NEUROENDOCRINE CONTROL OF ANTERIOR PITUITARY HORMONES

这项提案的目标是研究增长的调节。 激素(GH)分泌、下丘脑的释放和抑制 激素(生长激素释放激素(GRH)和生长抑素(SRIF)) 控制生长激素的分泌，并寻找 神经内分泌功能可能是导致心力衰竭的原因 人的生长激素分泌。每个组件的标识 这一调节系统中的激素(GRH、SRIF、GH和胰岛素样 生长因子-L(IGF-L)，许多生长的中介 促进生长激素的作用)和它们的分子克隆允许 下丘脑-垂体的综合研究方法 可以作为其他系统的模型的系统。这项建议 将利用分子生物学、细胞培养、蛋白质等技术 化学和活体测量脑垂体部激素水平 门静脉血，以及临床研究，以研究不同方面的 这个系统。下丘脑GRH基因表达的调控 将在体内研究对荷尔蒙和代谢的反应 (饥饿、糖尿病、肥胖)扰动，并在体外使用 GRH基因转染法。GRH前驱体向GRH的转化 成熟激素将在转基因动物中进行研究，表达 人类生长激素释放激素基因及其加工酶的潜在作用 监管机构将下定决心。GRH的代谢将是 在循环和GRH作用部位进行研究 将对所涉及的酶进行表征。神经内分泌 GRH和SRIF的调节将通过直接测量进行研究 门脉血浆和下丘脑中两种神经激素的比较 绵羊非麻醉灌流液及其分子形式的研究 每种激素都由高效液体测定。 层析法。含GRH神经元细胞分泌GRH的实验研究 在培养中将研究和分泌物的影响 下定决心。GRH和SRIF对垂体的作用将被研究 在生长激素缺乏的LIT/LIGT小鼠与膜融合 在尝试更正之前报告的 推测存在于GRH受体的异常。我们的新品 开发了第一个表现出生长激素释放激素的生长抑素细胞系 敏感性，将用于研究GRH和SRIF的影响 细胞膜和核的水平。外生性与外生性的比较 内源性(通过转导GRH基因)GRH效应也将 被比较。人血中生长激素释放激素的分子结构 血浆GH反馈效应的测定及作用机制 在正常人和生长激素分泌紊乱的受试者中 评估过了。这些研究的结果将提供更好的 对中枢神经系统在临床中作用的认识 生长激素分泌紊乱，最终可能导致新的 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.