Mechanisms of Growth Hormone Resistance in Sepsis

损伤或感染后的蛋白质分解代谢会导致多种并发症，从而延长康复时间。 死亡。正常情况下，GH通过肝脏诱导循环中的胰岛素样生长因子-L(IGF-I)的合成，从而 刺激肌肉蛋白质合成。在脓毒症期间，循环生长激素增加2-4倍，达50%。 血浆IGF-I的减少以及伴随而来的肌肉蛋白质合成和质量的减少。肿瘤坏死因子和 IL-1拮抗剂减轻脓毒症时血浆IGF-I和肌肉分解代谢的降低 侮辱。该项目的目标是阐明细胞因子介导的肝脏生长激素的机制。 耐药，全身炎症过程中的主要代谢紊乱之一。我们正处于一个独特的 基于细胞因子介导的生长激素抵抗的新细胞培养模型进行这些研究的位置 这是我们实验室研发的。CWSV1肝细胞已被用来表征肿瘤坏死因子、白介素1、 IL-6对GH信号转导和GH诱导基因表达的影响。生长激素诱导基因的受体后缺陷 表达似乎代表了细胞因子介导的生长激素抵抗的主要机制。 初步数据显示，肿瘤坏死因子激活NFkB抑制了40多个生长激素诱导基因的表达 参与调节中介新陈代谢。拟议中的研究将描述分子的特征 细胞因子和NFkB抑制生长激素诱导基因表达的机制，并将进行研究。： 肝脏生长激素抵抗的代谢后果。我们的假设是细胞因子介导的细胞因子激活 NFkB抑制脓毒症时生长激素的合成代谢基因转录，导致肝脏生长激素抵抗和肌肉 分解代谢。其具体目的是：1)研究细胞因子与脓毒症的信号通路 抑制生长激素诱导基因表达，2)确定NFkB抑制生长激素诱导基因表达的机制 基因表达，3)鉴定和鉴定启动子区域和转录因子 在脓毒症过程中调节生长激素诱导的、被细胞因子抑制的肝脏基因。 损伤和感染患者失去正常代谢调节与增加有关 死亡率和长期恢复。这个问题的部分原因是细胞因子(肿瘤坏死因子， IL-1、IL-6)对生长激素合成代谢的影响。对细胞因子和生长因子如何 调节蛋白质分解代谢对于为这些患者提供更好的护理非常重要。

Protein catabolism after injury or infection results in multiple complications which prolong recovery and cause death. Normally, GH induces circulating insulin-like growth factor-l (IGF-I) synthesis by liver, which stimulates muscle protein synthesis. During sepsis, a 2-4 fold increase in circulating GH is seen with a 50% decrease in plasma IGF-I and concomitant reductions in both muscle protein synthesis and mass. TNF and IL-1 antagonists attenuate the reductions in plasma IGF-I and muscle catabolism observed during the septic insult. The goal of this project is to elucidate the mechanisms responsible for cytokine-mediated hepatic GH resistance, one of the major metabolic derangements during systemic inflammation. We are in a unique position to perform these studies based on the novel cell culture model of cytokine-mediated GH resistance developed in our laboratory. CWSV1 hepatocytes have been utilized to characterize the effects of TNF, IL-1, and IL-6 on GH signaling and GH-inducible gene expression. Postreceptor defects in GH-inducible gene expression appear to represent.thepredominant mechanism for cytokine-mediated GH resistance. Preliminary data suggest NFkB activation by TNF inhibits the expression of over forty GH-inducible genes involved in regulating intermediary metabolism. The proposed research will characterize the molecular mechanisms by which cytokines and NFkB inhibit GH-inducible gene expression, and will investigate .the. : metabolic consequences of hepatic GH resistance. Our hypothesis is that cytokine-mediated activation of NFkB inhibits anabolic gene transcription by GH during sepsis resulting in hepatic GH resistance and muscle catabolism. The specific aims are to: 1) Investigate the signaling pathways by which cytokines and sepsis inhibit GH-inducible gene expression, 2) Determine the mechanisms by which NFkB inihbits GH-inducible gene expression, 3) Identify and characterize the promoter regions and transcription factors involved in regulating GH-inducible hepatic genes that are inhibited by cytokines during sepsis. The loss of normal metabolic regulation in patients with injury and infection is associated with increased mortality and prolonged recovery. This problem is caused in part by the inhibitory effects of cytokines (TNF, IL-1, IL-6) on the anabolic actions of GH. An improved understanding of how cytokines and growthfactors regulate protein catabolism is important to provide better care for these patients.