MECHANISMS OF GH RESISTANCE IN SEPSIS

描述：（改编自申请人摘要） 损伤和脓毒症后的生长激素（GH）抵抗导致 身体蛋白质的分解。 生长激素通常刺激释放 胰岛素样生长因子1（IGF-1），其上调蛋白质合成， 许多组织。 P.I.中使用的慢性腹腔脓毒症模型。的 实验室模拟了在受伤和 败血症患者 因此，申请人处于有利地位， 描述这种细胞信号缺陷的机制。 输注 特异性白细胞介素-1受体拮抗剂（IL-1 ra）显著 改善脓毒症大鼠的蛋白质代谢和GH抵抗。 这 提示IL-1是脓毒症GH抵抗的重要介质。 的 本项目的总体目标是确定 IL-1介导生长激素抵抗和蛋白催化剂的发展 慢性腹腔脓毒症 生长激素不敏感性可能是由以下改变引起的： 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应答基因的表达。 生长激素受体存在于许多组织中， 然而，肝脏中的浓度最高。 生长激素结合蛋白 结合循环GH并调节其生物利用度。 GH形成a 二聚复合物与GHR激活磷酸化级联反应。 受体后信号转导涉及Janus介导的GHR酪氨酸磷酸化 激酶2（JAK 2），JAK 2自磷酸化，转录激活 因子，并增加“靶”基因的表达，包括：IGF-1和 Spi-2（丝氨酸蛋白酶抑制剂）。 肝脏是主要的 循环IGF-1（内分泌），然而，大多数组织，包括肌肉 包含并转录IGF基因（旁分泌）。 申请人计划 检查肝脏和肌肉中GHBP/GHR和IGF-1的表达， 研究内分泌和旁分泌调节机制是否 在败血症中很重要 该项目的具体目标是：（1） 检测脓毒症和IL-1 ra对GHBP表达的影响;（2）检测 脓毒症和IL-1拮抗剂对GHR表达和GH结合的影响 （3）观察脓毒症和IL-1 ra对GH诱导的小鼠GH分泌的影响 肝蛋白酪氨酸磷酸化和JAK 2激酶激活; (4)检测脓毒症和IL-1 ra对IGF-1和Spi-2 mRNA表达的影响 表情 这些研究将揭示 IL-1 ra改善脓毒症GH抵抗的发展。

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.