胰岛素协同生长激素调节泛素-蛋白酶体途径介导的脓毒症高分解代谢及机理研究

项目名称： 胰岛素协同生长激素调节泛素-蛋白酶体途径介导的脓毒症高分解代谢及机理研究

项目编号： No.30801086

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 虞文魁

作者单位： 南京大学

项目金额： 21万元

中文摘要： 脓毒症状态下的高分解代谢是目前临床营养支持所面临的难题。生长激素（GH）虽对轻、中度应激病人具有良好的代谢调理作用，但脓毒症时炎症介质大量释放、泛素系统过度活化，导致机体存在明显的获得性生长激素抵抗（AGHR），从而使GH的促进合成效应受到抑制、不良效应增加。申请者前期研究表明，胰岛素能抑制炎症介质释放和泛素系统活性，减少脓毒症时骨骼肌降解。申请人推测胰岛素能通过抑制泛素系统活性，改善AGHR，从而协同GH改善脓毒症机体的高分解代谢。该研究采用动物实验和体外研究相结合的方式，应用代谢组学和传统检测手段相结合的方法，在国内外首次探讨脓毒症时胰岛素能否协同GH改善高分解代谢，及胰岛素发挥协同作用的给药时机和具体剂量；并探讨其机理：胰岛素→#27867;素系统→GHR→#21457;挥协同作用？最后了解胰岛素发挥GH协同等作用的可能信号通路。以期为临床脓毒症等严重应激状态下的代谢调理治疗提供新的治疗思路和研究方法

中文关键词： 胰岛素；生长激素；脓毒症；泛素-蛋白酶体途径；代谢组学

英文摘要： Excessive catabolism in sepsis is associated with high risk for morbidity and mortality, making his a major clinical problem. Growth hormone(GH) has a favourable effect on anabolism in patients with mild to moderate stress. But in patients with sepsis, due to the release of massive inflamamatory factor, excessive activation of ubiquitin-proteasome pathway and the existence of acquired growth hormone resisitance(AGHR), the beneficial effect of growth hormone (GH) on anabolism is inhibited and the adverse effectes are augmented. In our previous studies, we confirmed that insulin could lessen the release of inflamamtory factors, depress activation of ubiquitin-proteasome pathway and cut down the breakdown of skeletal muscle. Therefore,we hypothesize that insulin can synergize with GH to accommodate the excessive catabolism in sepsis. In this study, we incorporate the method of animal experiment and in vitro culture, and apply means of metabolomics and traditional analysis methods, to investigate whether insulin could synergize with GH to accommodate the excessive matabolism in sepsis. Furthermore, we also plan to identify the optimal dosage, the best time and the possible mechanism (insulin →biquitin-proteasome pathway→GHR→ynergistic effect) of insulin to induce the synergistic effect. Finally, we plan to investigate the potential signal pathway of insulin to synergize with GH to accommodate the excessive catabolism. We expected that the study would be helpful to find a new therapeutic approach and a new investigative way to regulate the excessive catabolism in sepsis.

英文关键词： insulin; growth hormone; sepsis;ubiquitin-proteasome pathway;metabolomics