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MECHANISMS OF GH RESISTANCE IN SEPSIS

脓毒症中 GH 抵抗的机制

基本信息

批准号：
6386676
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
项目类别：
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

项目摘要

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）的发展