Neuroendocrinology of Galanin-Like Peptide

甘丙肽样肽的神经内分泌学

• 批准号: 7014502
• 负责人: ROBERT A STEINER
• 金额: $ 19.28万
• 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 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014502
• 关键词: biological signal transduction; galanin; gene expression; gene targeting; genetically modified animals; ghrelin; 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（由申请人提供）：甘丙肽样肽（GALP）是神经肽甘丙肽家族的新发现成员。GALP与甘丙肽具有部分序列同源性;然而，GALP由单独的基因编码，并且可能具有其自己独特的受体。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中的一簇神经元。我们最近发现，GALP神经元是脂肪细胞源性激素瘦素的直接靶点。在瘦素缺乏状态下，GALP mRNA的表达减少，这可以通过同时给予瘦素来逆转。当给药到大脑中时，GALP产生对进食和体重的剂量依赖性抑制，并且还刺激促黄体生成激素（LH）和睾酮分泌。这些研究表明，GALP神经元作为下丘脑回路的一部分，将体重调节和生殖联系起来;然而，除了这些观察结果，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GALP细胞的解剖电路，映射其预测，并辨别GALP的功能意义。本研究的主要目的是：1）研究瘦素、胰岛素和ghrelin对GALP神经元的作用，并探讨这些神经元的突触输入和分子生理学特征，重点研究神经肽Y、阿黑皮素原和5-羟色胺的输入以及关键转录因子的作用; 2）确定GALP在脑内投射的靶点并揭示其信号传导机制;和3）通过评估具有GALP基因的靶向缺失的小鼠，检查GALP在介导瘦素对神经内分泌生殖轴的作用中的作用，以及评估NPY输入到GALP神经元的功能意义，特别是在促性腺激素分泌的情况下，来评估GALP的功能意义。了解GALP与其他神经元系统耦合的基本电路，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神经元如何受代谢激素调节，对于理解GALP在神经内分泌生殖系统的编排中的功能作用以及其他重要的生理过程至关重要。