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GROWTH HORMONE RELEASING FACTOR RECEPTOR

生长激素释放因子受体

基本信息

批准号：
6329367
负责人：
BRUCE D GAYLINN
金额：
$ 20.74万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-05-15 至 2002-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6329367
关键词：
acromegaly affinity labeling biological signal transduction cell line crosslink disease /disorder model growth hormone releasing hormone hormone inhibitor hormone receptor hormone regulation /control mechanism hypothalamic pituitary axis laboratory rat photochemistry protein kinase A protein kinase C protein structure function receptor expression

项目摘要

Growth hormone (GH) is secreted by the pituitary in a pulsatile pattern that acts on tissues throughout the body both directly and through the stimulation of insulin-like growth factor 1 (IGF-1). Treatments that increase GH have been shown to be effective in the treatment of GH deficient children and adults, and also have wide ranging potential applications toward the relative GH deficiency associated with aging and obesity, the weight loss and muscle wasting of AIDS, and the agricultural production of milk and lean meat. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide that acts as the major stimulus for GH synthesis and release. GHRH mediates its actions by binding to pituitary GHRH receptors (GHRH-R) and activating an intracellular signal transduction pathway. An improved understanding of GHRH receptor structure, function, physiology and regulation will reveal the information needed to facilitate clinical and pharmacological manipulations of the GH axis. Toward this goal we propose the following specific aims: 1. Which domains of the GHRH-R are in close proximity to bound GHRH? A panel of five GHRH photoaffinity crosslinking probes and three receptor-directed antisera will be used to identify receptor domains in close contact with specific residues of bound hormone. These results will then be used to establish structure/function relationships and suggest structural requirements for receptor activation. 2. What mechanisms are involved in GHRH-R down regulation? We will examine how the GHRH induced receptor modification we report here relates to receptor down regulation and internalization in stable cell lines, primary cultured rat pituitary, and in naturally truncated ovine receptor. The roles of PKC, PKA and betaARK kinases will be tested. Mutant receptors will be prepared to identify the receptor domains involved. 3. Is GHRH the primary regulator of GHRH-R and is GHRH-R expression directly correlates to hypothalamic GHRH drive? A rat model with GH suppression of hypothalamic drive to the somototroph will be examined. This suppression will be challenged by either elevating endogenous GHRH with intracerebroventricular injection of GH antagonist or by iv infusion of exogenous GHRH.

生长激素（GH）是由脑垂体以脉动方式分泌的它直接或通过刺激胰岛素样生长因子1（IGF-1）。的治疗增加GH已被证明是有效的治疗GH 有缺陷的儿童和成人，也有广泛的潜力，应用于与衰老相关的相对生长激素缺乏症，肥胖、艾滋病引起的体重减轻和肌肉萎缩，农业生产牛奶和瘦肉。生长激素释放激素（GHRH）是下丘脑神经肽，作为主要的刺激GH合成和释放。 GHRH通过以下方式调解其行动：与垂体GHRH受体（GHRH-R）结合并激活细胞内信号转导途径更好地了解 GHRH受体的结构、功能、生理学和调节将揭示促进临床和药理学所需的信息 GH轴的操作。为实现这一目标，我们提出以下建议：具体目标：1. GHRH-R的哪些结构域与去绑GHRH 一组五种GHRH光亲和交联探针三种受体定向抗血清将用于鉴定受体与结合激素的特定残基密切接触的结构域。这些然后将结果用于建立结构/功能关系并提出了受体激活的结构要求。 2.什么机制参与GHRH-R下调？我们会研究如何我们在此报告的GHRH诱导的受体修饰涉及稳定细胞系中的受体下调和内化，原代培养的大鼠垂体和自然截断的绵羊垂体受体的将测试PKC、PKA和β ARK激酶的作用。将制备突变受体以鉴定受体结构域涉案 3. GHRH是GHRH-R的主要调节因子吗？表达与下丘脑GHRH驱动直接相关？大鼠模型与GH抑制下丘脑驱动器的促生长素将是考察这种压制将受到挑战，内源性GHRH与侧脑室注射GH拮抗剂或静脉输注外源性GHRH。