GROWTH HORMONE RELEASING FACTOR RECEPTOR

生长激素(GH)是由脑下垂体以搏动性方式分泌的。 它直接作用于全身的组织，也通过 刺激胰岛素样生长因子-1(IGF-1)。治疗方法： 增加生长激素已被证明在治疗生长激素方面有效 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和 肥胖、艾滋病造成的体重减轻和肌肉萎缩，以及 牛奶和瘦肉的农业生产。生长激素释放 激素(GHRH)是一种下丘脑神经肽，主要作用于 刺激生长激素的合成和释放。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AN 细胞内信号转导途径。更好的理解 GHRH受体的结构、功能、生理和调节意志 揭示促进临床和药理学所需的信息 生长激素轴的操作。为了实现这一目标，我们提出如下建议 具体目标：1.GHRH-R的哪些结构域非常接近 把GHRH绑起来？一组5个GHRH光亲和交联探针 并将使用三种受体导向的抗血清来识别受体 与结合荷尔蒙的特定残留物密切接触的区域。这些 然后将使用结果来建立结构/功能关系 并提出了受体激活的结构要求。2.什么？ GHRH-R下调的机制有哪些？我们将研究如何 我们在这里报道的GHRH诱导的受体修饰与 稳定细胞系中受体下调和内化， 原代培养的大鼠垂体和自然截断的绵羊 受体。将测试PKC、PKA和BetaARK激酶的作用。 突变的受体将准备好识别受体域 牵涉其中。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 随着生长激素的抑制，下丘脑驱动的体细胞将被 检查过了。这种压制将受到挑战，要么是提升 内源性GHRH侧脑室注射GH拮抗剂 或静脉注射外源性GHRH。

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.