RELATIONSHIP OF APOPTOSIS AND BURN TRAUMA TO MULTIPLE ORGAN FAILURE

心功能障碍是烧伤或败血症患者发病和死亡的主要原因。我们之前已经证明，这种心功能障碍是介导的，至少部分是由细胞因子肿瘤坏死因子- α (TNF)局部产生的心肌。最近，我们已经确定烧伤创伤也显著增加心肌和胃肠道系统的细胞凋亡，并且细胞凋亡与生理性器官功能障碍有暂时的相关性。本研究的目的是确定烧伤损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的发病机制中的作用。首先，我们将确定TNF是否与体内细胞凋亡有关，以及细胞凋亡是否与促凋亡和抗凋亡基因表达的改变有关。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Ca2+和通过caspase 8发出的死亡域信号的作用。接下来，我们将通过使用生理抑制剂和隔离NF-kappaB的新型转基因小鼠，确定NF-kappaB的核易位是否被隔离，我们将确定烧伤后NF-kappaB的核易位是否与凋亡保护有关，以及这种保护是否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对心肌细胞凋亡进行保护，以及这种保护是否由于抗凋亡基因的表达增强。最后，通过使用新的转基因动物，心肌细胞凋亡被特别抑制，我们将确定细胞凋亡是否导致心脏生理功能障碍，或者细胞凋亡是否是一种减轻炎症和保持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，有可能开发出治疗烧伤、败血症和与心肌TNF合成相关的原发性心脏病的特异性靶向治疗策略。

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.