Myocardial Protein Synthesis After Thermal Injury

描述（由申请人提供）：心肌功能障碍仍然是一个主要的 热损伤后患者发病率和死亡率的原因。我们 初步数据提供的证据表明，烧伤引起的内在 机械功能与心肌蛋白质损伤有关 合成和翻译效率。待检验的工作假设是 烧伤引起的心肌蛋白质合成减少是由 翻译效率的缺陷是由两种功能的损害引起的， 肽链起始和延伸，这些变化是由 肿瘤坏死因子（TNF）a的过度产生， 心脏对胰岛素样生长（IGF）-1和生长激素的反应性 (GH)为了解决这一假设中隐含的问题，提出了 研究有以下具体目标：（1）确定时间 烧伤引起的蛋白质合成变化的进展， 肽链起始和心肌功能，并确定是否 这些变化是由TNF α介导的;（2）以确定机制， 热损伤降低了心脏中eIF 2B的活性， eIF 2Be的磷酸化，p67的含量，以及 针对eIF 2a和eIF 2Be的激酶和磷酸酶活性;（3）针对 确定烧伤改变eIF 4 E可用性的机制，通过评估 各种4 E结合蛋白和p7 OS 6激酶的磷酸化状态， 并对eIF 4G的降解进行定量;（4）通过 烧伤损害了心脏中的肽链延伸， 在体内条件下的延长，并通过确定心肌 延伸因子EF 1和EF 2的含量和磷酸化状态;和（5） 确定烧伤损伤GH和IGF-I的信号传导机制 行动在心中。我们的数据表明，烧伤引起的心脏变化， 蛋白质合成和翻译起始相对独特， 发生在骨骼肌，以响应烧伤或在心脏，以响应其他 创伤状况总的来说，这项研究将阐明机制， 热损伤后心肌蛋白质合成减少，导致 更好地理解和治疗由此产生的心肌病。-

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. -