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: 8897415
• 负责人: Matthias Majetschak
• 金额: $ 28.69万
• 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/8897415
• 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; Health; 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; Trauma patient; Ubiquitin; United States; Work; aged; biological adaptation to stress; cardiovascular collapse; chemokine; chemokine receptor; hemodynamics; improved; in vivo; insight; new therapeutic target; pressure; programs; receptor; response; treatment strategy; vascular bed; vasoconstriction

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.

描述（由适用提供）：该研究计划的目标是阐明在出血性休克期间控制心血管反应的机制，并确定创伤患者的新治疗靶标。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导致血管儿茶酚胺耐药性和心血管崩溃，而CXCR4激活在出血性休克期间对儿茶酚胺保持血管反应性。这导致了一个主要假设，即CXCR4和CXCR7是出血性休克期间心血管功能的关键调节剂，这通过调节肾上腺素受体（AR）信号传导影响血管张力。为了检验我们的假设，我们提出以下目的：1。确定药理学CXCR4/7调节如何影响体内血管功能。利用压力密集型作为测试平台，我们将回答以下关键问题：CXCR4/7激动剂对特定于1AR激活的血管反应性的影响吗？血管床之间有差异吗？内皮会导致观察到的影响吗？ SDF-1。对CXCR4和CXCR7的影响是否可以分化？ G蛋白的解偶联如何影响CXCR4/7调节剂的作用？出血性休克是否会导致血管反应性的持续变化？ 2。确定CXCR4/7如何影响体内儿茶酚胺暴露和出血性休克期间的心血管功能。我们将利用压力循环分析来确定CXCR4/7调制如何改变心脏血管功能对肾上腺激动剂的响应以及在出血性休克期间如何改变随后的流体复苏。此外，我们将确定是否可以检索CXCR7对正常心血管功能的有害影响，测试在其他毒死性出血性休克期间，在CXCR4激活后长期生存的动物是否可以从液体复苏中从心血管崩溃中挽救，并通过流体恢复并评估CXCR4激活和重点的长期后果，并评估了在频率上进行震动和重点。 3。确定CXCR4/7的血管作用的分子机制。特定的假设是CXCR4/7控制 - 1AR信号传导。为了检验这一假设，我们将确定CXCR4/7/�1AR之间的串扰机制，其信号传导串扰的机制，并阐明CXCR4/7调节血管平滑肌细胞中cxcr4/7调节血管收缩的途径。我们提出了一系列最先进的体内最先进的研究，并通过生化，分子和细胞生物学方法完成了体内研究，以阐明CXCR4和CXCR7通过该方法调节cxcr4和CXCR7在出血性休克期间控制血管张力的1AR信号。从该提案中获得的新知识将有助于建立CXCR4/7作为稳定心血管功能并增强冲击耐受性的药物靶标。