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（由申请人提供）：本研究计划的目标是阐明失血性休克期间心血管反应的机制，并确定创伤患者的新治疗靶点。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崩溃，而CXCR 4激活维持血管反应性，在失血性休克期间的儿茶酚胺。这导致了以下主要假设：CXCR 4和CXCR 7是失血性休克期间心血管功能的关键调节剂，其通过调节肾上腺素能受体（AR）信号传导来影响血管张力。为了验证我们的假设，我们提出了以下目标：1。以确定药理学CXCR 4/7调节如何影响离体血管功能。利用压力肌电图作为测试平台，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是否特异于β 1AR激活？血管床之间是否存在差异？内皮是否有助于观察到的效应？SDF-1 β对CXCR 4和CXCR 7的作用可以区分吗？G�i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.研究CXCR 4/7在体内儿茶酚胺暴露和失血性休克时对心血管功能的影响。我们将利用压力容量回路分析，以确定CXCR 4/7调节如何改变心血管功能，在响应肾上腺素能受体激动剂和失血性休克与随后的液体复苏。此外，我们将确定CXCR 7对正常心血管功能的有害作用是否可以被挽救，测试在其他致死性出血性休克期间CXCR 4激活后存活延长的动物是否可以通过液体复苏从心血管衰竭中被挽救，并评估休克和复苏期间选择性CXCR 4激活的长期后果。3.确定CXCR 4/7血管效应的分子机制。具体的假设是CXCR 4/7控制β 1AR信号传导。为了验证这一假设，我们将确定CXCR 4/7/β 1AR之间的串扰机制，它们的信号串扰机制，并阐明CXCR 4/7调节β 1AR诱导的血管平滑肌细胞收缩的途径。我们提出了一个全面的一系列最先进的体内和离体研究，辅以生物化学，分子和细胞生物学方法，以阐明CXCR 4和CXCR 7调节β 1AR信号传导以控制失血性休克期间血管张力的分子机制。从该提案中获得的新知识将有助于将CXCR 4/7确立为稳定心血管功能和增强休克耐受性的药物靶点。