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

基本信息

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
项目类别：
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

项目摘要

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）：本研究项目的目标是阐明控制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。我们之前的工作和新的初步数据表明，CXC 趋化因子受体的激活。 (CXCR) 7 导致血管儿茶酚胺抵抗和心血管衰竭，而 CXCR4 激活则在失血性休克期间维持血管对儿茶酚胺的反应性。假设 CXCR4 和 CXCR7 是失血性休克期间心血管功能的关键调节因子，通过调节肾上腺素能受体 (AR) 信号传导影响血管张力。为了检验我们的假设，我们提出以下目标： 1. 确定 CXCR4/7 的药理学调节方式。利用压力肌动描记法作为测试平台，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具有特异性。 �1AR 激活是否存在差异？内皮细胞对 CXCR4 和 CXCR7 的影响有影响吗？ G�i 蛋白的解偶联如何影响 CXCR4/7 调节剂的作用？ ? 失血性休克是否会引起血管反应性的持续变化？ 2. 确定 CXCR4/7 在儿茶酚胺暴露和失血性休克期间如何影响心血管功能？我们将利用压力容量环分析来确定 CXCR4/7 调节如何改变肾上腺素能激动剂和失血性休克期间的心血管功能以及随后的液体复苏。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 CXCR4 激活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获救，并评估选择性 CXCR4 激活的长期后果3. 确定 CXCR4/7 血管效应的分子机制。具体假设是 CXCR4/7 控制 1AR 信号传导。为了检验这一假设，我们将确定 CXCR4/7 之间的串扰机制。 /�1AR，它们的信号串扰机制，并阐明 CXCR4/7 调节血管平滑肌细胞中�1AR 诱导的血管收缩的途径。最先进的体内和离体研究，辅以生化、分子和细胞生物学方法，阐明 CXCR4 和 CXCR7 调节 �1AR 信号传导以控制失血性休克期间血管张力的分子机制。该提案将有助于建立CXCR4/7作为稳定心血管功能和增强休克耐受力的药物靶点。