Caveolae and Anesthetic Induced Cardiac Protection

小凹和麻醉诱导的心脏保护

基本信息

批准号：
7406084
负责人：
DAVID M ROTH
金额：
$ 34.65万
依托单位：
VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-16 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7406084
关键词：
Address Adult Affect Agonist Anesthetics Animals Apoptosis Attenuated Biochemical Cardiac Cardiac Myocytes Caveolae Caveolins Cell Surface Receptors Cell Survival Cell membrane Cell physiology Cholesterol Class Clinical Complex Condition Data Disruption Exposure to G-Protein-Coupled Receptors Goals Heart Hypoxia In Vitro Infarction Injury Isoflurane Knockout Mice Laboratories Lipids Mediator of activation protein Microscopic Molecular Mus Muscle Myocardial Ischemia Myosin Heavy Chains Naloxone Numbers Operative Surgical Procedures Opioid Opioid Receptor Pathway interactions Patients Pertussis Toxin Pharmacological Treatment Phosphorylation Play Protein Isoforms Protein Overexpression Proteins Proto-Oncogene Proteins c-akt Regulation Research Personnel Resistance Risk Role Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Small Interfering RNA Sphingolipids Stress Structural Protein Techniques Testing Transgenes Transgenic Mice Work body system caveolin 1 caveolin-3 flasks in vivo insight interest mouse model novel numb protein programs promoter protein expression scaffold size synergism trafficking

项目摘要

DESCRIPTION (provided by applicant): Opioids and volatile anesthetics are known to produce cardiac protection. Evidence suggests a common signal transduction pathway for opioid and volatile anesthetic-induced cardiac protection. The molecular pathways implicated in cardiac protection are complex. An emerging idea in signal transduction suggests the existence of spatially organized complexes of signaling molecules in lipid-rich microdomains of the plasma membrane known as caveolae. Caveolins, proteins abundant in caveolae, provide a scaffold to organize, traffic and regulate signaling molecules. We have evidence that caveolae are vitally important to opioid- induced cardiac protection and that volatile anesthetics can alter the number and protein content of caveolae. We also have shown that cardiac myocyte specific overexpression of caveolin-3 (a muscle specific isoform of caveolin) in mice results in: increased caveolin-3 protein expression exclusively in the heart; increased numbers of caveolae in cardiac myocytes; normal cardiac function and enhanced activation of Akt (a signaling molecule involved in cell survival). Our hypotheses are: 1) The localization of signaling molecules involved in cardiac protection into subcellular caveolar microdomains and the interaction of these molecules with caveolins are essential for cardiac protection produced by opioids and volatile anesthetics; 2) Cardiac specific overexpression of caveolin protein will increase interactions between signaling molecules and caveolin within caveolae to augment anesthetic-induced cardiac protection. We will test the hypotheses by addressing the following specific aims. Aim 1: Will define the effects of opioid- and volatile anesthetic-induced cardiac protection on caveolae in cardiac myocytes in vitro. Aim 2: Will determine if altered caveolae and caveolin expression in cardiac myocytes in vitro affects anesthetic-induced cardiac protection. Aim 3: Will determine if cardiac specific overexpression of caveolin in vivo enhances anesthetic-induced cardiac protection. The proposed work will provide novel data with specific clinical implications for patients with myocardial ischemia or patients at high cardiac risk undergoing cardiac or noncardiac surgery.

描述（由申请人提供）：已知阿片类药物和挥发性麻醉剂可产生心脏保护。证据表明阿片类药物和挥发性麻醉引起的心脏保护的常见信号转导途径。与心脏保护有关的分子途径很复杂。信号转导中的一个新兴思想表明，在富含脂质的质膜的脂质微域中的信号分子的空间有组织的复合物中存在称为Caveolae。小窝蛋白（在小窝中丰富的蛋白质）提供了组织，交通和调节信号分子的支架。我们有证据表明，小窝对阿片类药物诱导的心脏保护至关重要，并且挥发性麻醉药可以改变小窝的数量和蛋白质含量。我们还表明，小鼠中小鼠的心肌细胞特异性特异性过表达（小鼠特异性同工型）在：Caveolin-3蛋白表达中仅在心脏中升高；心肌细胞中小窝的数量增加；正常的心脏功能和AKT的激活增强（与细胞存活有关的信号分子）。我们的假设是：1）在心脏保护中涉及的信号传导分子的定位到亚细胞小切尔极微区中，这些分子与小窝蛋白的相互作用对于阿片类药物和挥发性麻醉剂产生的心脏保护至关重要。 2）小窝蛋白蛋白的心脏特异性过表达将增加小窝中信号分子和小窝蛋白之间的相互作用，以增强麻醉诱导的心脏保护。我们将通过解决以下特定目标来检验假设。 AIM 1：将定义阿片类和挥发性麻醉诱导的心脏保护对心脏心肌细胞中小窝的影响。 AIM 2：将确定体外心肌细胞中的口腔和小窝蛋白表达是否改变会影响麻醉诱导的心脏保护。 AIM 3：将确定可爱的心脏特异性在体内过表达是否可以增强麻醉剂诱导的心脏保护。拟议的工作将为心肌缺血患者或患心脏或心脏手术的高心脏风险患者提供具有特定临床意义的新数据。