MECHANISMS OF GH RESISTANCE IN SEPSIS

脓毒症中 GH 抵抗的机制

• 批准号: 6180700
• 负责人: ROBERT N. COONEY
• 金额: $ 10.51万
• 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 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6180700
• 关键词: JAK kinase; bacterial disease; binding proteins; biological signal transduction; blood toxicology; cytokine receptors; disease /disorder model; enzyme activity; gastrocnemius muscle; gene expression; hormone inhibitor; hormone receptor; hormone regulation /control mechanism; insulinlike growth factor; interleukin 1; laboratory rat; liver cells; messenger RNA; northern blottings; phosphorylation; protein metabolism; receptor expression; somatotropin; transcription factor; western blottings

DESCRIPTION: (Adapted from the applicant's abstract) The development of growth hormone (GH) resistance following injury and sepsis results in the catabolism of body protein. GH normally stimulates the release of insulin-like growth factor 1 (IGF-1) which upregulates protein synthesis in many tissues. The chronic abdominal sepsis model used in the P.I.'s laboratory mimics many features of GH resistance observed in injured and septic patients. Thus, the applicant is in an excellent position to delineate the mechanisms of this cell signaling defect. Infusion of a specific interleukin-1 receptor antagonist (IL-1ra) significantly ameliorates protein catabolism and GH resistance in septic rats. This suggests that IL-1 is an important mediator of GH resistance in sepsis. The overall goal of this project will be to determine the mechanisms by which IL-1 mediates the development of GH resistance and protein catabolism in chronic abdominal sepsis. GH insensitivity may be caused by alterations in GH bioavailability, quantitative or qualitative defects in the GH receptor (GHR), postreceptor defects in GHR signal transduction, or by altered expression of GH responsive genes. The GHR is present in many tissues, however, the highest concentrations are in liver. GH binding protein (GHBP) binds circulating GH and modulates its bioavailability. GH forms a dimerized complex with GHR activating a phosphorylation cascade. Postreceptor signaling involves tyrosine phosphorylation of GHR by Janus kinase 2 (JAK2), JAK2 autophosphorylation, activation of transcription factor(s), and increased expression of "target" genes including: IGF-1 and Spi-2 (serine protease inhibitor). The liver is the major source of circulating IGF-1 (endocrine), however, most tissues including muscle contain and transcribe the IGF genes (paracrine). The applicant plans to examine GHBP/GHR and IGF-1 expression in both liver and muscle to investigate whether endocrine and paracrine regulation regulatory mechanisms are important in sepsis. The specific aims of the project are: (1) to examine the effects of sepsis and IL-1ra on GHBP expression; (2) to examine the effects of sepsis and IL-1 antagonism on GHR expression and GH binding activity; (3) to examine the effects of sepsis and IL-1ra on GH induced tyrosine phosphorylation of hepatic proteins and JAK 2 kinase activation; (4) and to examine the effects of sepsis and IL-1ra on IGF-1 and Spi-2 mRNA expression. These studies will reveal the molecular mechanisms by which IL-1ra ameliorates the development of GH resistance in sepsis.

描述：（改编自申请人的摘要） 损伤和脓毒症后生长激素（GH）抵抗会导致 体内蛋白质的分解代谢。 GH 通常会刺激释放 胰岛素样生长因子 1 (IGF-1) 上调蛋白质合成 许多组织。 P.I. 使用的慢性腹部脓毒症模型 实验室模拟了在受伤和 脓毒症患者。 因此，申请人处于有利地位 描述这种细胞信号传导缺陷的机制。 输注一个 特异性白细胞介素 1 受体拮抗剂 (IL-1ra) 显着 改善脓毒症大鼠的蛋白质分解代谢和 GH 抵抗。 这 表明IL-1是败血症中GH抵抗的重要介质。 这 该项目的总体目标是确定机制 IL-1 介导 GH 抗性和蛋白质分解代谢的发展 慢性腹部败血症。 GH不敏感可能是由于以下因素的改变引起的 GH 生物利用度、GH 受体的定量或定性缺陷 (GHR)、GHR 信号转导中的受体后缺陷，或通过改变 GH 反应基因的表达。 GHR 存在于许多组织中， 然而，最高浓度是在肝脏中。 GH 结合蛋白 (GHBP) 结合循环 GH 并调节其生物利用度。 GH 形成 与 GHR 激活磷酸化级联的二聚复合物。 受体后信号传导涉及 Janus 对 GHR 的酪氨酸磷酸化 激酶 2 (JAK2)、JAK2 自磷酸化、转录激活 因素，以及“目标”基因表达增加，包括：IGF-1 和 Spi-2（丝氨酸蛋白酶抑制剂）。 肝脏是主要来源 循环 IGF-1（内分泌），然而，大多数组织，包括肌肉 含有并转录 IGF 基因（旁分泌）。 申请人计划 检查肝脏和肌肉中的 GHBP/GHR 和 IGF-1 表达，以了解 研究内分泌和旁分泌调节机制 在脓毒症中很重要。 该项目的具体目标是：（1） 检查脓毒症和 IL-1ra 对 GHBP 表达的影响； (2) 检验 脓毒症和 IL-1 拮抗作用对 GHR 表达和 GH 结合的影响 活动; (3)考察脓毒症和IL-1ra对GH诱导的影响 肝蛋白酪氨酸磷酸化和 JAK 2 激酶激活； (4)并检查脓毒症和IL-1ra对IGF-1和Spi-2 mRNA的影响 表达。 这些研究将揭示其分子机制 IL-1ra 可改善脓毒症中 GH 耐药的发展。