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Neuroendocrine control of anterior pituitary hormones

垂体前叶激素的神经内分泌控制

基本信息

批准号：
7004508
负责人：
Rhonda D Kineman
金额：
$ 28.08万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1981
资助国家：
美国
起止时间：
1981-07-02 至 2009-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Growth hormone (GH) promotes protein synthesis and lipolysis. In turn, metabolic disturbances are associated with alteration in GH production which contribute to the pathophysiology of clinically relevant disorders such as malnutrition, anorexia nervosa, obesity and diabetes. Despite the strong association between metabolism and GH, little is known regarding the basic mechanisms by which perturbations in metabolic pathways bring about changes in GH synthesis and release. Therefore, this application will determine the mechanisms by which alterations in nutrient availability; 1) regulate hypothalamic expression of neuropeptides essential for normal pituitary GH production (GH-releasing hormone [GHRH] and somatostatin [SRIF]), and 2) modify pituitary sensitivity to the GH-stimulatory peptides, GHRH and ghrelin. It has been proposed that changes in circulating leptin (an adipocyte factor) and ghrelin (a GH-releasing peptide produced in the stomach) mediates hypothalamic expression of GHRH and SRIF through activation of neuropeptide Y (NPY) neurons. To test this hypothesis, the effects of fasting on neuropeptide mRNA levels, in mice harboring defects in leptin synthesis (ob/ob), tissue source of leptin (AZIP-F1), NPY synthesis (NPY-/-), SRIF synthesis (smst-/-) and SRIF signaling (ss1l/2-/-) will be examined by ribonuclease protection assay and in situ hybridization. Also the effects of fasting in normal mice following exogenous hormone replacement (to increase NPY, leptin or ghrelin), pharmacological treatment (to block endogenous NPY production) or passive immunoneutralization (to block the actions of ghrelin) will be tested. Fasting not only alters expression of GH-regulatory neuropeptides but also enhances pituitary sensitivity to GHRH and ghrelin by increasing GHRH-R and GHS-R mRNA levels. In vitro, FFAs alone or in conjunction with glucocorticoids increase GHS-R synthesis. Therefore it is hypothesized that fasting induced elevations in FFA and glucocorticoids are required to enhance pituitary receptor synthesis and sensitivity, and thus compensate for fasting-induced alteration in central signals. To test this hypothesis, studies will examine the ability of fasting to alter pituitary receptor expression (by quantitative RT-PCR) and dynamic GH release (by RIA of serial blood samples) following blockade of FFA formation (by the anti-lipolytic Acipimox) or glucocorticoid actions (by the glucocorticoid receptor antagonist, RU-486). Also primary rat and non-human primate (baboon) pituitary call cultures will be used to determine if FFA and glucocorticoids mediate their effects on receptor synthesis via transcriptional or post-transcriptional processes and if the effects of FFA can be mimicked by activation of the putative FFA nuclear receptors, peroxisome proliferator-activated receptors (PPAR). This is the second revision of a competitive renewal of an RO1 application which continues to study the regulation of the GH axis. The current application centers on the interrelationship between changes in metabolic function and the GH axis.

性状（由申请方提供）：生长激素（GH）促进蛋白质合成和脂解。反过来，代谢紊乱与GH产生的改变有关，这有助于临床相关疾病的病理生理学，如营养不良、神经性厌食症、肥胖和糖尿病。尽管代谢和生长激素之间的强关联，很少有人知道的基本机制，通过代谢途径的扰动引起生长激素的合成和释放的变化。因此，本申请将确定营养物质利用率改变的机制：1）调节正常垂体GH产生所必需的神经肽（GH释放激素[GHRH]和生长抑素[SRIF]）的下丘脑表达，2）改变垂体对GH刺激肽GHRH和ghrelin的敏感性。已经提出，循环瘦素（脂肪细胞因子）和生长激素释放肽（胃中产生的GH释放肽）的变化通过激活神经肽Y（NPY）神经元介导下丘脑GHRH和SRIF的表达。为了验证这一假设，将通过核糖核酸酶保护试验和原位杂交检查禁食对瘦素合成（ob/ob）、瘦素组织来源（AZIP-F1）、NPY合成（NPY-/-）、SRIF合成（smst-/-）和SRIF信号传导（ss 1 l/2-/-）缺陷小鼠中神经肽mRNA水平的影响。还将测试在外源性激素替代（以增加NPY、瘦素或生长素释放肽）、药物治疗（以阻断内源性NPY产生）或被动免疫中和（以阻断生长素释放肽的作用）后禁食对正常小鼠的影响。禁食不仅改变GH调节神经肽的表达，而且通过增加GHRH-R和GHS-R mRNA水平来增强垂体对GHRH和ghrelin的敏感性。在体外，FFA单独或与糖皮质激素结合增加GHS-R的合成。因此，假设禁食诱导的FFA和糖皮质激素升高是增强垂体受体合成和敏感性所必需的，从而补偿禁食诱导的中枢信号改变。为了验证这一假设，研究将检查禁食改变垂体受体表达（通过定量RT-PCR）和动态GH释放（通过系列血液样本的RIA）的能力，阻断FFA形成（通过抗脂解的Acipimox）或糖皮质激素作用（通过糖皮质激素受体拮抗剂RU-486）。还将使用原代大鼠和非人灵长类动物（狒狒）垂体细胞培养物来确定FFA和糖皮质激素是否通过转录或转录后过程介导其对受体合成的影响，以及FFA的影响是否可以通过激活推定的FFA核受体、过氧化物酶体增殖物激活受体（PPAR）来模拟。这是RO 1申请的竞争性更新的第二次修订，该申请继续研究GH轴的调节。当前的应用集中在代谢功能变化与GH轴之间的相互关系上。