PRECONDITIONING IN OPEN HEART SURGERY

描述(研究人员摘要)：“心肌预适应是 被认为是最先进的缺血保护技术 受伤。然而，预适应并未与 心脏直视手术。预适应的机制也不清楚。 拟议的研究将检查预适应的机制和 试图开发预适应方式来挽救心脏骤停 在心脏直视手术期间。由细胞因子激活的生化途径 基因的预适应现象及其分子机制(S) 我们将对其表达进行研究。麻醉大鼠和兔的心脏 将被切除用于隔离灌流心脏的准备。诱发脑缺血 预适应，孤立心脏将被制成5次全球缺血 再灌流10分钟。这一过程将重复进行 四次。随后将使心脏缺血30分钟 再灌流60分钟。来检验我们的假设预适应 通过激活酪氨酸激酶受体，我们将使用一种酪氨酸激酶 抑制预适应的阻滞剂。为了进一步探索是否 细胞内信号转导通过酪氨酸激酶-磷脂酶 D-蛋白激酶途径、抗磷脂酶D抗体将用于 抑制与预适应相关的磷脂酶D激活。 蛋白C激酶及其上游调节因子MAP-K和MAP的激活 同时检测MAPKAP激酶活性。活组织检查和灌流 样本将用于测量生化参数，其中包括 磷脂酶C和D、甘油二酯、磷脂酸、 蛋白激酶C、MAP激酶和MAPKAP激酶2。细胞损伤将 通过测量LDH和CK的释放来进行生化监测。 在功能上，左心室收缩和舒张期都有功能 将逐个节拍地持续监测参数。这些 将包括左心室每搏功、弹性和时间 等容松弛常数。目的基因的诱导表达 应激相关基因将通过差异显示技术进行研究。这个 这项研究的结果不仅使我们能够了解酪氨酸 激酶-磷脂酶D-蛋白C激酶-MAPK-MAPKAP激酶2信号转导 通路是否参与预适应，还将决定是否 通过对基因重新编程，在分子水平上进行预适应 表情。这一结果将有助于开发治疗方法。 在心内直视手术期间对心脏进行预适应。

DESCRIPTION (Investigator's abstract): "Myocardial preconditioning is believed to be the state of the art protective technique against ischemic injury. However, Preconditioning has not been applied in conjunction with open heart surgery. The mechanism of preconditioning is also not known. The proposed research will examine the mechanism of preconditioning and attempt to develop preconditioning modalities to salvage arrested heart during open heart surgery. The biochemical pathways activated by the preconditioning phenomenon and the molecular mechanism(s) of the gene expression will be studied. Hearts from the anesthetized rats and rabbits will be excised for isolated perfused heart preparation. To induce ischemic preconditioning, isolated hearts will be made globally ischemic for 5 minutes followed by 10 minutes of reperfusion. The process will be repeated four times. The hearts will then be made ischemic for 30 minutes followed by 60 minutes of reperfusion. To test our hypothesis that preconditioning occurs by tyrosine kinase receptor activation, we will use a tyrosine kinase blocker to inhibit preconditioning. To further explore whether the intracellular signaling occurs through tyrosine kinase-phospholipase D-protein kinase pathway, antiphospholipase D antibody will be used to inhibit phospholipase D activation associated with preconditioning. Activation of protein C kinase and its upstream regulators MAP kinase and MAPKAP kinase will be examined simultaneously. Biopsies and perfusate samples will be used to measure biochemical parameters which will include quantification of phospholipase C and D, diacyl glycerol, phosphatidic acid, protein kinase C, MAP kinase and MAPKAP kinase 2. The cellular injury will be monitored biochemically by measuring the LDH and CK releases. Functionally, both left ventricular systolic and diastolic functional parameters will be continuously monitored on a beat to beat basis. These will include the left ventricular stroke work, elastance, and the time constant of isovolumic relaxation. Induction for the expression of stress-related genes will be studied by Differential Display Technique. The results of this study will not only enable us to understand whether tyrosine kinase-phospholipase D-protein C kinase-MAP kinase-MAPKAP kinase 2 signaling pathway is involved in preconditioning, but also will determine whether preconditioning occurs at the molecular level by reprogramming the gene expression. The results will be useful to develop treatment modalities for preconditioning the heart during open heart surgery."