RELATIONSHIP OF APOPTOSIS AND BURN TRAUMA TO MULTIPLE ORGAN FAILURE

细胞凋亡和烧伤与多器官衰竭的关系

• 批准号: 6435855
• 负责人: BRETT P GIROIR
• 金额: $ 19.72万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6435855
• 关键词: apoptosis; biological signal transduction; burn therapy; burns; calcium flux; cysteine endopeptidases; gastrointestinal epithelium; gene expression; genetically modified animals; laboratory mouse; laboratory rat; multiple organ failure; myocardium; nitric oxide; nuclear factor kappa beta; pathologic process; respiratory epithelium; tissue /cell culture

Cardiac dysfunction is a primary contributor to morbidity and mortality in patients suffering burn trauma or sepsis. We have previously demonstrated that this cardiac dysfunction is mediated, at least in part, by the cytokine tumor necrosis factor-alpha (TNF) which is locally produced in the myocardium. Recently, we have determined that burn trauma also markedly increased apoptosis in both the myocardium and the gastrointestinal system, and that apoptosis is temporally associated with physiologic organ dysfunction. The goal of this proposal is to determine the molecular mechanisms by which burn trauma induces apoptosis, and to elucidate the role of apoptosis in the pathogenesis of organ injury both in the heart and the endothelium. First, we will determine whether TNF is responsible for apoptosis in vivo, and whether apoptosis is associated with alterations in the expression of pro- and anti-apoptosis genes. We will also utilize an in vitro model to precisely characterize the molecular mechanisms of apoptosis, including the role of nitric oxide, intracellular Ca2+, and death domain signaling via caspase 8. Next, through the use of physiological inhibitors and novel transgenic mice in which NF-kappaB is sequestered, we will determine whether the nuclear translocation of NF-kappaB is sequestered, we will determine whether the nuclear translocation of NF-kappaB following burn trauma is associated with apoptosis protection, and whether this protection is due to enhanced expression of anti-apoptotic genes. Finally, through the use of novel transgenic animals in which cardiac myocyte apoptosis protection, and whether this protection is due to enhanced expression of anti-apoptotic genes. Finally, through the use of novel transgenic animals in which cardiac myocyte apoptosis is specially inhibited we will determine whether apoptosis is responsible for cardiac physiologic dysfunction, or whether apoptosis is an adaptive mechanism which mitigates inflammation and preserves physiological function. By understanding the molecular mechanisms and role of apoptosis in burn shock, it may be possible to develop specific targeted therapeutic strategies for the treatment of burns, sepsis, and primary cardiac diseases associated with myocardial synthesis of TNF.

心脏功能障碍是烧伤或败血症患者发病率和死亡率的主要原因。我们以前已经证明，这种心脏功能障碍是介导的，至少部分是由细胞因子肿瘤坏死因子-α（TNF），这是局部产生的心肌。最近，我们已经确定，烧伤创伤也显着增加心肌和胃肠道系统的细胞凋亡，细胞凋亡是暂时与生理器官功能障碍。本研究的目的是确定烧伤创伤诱导细胞凋亡的分子机制，并阐明细胞凋亡在心脏和内皮细胞器官损伤发病机制中的作用。首先，我们将确定是否TNF是负责细胞凋亡在体内，以及是否凋亡与前和抗凋亡基因的表达改变。我们还将利用体外模型来精确表征细胞凋亡的分子机制，包括一氧化氮，细胞内Ca 2+和死亡结构域通过caspase 8的信号传导的作用。接下来，通过使用生理抑制剂和新的转基因小鼠，其中NF-κ B被隔离，我们将确定NF-κ B的核转位是否被隔离，我们将确定烧伤创伤后NF-κ B的核转位是否与凋亡保护相关，以及这种保护是否是由于抗凋亡基因的表达增强。最后，通过使用新型转基因动物，研究其对心肌细胞凋亡的保护作用，以及这种保护作用是否是由于抗凋亡基因表达增强所致。最后，通过使用心肌细胞凋亡被特别抑制的新型转基因动物，我们将确定细胞凋亡是否是心脏生理功能障碍的原因，或者细胞凋亡是否是减轻炎症和保护生理功能的适应性机制。通过了解细胞凋亡在烧伤休克中的分子机制和作用，有可能为烧伤、脓毒症和与心肌TNF合成相关的原发性心脏病的治疗开发特异性靶向治疗策略。