STRESS RESPONSE PROTECT AGAINST REPERFUSION INJURY

应激反应可防止再灌注损伤

• 批准号: 2029109
• 负责人: CHING-YUAN SU
• 金额: $ 9.92万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2029109
• 关键词: antioxidants; cell age; complementary DNA; ethanol; free radical oxygen; gel electrophoresis; genetic library; heart cell; homeostasis; hydrogen peroxide; hydroxyl group; hyperthermia; reperfusion; stress proteins; superoxides; western blottings

DESCRIPTION: (Adapted from Applicant' Abstract) Reactive oxygen species, such as superoxide, hydrogen peroxide, and hydroxyl radical, are formed excessively during the initial phase of reoxygenation of the ischemic heart. Increasing evidence suggests that these oxygen byproducts initiate a cascade of damage in membrane integrity, calcium sequestration, and energy homeostasis. The inability of the myocardium to defend itself against the toxic effect of the reactive oxygen species leads to reperfusion injury. Therefore, modulation of antioxidant defense mechanism has clinical significance with respect to the preservation of the myocardium during reperfusion.There exists in cells a universal adaptive response to thermal stress, which is termed the stress response. It has been reported that whole-body hyperthermia protects the isolated heart during ischemia-reperfusion. The applicant has studied heat-induced protection in H9c2 rat heart myocytes, a simple and manipulable model of the myocardium in vitro. The investigator has found that transient or chronic induction of the stress response in heart cells improved the survival to subsequent lethal doses of hydrogen peroxide. Also, she observed a positive correlation between oxidative resistance and induction of heat shock proteins or antioxidant enzymes. The overall objectives of this study are to examine the beneficial effect of continuous activation of the stress response on oxidative resistance, and the mechanism of the acquired oxidative protection. The applicant proposes to study these objectives: (1) To develop the conditions which allow continuous activation of the stress response by long-term conditioning of myocytes with mild hyperthermia or ethanol treatment. (2) To examine if eliciting the chronic stress response enhances myocardial resistance to reactive oxygen species, by measuring the changes in cell survival, plasma membrane structures, intracellular ATP and calcium homeostasis. (3) To test if suppression of the endogenous antioxidant enzyme activities or heat shock proteins results in an increased susceptibility to reactive oxygen species. (4) To study the other factors involved in the stress-induced protection by two- dimensional gel electrophoresis followed with the isolation of their cDNAs by the expression cloning strategy. This study should improve one's understanding of the protective nature of the stress response. Furthermore, identification of potential regulatory mechanisms or other defense mechanisms involved in stress response may lead to a new avenue of clinical management for reperfusion injury.

描述：（改编自申请人“摘要）活性氧 物种，例如超氧化物，过氧化氢和羟​​基自由基， 在初始阶段的重氧中过度形成 缺血性的心。 越来越多的证据表明这些氧气 副产品在膜完整性中引发了一系列损害， 钙隔离和能量稳态。无法 心肌防御反应性的有毒作用 氧气导致再灌注损伤。 因此，调制 抗氧化剂防御机制具有临床意义 在再灌注期间保存心肌。存在 在细胞中，对热应力的普遍自适应反应，这是 称为压力反应。 据报道全身 热疗在缺血 - 重灌注过程中保护孤立的心脏。 申请人研究了H9C2大鼠心脏的热诱导保护 心肌细胞，体外心肌的简单且可操作的模型。 研究者发现瞬时或慢性诱导 心脏细胞中的压力反应改善了随后的生存率 致命的过氧化氢剂量。 另外，她观察到了积极的 氧化抗性与热休克的诱导之间的相关性 蛋白质或抗氧化剂酶。 总体目标 研究是为了检查连续激活的有益效果 对氧化抗性的应力反应以及 获得的氧化保护。 申请人建议学习 这些目标：（1）发展允许的条件 通过长期调节连续激活应力反应 轻度热疗或乙醇治疗的肌细胞。 （2）至 检查引起慢性应激反应是否增强心肌 通过测量的变化，对活性氧的抗性 细胞存活，质膜结构，细胞内ATP和 钙稳态。 （3）测试是否抑制内源性 抗氧化剂酶活性或热激蛋白导致 增加对活性氧的敏感性。 （4）学习 两种压力引起的保护涉及的其他因素 尺寸凝胶电泳随后分离 表达克隆策略的cDNA。 这项研究应该改善 一个人对压力反应的保护性的理解。 此外，识别潜在的调节机制或 压力反应涉及的其他防御机制可能会导致新的 再灌注损伤的临床管理大道。