NEUROENDOCRINE CONTROL OF ANTERIOR PITUITARY HORMONES

生长激素(GH)是正常的身体生长所必需的，它还 在新陈代谢、免疫功能和整体健康方面发挥着重要作用 是存在的。下丘脑生长激素释放激素(GHRH)缺乏 被认为是儿童期出现生长激素缺乏症的主要原因 与观察到的老年人循环中较低的生长激素浓度有关 个人。各种生物生长激素释放激素类化合物正在被 为治疗用途而开发的。然而，人们对此知之甚少。 关于内源性GHRH合成和信号的调节。至 更好地了解GHRH/GHRH受体(GHRH-R)系统的调节 该提案侧重于生长激素轴内的反调节机制。 它缓和了脑下垂体促生长激素对 GHRH(同源脱敏)和调节利用度 GHRH(GH/IGF-I负反馈)。原代大鼠垂体细胞 培养物将用于研究GHRH对GHRH-R合成的影响 (GHRH-rmRNA的RT-PCR)和对GHRH(配体刺激的)的敏感性 腺苷环化酶活性和cAMP生成)。研究将检验： ICER(cAMP诱导抑制物)，G蛋白激酶介导的受体 GHRH介导的磷酸化或受体内化作用 GHRH-R在体外的下调。反常生长激素的动物模型 生产将检测GHRH高-(MT-hGHRH)转基因的效果 小鼠)和次要(谷氨酸单钠处理的大鼠)分泌 GHRH-R信号系统，体内。此外，动物模型将被用来 确定1)循环中的IGF-I是否在 下丘脑反馈抑制(GH受体基因敲除小鼠)，2)如果GH 诱导下丘脑神经肽Y的表达是必不可少的 GH介导的抑制GHRH合成的成分(自发性矮小 大鼠(SDR和TH-hGH转基因侏儒小鼠)和3)GH下丘脑 负反馈导致循环生长激素减少 随年龄变化观察到的浓度(SDR)。最后，研究将是 进行的目的是了解新的 GH促分泌素受体(GHS-R)系统的鉴定 生长激素轴的调节。拟议的研究代表了一个系统的 确定生长激素轴的反调节机制的方法 维持正常的GHRH合成和信号。更好地理解 这些机构的设计和合理应用将有助于 GHRH类似物和模拟物，可用于减轻有害的 生长激素分泌不足的影响。

Growth hormone(GH) is required for normal somatic growth and it also plays important roles in metabolism, immune function, and overall well being. A hypothalamic GH-releasing hormone (GHRH) deficit is now recognized as the primary cause of childhood onset GH deficiency and is linked to the lower circulating GH concentrations observed in elderly individuals. A variety of biopotent GHRH-like compounds are being developed for therapeutic use. However, relatively little is known about the regulation of endogenous GHRH synthesis and signaling. To better understand regulation of the GHRH/GHRH-receptor (GHRH-R) system this proposal focuses on counterregulatory mechanisms within the GH-axis which temper the pituitary somatotrope sensitivity to the actions of GHRH (homologous desensitization) and which regulate the availability of GHRH (GH/IGF-I negative feedback). Primary rat pituitary cell cultures will be used to study the effects of GHRH on GHRH-R synthesis (RT-PCR of GHRH-R mRNA) and sensitivity to GHRH (ligand stimulated adenylate cylase activity and cAMP generation). Studies will examine: ICER (cAMP inducible repressor), G-protein kinase-mediated receptor phosphorylation or receptor internalization roles in GHRH-mediated downregulation of the GHRH-R, in vitro. Animal models of aberrant GH production will examine the effects of GHRH hyper-(MT-hGHRH transgenic mice) and hypo-(monosodium glutamate treated rats) secretion on the GHRH-R signaling system, in vivo. Also, animal models will be used to determine 1) if circulating IGF-I plays an important role in hypothalamic feedback inhibition (GH receptor knockout mouse), 2) if GH induction of hypothalamic neuropeptide Y expression is an essential component of GH-mediated inhibition of GHRH synthesis (spontaneous dwarf rat [SDR] and TH-hGH transgenic dwarf mouse) and 3) if GH hypothalamic negative feedback contributes to diminished circulating GH concentrations observed with age (SDR). Finally, studies will be conducted to understand the relative contribution of the newly identified GH secretagogue receptor (GHS-R) system to the coordinate regulation of the GH-axis. The proposed studies represent a systematic approach to determine how counterregulatory mechanisms of the GH-axis maintain normal GHRH synthesis and signaling. A better understanding of these mechanisms will aid in the design and rational application of GHRH analogues and mimics which could serve to alleviate the deleterious effect of GH hyposecretion.