程中选择性激活CXCR4的后果。3.分子鉴定 CXCR4/7血管效应的机制。具体假设是CXCR4/7控制 ？1AR信令。为了验证这一假设，我们将确定串扰的机制 CXCR4/7/？1AR的信号串扰机制，阐明CXCR4/7的信号传导途径 调节1AR诱导的血管平滑肌细胞的血管收缩。 我们提出了一系列全面的最先进的体内和体外研究，并辅之以 生物化学、分子和细胞生物学方法阐明的分子机制 CXCR4和CXCR7在失血性休克时调节1AR信号以控制血管张力。新的 从这项提议中获得的知识将有助于将CXCR4/7确立为稳定心血管疾病的药物靶点 功能，增强耐震性。