Studies for identification and physiological functions of novel endogenous ligands for G-protein coupled orphan receptors.

本研究对本课题组新近发现的新型配体的生理功能进行了分析，并寻找了孤儿GPCR的内源性配体。本研究取得了以下成果. Ghrelin是一种生长激素（GH）释放肽和促食欲肽，其生理功能的阐明：Ghrelin作为GH释放肽在胃中被发现，并且已知其主要在胃中产生和分泌，并且对GH释放和食欲具有强效刺激活性。本研究表明，ghrelin也在下丘脑和胃以外的外周组织中产生，并且在消化道、能量代谢、心血管系统和组织再生中具有多种中枢和外周调节作用。Ghrelin的研究正在向临床应用迈进。另一方面，去酰基-生长素释放肽，缺乏生长素释放肽的脂肪酸修饰并且已知是无活性形式，显示通过除GHS-R之外的未鉴定受体在细胞增殖中具有生理功能。神经调节肽U（NMU）的生理功能的阐明：在本研究中，阐明了NMU的新功能，如厌食活性，以及在应激反应和代谢中的作用。值得注意的是，我们已经将NMU确定为一种新的昼夜节律调节因子。通过使用孤儿受体表达细胞的测定系统寻找新的内源性配体：在这项研究中，我们成功地从大鼠脑中发现了一种新的肽，Neuromedin S（NMS）。我们还揭示了非常有趣的事实，NMS，限制性表达在视交叉上核（SCN）在大脑中，有一个调节昼夜节律的作用，从NMU不同的机制，并有更强的厌食活性比NMU。

In this research project, we have analyzed the physiological functions of the novel ligands recently discovered by our group, and also searched for endogenous ligands of orphan GPCRs. We obteined fruitful results from this study as listed below.1. Elucidation of physiological functions of ghrelin, a growth hormone (GH)- releasing and orexigenic peptide :Ghrelin was discovered in the stomach as a GH-releasing peptide, and is known that it is mainly produced and secreted in the stomach, and has potent stimulating activities on GH release and appetite. In the present study, it is shown that ghrelin is also produced in the hypothalamus and peripheral tissues other than stomach, and has various central and peripheral regulatory roles in digestive tract, energy metabolism, cardiovascular system and regeneration of tissues. The research of ghrelin is now proceeding for clinical application. On the other hand, desacyl-ghrelin, lacking fatty acid modification of ghrelin and known to be an inactive form, is shown to have physiological function in cellular proliferation via unidentified receptor other than GHS-R.2. Elucidation of physiological functions of Neuromedin U (NMU), an anorectic peptide :In this study, novel functions of NMU are clarified such as anorectic activity, and the roles in stress response and metabolism. It should be noted that we have identified NMU as a novel regulatory factor of circadian rhythm.3. Search for novel endogenous ligands by using assay systems of orphan receptor expressing cells :In this study, we have succeeded in discovering a novel peptide, Neuromedin S (NMS), from rat brain. We also revealed very interesting facts that NMS, restrictedly expressed in suprachiasmatic nuclei (SCN) in the brain, has a role in regulating circadian rhythm by the mechanism different from NMU, and has more potent anorectic activity than NMU.