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

在本研究项目中，我们对本课题组最近发现的新配体的生理功能进行了分析，并寻找了孤儿GPCRs的内源性配体。本研究取得了如下丰硕成果1.Ghrelin是一种生长激素(GH)释放和食欲肽，其生理功能的阐明：Ghrelin是在胃中发现的一种GH释放肽，已知它主要在胃内产生和分泌，对GH释放和食欲有很强的刺激作用。目前的研究表明，Ghrelin在下丘脑和胃以外的外周组织中也有产生，并在消化道、能量代谢、心血管系统和组织再生等方面具有多种中枢和外周调节作用。Ghrelin的研究目前正在进行临床应用。另一方面，去脂酰-Ghrelin缺乏对Ghrelin的脂肪酸修饰，是一种已知的非活性形式，通过GHS-R2以外的未知受体在细胞增殖中发挥生理功能。NMU是一种厌食多肽，其生理功能的阐明：在本研究中，NMU的新功能被阐明，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，我们已经确认NMU是一种新的昼夜节律调节因子。利用孤儿受体表达细胞检测系统寻找新的内源性配体：在本研究中，我们成功地从大鼠脑中发现了一种新的多肽--神经梅第素S(Neuromedin NMS，NMS)。我们还揭示了非常有趣的事实，NMS限制性地表达在大脑的视交叉上核(SCN)中，通过与NMU不同的机制来调节昼夜节律，并且具有比NMU更强的厌食活性。

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.