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: 9111960
• 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/9111960
• 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; Vascular Smooth Muscle; 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(申请人提供)：本研究计划的目标是阐明失血性休克时心血管反应的控制机制，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的激活会导致血管内儿茶酚胺抵抗和心血管衰竭，而CXCR4的激活则维持失血性休克时血管对儿茶酚胺的反应性。这导致了CXCR4和CXCR7是失血性休克时心血管功能的关键调节者的主要假说，它们通过调节肾上腺素能受体(AR)信号来影响血管张力。为了验证我们的假设，我们提出了以下目标：1.确定药物对CXCR4/7的调节在体外如何影响血管功能。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专用于�1AR的激活？不同的血管床有区别吗？内皮细胞对观察到的效应有贡献吗？能否区分SDF-1�对CXCR4和CXCR7的影响？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在体内对儿茶酚胺暴露和失血性休克时心血管功能的影响。我们将利用压力-容积环分析来确定CXCR4/7如何在肾上腺素能激动剂的作用下以及在失血性休克和随后的液体复苏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，测试在其他致命性失血性休克期间激活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，并评估休克和复苏期间选择性激活CXCR4的长期后果。3.明确CXCR4/7血管效应的分子机制。具体假设是CXCR4/7控制�1AR信号转导。为了验证这一假设，我们将确定CXCR4/7/�1AR之间的信号串扰机制及其信号串扰机制，并阐明CXCR4/7调节�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体外研究，并辅之以生化、分子和细胞生物学方法，以阐明失血性休克期间CXCR4和CXCR7调节�1AR信号以控制血管张力的分子机制。从这项提议中获得的新知识将有助于将CXCR4/7作为稳定心血管功能和增强休克耐受性的药物靶点。