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: 6449009
• 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/6449009
• 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.

心功能不全是烧伤、创伤或脓毒症患者发病率和死亡率的主要因素。我们以前已经证明，这种心功能障碍至少部分是由心肌局部产生的细胞因子肿瘤坏死因子-α(TNF)介导的。最近，我们发现烧伤还显著增加了心肌和胃肠系统的细胞凋亡，细胞凋亡与生理性器官功能障碍在时间上是相关的。本研究的目的是确定烧伤诱导细胞凋亡的分子机制，并阐明细胞凋亡在心脏和血管内皮细胞损伤发病机制中的作用。首先，我们将确定肿瘤坏死因子是否与体内的细胞凋亡有关，以及细胞凋亡是否与促凋亡和抗凋亡基因的表达变化有关。我们还将利用体外模型来精确描述细胞凋亡的分子机制，包括一氧化氮、细胞内钙离子和caspase 8死亡结构域信号的作用。接下来，我们将通过使用生理抑制剂和新型转基因小鼠来确定是否隔离了核转录因子-kappaB的核转位，我们将确定烧伤后核转录因子-kappaB的核转位是否与细胞凋亡保护有关，以及这种保护是否源于抗凋亡基因的增强表达。最后，通过使用新型转基因动物来保护心肌细胞的凋亡，以及这种保护是否是由于增强了抗凋亡基因的表达。最后，通过使用特殊抑制心肌细胞凋亡的新型转基因动物，我们将确定细胞凋亡是否与心脏生理性功能障碍有关，或者细胞凋亡是否是一种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，有可能开发特定的靶向治疗策略来治疗烧伤、脓毒症和与心肌合成肿瘤坏死因子相关的原发心脏病。