Analysis and Clinical Application of Gene Expression Changes Induced by Perioperative Stresses

围手术期应激引起的基因表达变化分析及临床应用

基本信息

批准号：
16209046
负责人：
FUKUDA Kazuhiko
金额：
$ 31.78万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

This research was aimed to clarify cellular stress responses at molecular levels, to analyze modification of stress responses by perioperatively used drugs, and identify gene expression changes induced by perioperatively used drugs. The results obtained are summarized below.1.Increase in plasma norepinephrine concentration induced by laparotomy in rats was suppressed by CRF-1 receptor antagonists. It was suggested that a pathway exists in the central nervous system which inhibits sympathetic nervous responses induced by surgical insults.2.Effects of perioperatively used drugs on the proopiomelanocortin (POMC) gene expression was analyzed by a pituitary tumor cell line (AtT20PL) which was stably transfected with the POMC gene promoter linked with the luciferase gene. It was shown that calcium channel blockers and local anesthetics can potentiate CRH-induced POMC gene expression.3.Isoflurane, a prototype of volatile anesthetics, suppresses serotonin release in the cerebral cortex, which can be related with sedative action of isoflurane. On the other hand, nitrous oxide was shown to increase serotonin release in the spinal cord, which was suggested to be involved in the antinociceptive action of nitrous oxide at the spinal cord level. Furthermore, analysis of nociceptin receptor knockout mice suggested that the nociceptin receptor is not involved in the anesthetic action of volatile anesthetics but contributes to the antinociceptive action of nitrous oxide.4.Effects of various drugs on the hypoxia-induced gene expression changes mediated by hypoxia-inducible factor (HIF- 1). It was shown that a vasodilator sodium nitroprusside and a n intravenous anesthetic agent propofol inhibit hypoxia-induced HIF-1 activation.5.Morphine-induced gene expression changes in T-lymphocytes were identified. It was shown that expression of apoptosis-related genes was increased by morphine.

本研究旨在从分子水平阐明细胞应激反应，分析围手术期使用药物对应激反应的改变，并鉴定围手术期使用药物诱导的基因表达变化。所得结果总结如下： 1.CRF-1受体拮抗剂可抑制大鼠剖腹手术引起的血浆去甲肾上腺素浓度升高。提示中枢神经系统中存在一条抑制手术损伤引起的交感神经反应的通路。2.采用垂体肿瘤细胞系(AtT20PL)分析围术期使用药物对阿黑皮素原(POMC)基因表达的影响。用与荧光素酶基因连接的POMC基因启动子稳定转染。结果表明，钙通道阻滞剂和局麻药可增强CRH诱导的POMC基因表达。3.异氟烷是挥发性麻醉药的原型，可抑制大脑皮层5-羟色胺的释放，这可能与异氟烷的镇静作用有关。另一方面，一氧化二氮被证明可以增加脊髓中血清素的释放，这被认为与一氧化二氮在脊髓水平的抗伤害作用有关。此外，对伤害感受肽受体敲除小鼠的分析表明，伤害感受肽受体不参与挥发性麻醉药的麻醉作用，但有助于一氧化二氮的镇痛作用。4.各种药物对缺氧介导的缺氧诱导的基因表达变化的影响-诱导因子(HIF-1)。结果表明，血管扩张剂硝普钠和静脉麻醉剂异丙酚可抑制缺氧诱导的HIF-1激活。5.吗啡诱导的T淋巴细胞基因表达变化。结果表明，吗啡可增加凋亡相关基因的表达。