Neuroendocrinology of Galanin-Like Peptide

甘丙肽样肽的神经内分泌学

• 批准号: 6607889
• 负责人: ROBERT A STEINER
• 金额: $ 19.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607889
• 关键词: biological signal transduction; galanin; gene expression; gene targeting; genetically modified animals; hypothalamus; immunocytochemistry; in situ hybridization; insulin; laboratory mouse; leptin; messenger RNA; microarray technology; neuroendocrine system; neurons; neuropeptide Y; proopiomelanocortin; serotonin; transcription factor; transfection

DESCRIPTION (provided by applicant): Galanin-like peptide (GALP) is a newly discovered member of the galanin family of neuropeptides. GALP shares a partial sequence homology with galanin; however, GALP is coded by a separate gene and is likely to have its own unique receptor. Work from our laboratory and others has shown that the expression of GALP mRNA in the brain is limited to a cluster of neurons in the hypothalamic arcuate nucleus and the median eminence. We have recently discovered that GALP neurons are direct targets for the adipocyte-derived hormone leptin. The expression of GALP mRNA is reduced in leptin-deficient states, which can be reversed by the concomitant administration of leptin. When administered into the brain, GALP produces a dose-dependent inhibition of feeding and body weight and also stimulates luteinizing hormone (LH) and testosterone secretion. These studies suggest that GALP neurons serve as part of the hypothalamic circuitry linking the regulation of body weight and reproduction; however, beyond these observations, we understand little about GALP's physiological importance. We propose to use neuroanatomical, pharmacological, and molecular biological techniques to reveal the anatomical circuitry governing GALP cells, map their projections, and discern GALP's functional significance. Our primary aims are 1) to examine the effects of leptin, insulin and ghrelin on GALP neurons and characterize the synaptic inputs and molecular physiology of these cells-focusing on inputs from NPY, proopiomelanocortin, and serotonin, as well as on key transcription factors; 2) to identify the targets of GALP projections in the brain and to reveal its signaling mechanisms; and 3) to assess the functional significance of GALP by evaluating mice with a targeted deletion of the GALP gene, examining the role of GALP in mediating the effects of leptin on the neuroendocrine reproductive axis, and evaluating the functional significance of NPY inputs to GALP neurons, particularly in the context of gonadotropin secretion. Learning the basic circuitry that couples GALP to other neuronal systems, understanding more about the molecular physiology of GALP neurons, establishing the cellular, molecular, and physiological effects of GALP, and learning how GALP neurons are regulated by metabolic hormones are fundamental to understanding GALP's functional role in the orchestration of the neuroendocrine reproductive system, as well as other important physiological processes.

描述(申请人提供)：甘丙肽样肽(GALP)是神经肽甘丙肽家族中新发现的成员。Galp与Galanin有部分序列同源性；然而，GALP由一个单独的基因编码，可能有自己独特的受体。我们实验室和其他实验室的工作表明，GALP mRNA在大脑中的表达仅限于下丘脑弓状核和正中隆起的一群神经元。我们最近发现，GALP神经元是脂肪细胞衍生的激素瘦素的直接靶点。在瘦素缺乏的状态下，GALP mRNA的表达减少，同时应用瘦素可以逆转这一现象。当GALP注射到大脑中时，它会对摄食和体重产生剂量依赖性的抑制，还会刺激黄体生成素(LH)和睾酮的分泌。这些研究表明，GALP神经元是连接体重调节和生殖的下丘脑回路的一部分；然而，除了这些观察之外，我们对GALP的生理重要性知之甚少。我们建议使用神经解剖学、药理学和分子生物学技术来揭示支配GALP细胞的解剖回路，绘制它们的投射图，并辨别GALP的功能意义。我们的主要目标是1)检测瘦素、胰岛素和Ghrelin对GALP神经元的影响并表征这些细胞的突触输入和分子生理学-侧重于NPY、前阿片黑素皮质素和5-羟色胺的输入以及关键转录因子；2)确定GALP在大脑中的投射靶点并揭示其信号机制；以及3)通过评估GALP基因的定向缺失小鼠，研究GALP在调节瘦素对神经内分泌轴的影响中的作用，以及评估NPY输入对GALP神经元的功能意义，尤其是在促性腺激素分泌的背景下，评估GALP的功能意义。了解连接GALP与其他神经系统的基本电路，更多地了解GALP神经元的分子生理学，建立GALP的细胞、分子和生理效应，以及了解GALP神经元如何受到代谢激素的调节，对于了解GALP在神经内分泌生殖系统的协调以及其他重要的生理过程中的功能作用是至关重要的。