Myocardial Protein Synthesis After Thermal Injury

描述(由申请人提供)：心肌功能障碍仍然是热损伤后患者发病率和死亡率的主要原因。我们的 初步数据提供的证据表明，烧伤导致内源性神经递质减少 机械功能与心肌蛋白损伤有关 合成和翻译效率。需要检验的工作假说是 烧伤引起的心肌蛋白质合成减少是由 由于两者的缺陷而导致的翻译效率缺陷 多肽链的启动和延长，这些变化是由 肿瘤坏死因子(TNF)α的过量生产改变了 心脏对胰岛素样生长的反应性--L与生长激素 (Gh)，为了解决这一假设中隐含的问题，建议的 研究有以下具体目的：(1)确定时间 烧伤后蛋白质合成、蛋白质合成指标变化的研究进展 肽链启动和心肌功能，并确定是否 这些变化是由TNFa介导的；(2)确定 热损伤降低心脏中eIF2B的活性，通过评估 ElF2Be的磷酸化、p67的含量及其改变的重要性 针对eIF2a和eIF2Be的激酶和磷酸酶活性； 通过评估确定烧伤改变elF4E可用性的机制 各种4E结合蛋白和p7OS6蛋白的磷酸化状态， 以及对eIF4G的降解进行定量；(4)通过以下方法确定其机制 烧伤会损害心脏的肽链延长，这是通过量化 在活体条件下的伸长率，并通过测定心肌 延伸因子EF1和EF2的含量和磷酸化状态；和(5)至 烧伤损害GH和IGF-I信号转导机制的研究 发自内心的行动。我们的数据表明，烧伤引起的心脏改变 蛋白质合成和翻译启动是相对独特的，而不是 发生在骨骼肌对烧伤的反应或在心脏对其他 创伤性条件。总体而言，该研究将通过以下方式阐明这些机制 烫伤后心肌蛋白质合成减少，导致 对由此引起的心肌病有更好的认识和治疗。-

DESCRIPTION (provided by applicant): Myocardial dysfunction remains a major cause of morbidity and mortality in patients after thermal injury. Our preliminary data provide evidence that the burn-induced decrease in intrinsic mechanical function is associated with an impairment in myocardial protein synthesis and translational efficiency. The working hypothesis to be tested is that the burn-induced decrease in myocardial protein synthesis is mediated by defects in translational efficiency resulting from an impairment in both peptide-chain initiation and elongation, and that these changes are mediated by the overproduction of tumor necrosis factor (TNF)a which alters the responsiveness of the heart to insulin-like growth (IGF)-l and growth hormone (GH), To address the questions implicit in this hypothesis, the proposed research has the following specific aims: (1) to determine the temporal progression of burn-induced changes in protein synthesis, indices of peptide-chain initiation and myocardial function, and to determine whether these changes are mediated by TNFa; (2) to determine the mechanism by which thermal injury decreases activity of eIF2B in heart, by assessing the phosphorylation of elF2Be, content of p67, and the importance of alterations in kinase and phosphatase activities directed towards eIF2a and eIF2Be; (3) to determine the mechanism by which burn alters elF4E availability, by assessing the phosphorylation status of the various 4E-binding proteins and p7OS6 kinase, and quantitating the degradation of eIF4G; (4) to determine the mechanism by which burn impairs peptide-chain elongation in heart, by quantitating the rate of elongation under in vivo conditions and by determining the myocardial content and phosphorylation state of elongation factors EFI and EF2; and (5) to determine the signaling mechanisms by which burn injury impairs GH and IGF-I action in heart. Our data suggest that the bum-induced changes in cardiac protein synthesis and translation initiation are relatively unique, and do not occur in skeletal muscle in response to burn or in heart in response to other traumatic conditions. Overall, the research will elucidate the mechanisms by which myocardial protein synthesis is reduced after thermal injury, leading to the better understanding and treatment of the resulting cardiomyopathy. -