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ROLE OF HORMONES IN THE PROCESSING OF NEURONAL PEPTIDES

激素在神经元肽加工中的作用

基本信息

批准号：
3227540
负责人：
AYALLA BARNEA
金额：
$ 19.74万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-06-01 至 1994-01-31
项目状态：
已结题

项目摘要

Our goals are to elucidate the mechanisms underlying release of LH- releasing hormone (LHRH) from hypothalamic neurons and its regulation by steroids. Our studies led to the formulation of this working hypothesis: Copper (Cu), co-released with norepinephrine (NE) or a-amidated peptides, modulates LHRH relaease; one such action of Cu is the amplification of prostaglandin E2 (PGE2) stimulation of LHRH release. Adrenal steroids exert a positive input on LHRH relaease in the maturing male rat, by regulating the plasma-membrane machinery involved in the process of Cu- amplified PGE2 (Cu/PGE2) stimulation of LHRH release and by regulating Cu release from neurons impinging on the LHRH neuron. S.A.1 is to elucidate the mechanism(s) by which Cu modulates LHRH release; using explants of the median eminence as a model. We will investigate (i) whether and how a CuNE complex mixture stimulates LHRH release; (ii) whether Cu amplification of PGE2 stimulation of LHRH release is a result of Cu interaction with the opioid receptor and/or Cu inhibition of cAMP efflux. S.A.2. is to elucidate the mechanism(s) underlying adrenal regulation of LHRH release in the maturing male rat; specifically Cu/PGE2- stimulated release. We will (i) characterize the ontogeny of the positive feedback of adrenals steroids on LHRH release and identify the regulatory steroid; (ii) examine the specificity of steroid action on Cu/PGE2 -stimulated release of LHRH by examining the effects on CuHis-, veratridine- and K- induced release; and (iii) study the effect of steroids on the kinetic parameters of Cu and PGE2 interactive sites ad on uptake and release of 67-Cu in various brain regions. S.A3. is to elucidate the biochemical mechanisms underlying Cu homeostasis in the hyothalamus; uptake, release, and intracellular processing. We will (i) further establish the process of 67-Cu release, using veratridine (Na-influx) induced release as a model; (ii) analyse the kinetics of 67-Cu uptake into the releasable pool of Cu; and (iii) study the intracellular processing of newly taken-up CuHis, specifically ligand exchange of the His. Understanding the mechanisms underlying Cu action on the LHRH neuron and steroid regulation of LHRH release in teh maturing male, will provide insight into integrative regulatory processes in the brain and into developmental and hormonally regulated brain functions.

我们的目标是阐明潜在的释放机制下丘脑神经元的促黄体生成素释放激素及其功能类固醇的调节作用。我们的研究导致了这一点的形成工作假设：铜(铜)，与去甲肾上腺素共同释放 (NE)或α-酰胺化肽，调节LHRH重新释放；铜的作用是放大前列腺素E_2(PGE_2) 刺激LHRH的释放。肾上腺类固醇发挥积极作用 LHRH在成熟雄性大鼠体内的输入，通过调节铜矿生产过程中涉及的质膜机械扩增的前列腺素E_2(铜/前列腺素E_2)刺激LHRH的释放调节撞击LHRH的神经元的铜释放神经元。S.A.1是为了阐明铜的致病机理(S) 调节LHRH的释放；使用正中隆起的外植体作为一名模特。我们将调查(I)是否以及如何形成Cune 复合混合物刺激LHRH释放；(Ii)铜是否扩增PGE2刺激LHRH释放的结果是铜与阿片受体的相互作用和/或铜抑制阿片受体夏令营流出物。S.A.2。就是要阐明(S)背后的机制肾上腺对成熟雄性大鼠促性腺激素释放激素的调节；尤其是铜/前列腺素E_2刺激的释放。我们将(I)描述肾上腺皮质类固醇激素正反馈作用的个体发育 LHRH释放并确定调节类固醇；(Ii)检查类固醇对铜/前列腺素E_2刺激释放的特异性作用 LHRH通过检测CuHis-、Veratridine-和K- 诱导释放；及(Iii)研究类固醇对脑组织的影响。铜和前列腺素E_2相互作用部位吸附的动力学参数并在不同的脑区释放67-铜。S.A3.是为了阐明铜稳态的生化机制在舌骨中；摄取、释放和细胞内处理。我们将(I)进一步建立67-铜的释放过程，使用藜芦碱(Na-内流)诱导释放作为模型；(Ii)分析可释放铜库吸收~(67)Cu的动力学；和(Iii) 研究新摄取的CuHis的细胞内处理，具体地说，是组氨酸的配体交换。了解铜对LHRH作用的机制成熟过程中神经元和类固醇对LHRH释放的调节将提供对综合监管流程的见解大脑和发育和激素调节的大脑功能。