NEUROENDOCRINE CONTROL OF ANTERIOR PITUITARY HORMONES

垂体前叶激素的神经内分泌控制

• 批准号: 3483570
• 负责人: LAWRENCE A FROHMAN
• 金额: $ 31.27万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-07-02 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3483570
• 关键词: acromegaly; alpha methyldopamine; blood chemistry; catecholamine inhibitor; dopamine; endocrine disorder; endocrine pharmacology; estrogens; hormone receptor; hormone regulation /control mechanism; human subject; hyperprolactinemia; insulinlike growth factor; laboratory rat; neural information processing; neuroendocrine system; neuropeptides; orphan disease /drug; peptide hormone metabolism; pituitary disorders; pituitary hormones; pituitary neoplasms; prolactin; prolactin releasing /inhibiting factor; radioimmunoassay; somatostatin; somatotropin; thyroid hormones; tissue /cell culture

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.

这项提案的目标是研究生长的调节 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））， 控制生长激素的分泌，并寻找改变 神经内分泌功能，可能负责的疾病， 人的生长激素分泌。每种成分的鉴定 调节系统中的激素（GRH、SRIF、GH和胰岛素样 生长因子-I（IGF-I），许多生长因子的介质， GH的促进作用）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。 该提案 将利用分子生物学、细胞培养、蛋白质 化学，垂体中激素水平的体内测量 门静脉血，和临床研究，研究不同方面的 这系统. 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，以及体外使用 GRH基因转染。 将GRH前体转化为 成熟激素将在转基因动物中研究， 人类GRH基因和加工酶的作用， 监管机构将作出决定。 GRH的代谢将是 在循环中和GRH作用部位的研究， 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来研究 门静脉血浆和下丘脑中的两种神经激素 未麻醉绵羊的灌流液和 每种激素都将通过高效液相色谱法测定， 层析 含GRH神经细胞的GRH分泌 在文化将被研究和分泌的影响 测定 将研究GRH和SRIF对垂体的作用 在GH缺乏的lit/lit小鼠中， 试图纠正之前报道的 假定存在于GRH受体中的异常。 我们新 开发了第一个表现出GRH的体乳细胞系， 敏感性，将用于研究GRH和SRIF的影响， 细胞膜和细胞核水平。 外生和 内源性（通过GRH基因的转染）GRH效应也将 被比较。 人循环GRH的分子结构 等离子体将被确定和GH反馈效应的机制 在正常人和GH分泌紊乱的受试者中， 评估。 这些研究的结果将提供更好的 了解中枢神经系统在临床中的作用 生长激素分泌失调，并可能最终导致新的 治疗方法。