Mechanisms of Growth Hormone Resistance in Sepsis

脓毒症生长激素抵抗机制

• 批准号: 7319337
• 负责人: ROBERT N. COONEY
• 金额: $ 26.99万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7319337
• 关键词: Attenuated; Binding; Binding Sites; Catabolism; Cause of Death; Chromatin; Cultured Cells; Cytokine Signaling; DNA Binding; Data; Defect; Development; Dominant-Negative Mutation; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Growth Factor; Hepatic; Hepatocyte; Hindlimb; Hormones; I-kappa B Proteins; Incubated; Infection; Inflammation; Inflammatory; Injury; Insulin-Like Growth Factor I; Interleukin-1; Interleukin-1 Receptors; Interleukin-6; Laboratories; Liver; Mediating; Metabolic; Metabolism; Microarray Analysis; Mitogen-Activated Protein Kinases; Modeling; Molecular; Muscle; Muscle Proteins; NF-kappa B; NFKB Signaling Pathway; Nuclear Translocation; Nucleic Acid Regulatory Sequences; Numbers; Pathway interactions; Patient Care; Patients; Phosphotransferases; Plasma; Positioning Attribute; Preparation; Promoter Regions; Protein Biosynthesis; Proteins; Rattus; Recovery; Regulation; Research; Research Personnel; Resistance; Resistance development; Reverse Transcriptase Polymerase Chain Reaction; Role; Sepsis; Signal Pathway; Signal Transduction; Somatomedins; Somatotropin; TNF gene; TNFRSF5 gene; Time; Tissues; Toll-like receptors; Transcription Coactivator; base; cytokine; hormone resistance; human GHR protein; improved; inhibitor/antagonist; mortality; novel; prevent; programs; promoter; protein protein interaction; receptor; response; septic; synaptotagmin I; therapeutic target; transcription factor

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.

描述（由申请人提供）：受伤或感染后的蛋白质分解代谢导致多种并发症，延长恢复时间并导致死亡。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- 1 （igf - 1）合成，从而刺激肌肉蛋白的合成。在败血症期间，循环GH增加2-4倍，血浆igf - 1减少50%，同时肌肉蛋白合成和质量减少。TNF和IL-1拮抗剂可减弱脓毒性损伤期间血浆igf -1和肌肉分解代谢的减少。本项目的目的是阐明细胞因子介导的肝生长激素抵抗的机制，这是全体性炎症期间主要的代谢紊乱之一。基于我们实验室开发的细胞因子介导的生长激素抗性的新型细胞培养模型，我们处于一个独特的位置来进行这些研究。CWSV1肝细胞已被用于表征TNF、IL-1和IL-6对GH信号传导和GH诱导基因表达的影响。GH诱导基因表达中的受体后缺陷似乎是细胞因子介导的GH抗性的主要机制。初步数据表明，TNF激活NFkB可抑制参与调节中间代谢的40多种gh诱导基因的表达。本研究将对细胞因子和NFkB抑制gh诱导基因表达的分子机制进行研究。：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NFkB激活在败血症期间抑制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。具体目的是：1)研究细胞因子和脓毒症抑制gh诱导基因表达的信号通路；2)确定NFkB抑制gh诱导基因表达的机制；3)鉴定脓毒症中受细胞因子抑制的gh诱导肝脏基因调控的启动子区和转录因子。损伤和感染患者正常代谢调节的丧失与死亡率增加和恢复时间延长有关。这个问题部分是由于细胞因子（TNF, IL-1, IL-6）对生长激素合成代谢作用的抑制作用引起的。提高对细胞因子和生长因子如何调节蛋白质分解代谢的理解对于为这些患者提供更好的护理是重要的。