Mechanisms of Growth Hormone Resistance in Sepsis

描述(申请人提供)：受伤或感染后的蛋白质分解代谢会导致多种并发症，延长康复时间并导致死亡。正常情况下，生长激素通过肝脏诱导循环胰岛素样生长因子-L(IGFI)的合成，从而刺激肌肉蛋白质的合成。在脓毒症期间，循环生长激素增加2-4倍，血浆IGF-I减少50%，肌肉蛋白质合成和质量也随之减少。肿瘤坏死因子和白介素1拮抗剂可减轻败血症期间观察到的血浆IGF-I和肌肉分解代谢的减少。该项目的目的是阐明细胞因子介导的肝脏生长激素抵抗的机制，这是全身炎症过程中的主要代谢紊乱之一。根据我们实验室开发的细胞因子介导的生长激素抵抗的新的细胞培养模型，我们处于一个独特的位置来进行这些研究。CWSV1肝细胞已被用来研究肿瘤坏死因子、白介素1和白介素6对生长激素信号和生长激素诱导基因表达的影响。受体后缺陷的生长激素诱导基因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。初步数据表明，由肿瘤坏死因子激活的NFkB抑制了40多个GH诱导基因的表达，这些基因参与调节中间代谢。这项拟议的研究将描述细胞因子和NFkB抑制生长激素诱导基因表达的分子机制，并将进行调查。：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NFkB激活抑制了脓毒症时生长激素对合成代谢基因的转录，导致肝脏生长激素抵抗和肌肉分解代谢。其具体目的是：1)研究细胞因子和脓毒症抑制生长激素诱导基因表达的信号通路；2)确定NFkB抑制生长激素诱导基因表达的机制；3)鉴定和鉴定参与调节细胞因子抑制的生长激素诱导基因表达的启动子区域和转录因子。损伤和感染患者失去正常代谢调节与死亡率增加和恢复时间延长有关。这个问题的部分原因是细胞因子(肿瘤坏死因子、白介素1、白介素6)对生长激素合成代谢的抑制作用。更好地了解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是重要的。

DESCRIPTION (provided by applicant): 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 the predominant 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 growth factors regulate protein catabolism is important to provide better care for these patients.