Neuroendocrinology of Galanin-Like Peptide

描述（由申请人提供）：galanine -like peptide （GALP）是神经肽中新发现的galanine家族成员。GALP与丙氨酸具有部分序列同源性；然而，GALP是由一个单独的基因编码的，可能有自己独特的受体。我们的实验室和其他人的研究表明，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组神经元。我们最近发现GALP神经元是脂肪细胞衍生激素瘦素的直接靶点。GALP mRNA的表达在瘦素缺乏状态下降低，这可以通过同时服用瘦素来逆转。当GALP进入大脑时，会产生剂量依赖性的摄食和体重抑制，并刺激黄体生成素（LH）和睾酮的分泌。这些研究表明GALP神经元是连接体重和生殖调节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控制GALP细胞的解剖电路，绘制它们的投影，并辨别GALP的功能意义。我们的主要目标是1)研究瘦素、胰岛素和胃饥饿素对GALP神经元的影响，并描述这些细胞的突触输入和分子生理学特征——重点关注NPY、propropiomelocortin、血清素以及关键转录因子的输入；2)确定GALP在脑内的投射靶标，揭示其信号传导机制；3)通过评估GALP基因靶向缺失的小鼠，检查GALP在介导瘦素对神经内分泌生殖轴的影响中的作用，以及评估NPY输入GALP神经元的功能意义，特别是在促性腺激素分泌的背景下，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、分子和生理作用，以及了解GALP神经元如何受代谢激素调节，是理解GALP在神经内分泌生殖系统以及其他重要生理过程中的功能作用的基础。

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.