MECHANISMS OF GH RESISTANCE IN SEPSIS

描述：(改编自申请人的摘要) 创伤和脓毒症后生长激素(GH)抵抗导致 身体蛋白质的分解代谢。正常情况下，GH刺激释放 胰岛素样生长因子1(IGF-1)上调心肌细胞蛋白质合成 很多纸巾。慢性腹腔脓毒症模型在P.I.‘S中的应用 实验室模拟了观察到的许多生长激素抵抗的特点 败血症患者。因此，申请者处于非常有利的地位 描述这种细胞信号缺陷的机制。输注一种新的 特异性白介素1受体拮抗剂(IL-1ra) 改善脓毒症大鼠的蛋白质分解代谢和生长激素抵抗。这 提示IL-1是脓毒症患者生长激素抵抗的重要介质。这个 该项目的总体目标将是确定 IL-1介导大鼠生长激素抵抗及蛋白质分解代谢 慢性腹部败血症。生长激素不敏感可能是由于 生长激素受体的生物利用度、数量或质量缺陷 (GHR)，GHR信号转导中的受体后缺陷，或由改变 生长激素应答基因的表达。GHR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(GHBP) 结合循环生长激素并调节其生物利用度。GH构成了一个 具有GHR激活磷酸化级联的二聚化复合体。 受体后信号涉及JANUS对GHR的酪氨酸磷酸化 蛋白激酶2(JAK2)、JAK2自身磷酸化、转录激活 因子(S)和增加表达的“靶”基因，包括：胰岛素样生长因子-1和 SPI-2(丝氨酸蛋白酶抑制剂)。肝脏是人体的主要来源。 循环中的IGF-1(内分泌)，然而，包括肌肉在内的大多数组织 含有和转录IGF基因(旁分泌)。申请人计划 检测肝脏和肌肉中GHBP/GHR和IGF-1的表达 探讨内分泌和旁分泌的调控机制 在脓毒症中很重要。该项目的具体目标是：(1) 检测脓毒症和IL-1ra对GHBP表达的影响；(2)检测 脓毒症及IL-1拮抗对GHR表达及GH结合的影响 (3)观察脓毒症和IL-1ra对生长激素的影响。 肝脏蛋白酪氨酸磷酸化和JAK-2蛋白活化； (4)观察脓毒症及IL-1ra对IGF-1、SPI-2mRNA表达的影响 表情。这些研究将揭示 IL-1ra可改善脓毒症患者生长激素抵抗的形成。

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.