NEUROENDOCRINE CONTROL OF ANTERIOR PITUITARY HORMONES

该提案的目标是研究生长调节 激素（GH）分泌，下丘脑释放和抑制 激素（生长激素释放激素 (GRH) 和生长抑素 (SRIF)） 控制 GH 的分泌，并寻找 神经内分泌功能可能与以下疾病有关 人体内的 GH 分泌。 每个组件的标识 该调节系统中的激素（GRH、SRIF、GH 和胰岛素样 生长因子-l (IGF-l)，许多生长的介质 GH 的促进作用）及其分子克隆允许 研究下丘脑-垂体的综合方法 系统可以作为其他系统的模型。 提案 将利用分子生物学、细胞培养、蛋白质技术 化学，垂体激素水平的体内测量 门静脉血和临床研究来研究不同方面 这个系统。 下丘脑GRH基因表达的调控 将在体内研究对激素和代谢的反应 （饥饿、糖尿病、肥胖）扰动和体外使用 GRH基因转染。 GRH 前体转化为 将在表达成熟激素的转基因动物中进行研究 人类 GRH 基因和加工酶的潜在作用 监管机构将确定。 GRH 的代谢为 在循环系统和 GRH 作用部位进行研究 所涉及的酶将被表征。 神经内分泌 GRH 和 SRIF 的调节将通过直接测量来研究 门静脉血浆和下丘脑中两种神经激素的 未麻醉羊的灌流液及其分子形式 每种激素均由高性能液体测定 色谱法。 含有 GRH 的神经元细胞分泌 GRH 将研究在文化中的作用以及促分泌素的影响 确定。 将研究 GRH 和 SRIF 对垂体的作用 在 GH 缺乏的点燃/点燃小鼠中，膜融合将 试图纠正之前报告的情况 推测异常存在于 GRH 受体中。 我们新的 开发出第一个表现出 GRH 的生长激素细胞系 灵敏度，将用于研究 GRH 和 SRIF 在 细胞膜和核水平。 外源性与内源性的比较 内源性（通过转染 GRH 基因）GRH 效应也会 进行比较。 人体循环GRH的分子结构 血浆测定及GH反馈效应机制 在正常人和患有 GH 分泌障碍的受试者中 评估。 这些研究结果将提供更好的 了解中枢神经系统在临床中的作用 GH 分泌失调并可能最终导致新的 治疗方法。

The goals of this proposal are to study the regulation of growth hormone (GH) secretion, the hypothalamic releasing and inhibiting hormones (GH-releasing hormone (GRH) and somatostatin (SRIF)) that control the secretion of GH, and to search for alterations in neuroendocrine function that may be responsible for disorders of GH secretion in man. The identification of each of the component hormones in this regulatory system (GRH, SRIF, GH, and insulin-like growth factor-l (IGF-l), the mediator of many of the growth promoting action of GH) and their molecular cloning allows for an integrated approach to the study of this hypothalamic-pituitary system that may serve as a model for other systems. The proposal will utilize techniques of molecular biology, cell culture, protein chemistry, in vivo measurements of hormone levels in hypophyseal portal blood, and clinical studies to study different aspects of this system. The regulation of hypothalamic GRH gene expression will be studied in vivo in response to hormonal and metabolic (starvation, diabetes, obesity) perturbations, and in vitro using GRH gene transfection. The conversion of the GRH precursor to the mature hormone will be studied in transgenic animals expressing the human GRH gene and the role of processing enzymes as potential regulators will be determined. The metabolism of GRH will be studied in circulation and at the sites of GRH action and the enzymes involved will be characterized. The neuroendocrine regulation of GRH and SRIF will be studied by direct measurements of the two neurohormones in portal plasma and in hypothalamic perfusate fluid of unanesthetized sheep and the molecular forms of each hormone will be determined by high performance liquid chromatography. GRH secretion from GRH-containing neuronal cells in culture will be studied and the effects of secretogogues determined. GRH and SRIF action on the pituitary will be studied in the GH deficient lit/lit mouse and membrane fusion will be performed in an attempt to correct the previously reported abnormality presumed to reside in the GRH receptor. Our newly developed somatomammotroph cell line, the first that exhibits GRH sensitivity, will be used to study the effects of GRH and SRIF at cell membrane and nuclear levels. A comparison of exogenous and endogenous (by transfection of the GRH gene) GRH effects will also be compared. The molecular structure of circulating GRH in human plasma will be determined and the mechanism of GH feedback effects in normals and in subjects with disorders of GH secretion will be assessed. The results of these studies will provide a better understanding of the role of the central nervous system in clinical disorders of GH secretion and may ultimately lead to new therapeutic approaches.