Characterization of two novel neuropeptides

描述(申请人提供)：大脑功能由神经递质和神经肽与其特定受体的相互作用来调节。这些相互作用的功能障碍是许多神经和精神疾病的原因。如今，已鉴定出100多种不同的神经递质和神经肽。然而，基因组序列分析显示，大约50%的调节大脑功能的分子仍然未知。找到并表征这些分子应该会大大扩展我们对大脑功能的理解。我们已经开发了一种策略，称为孤儿受体策略，它允许我们发现新的神经递质和神经肽。这一策略利用孤儿G蛋白偶联受体(GPCRs)作为“诱饵”来分离它们的天然配体。我们分析了两个孤立的GPCRs，并确定了它们的天然配体神经肽：黑色素浓缩激素(MCH)和尾加压素II(UII)。我们从解剖学、药理学和生物学的角度研究了这些系统。我们已经分离了一种MCH受体拮抗剂，并发现它可以抑制食物摄入的享乐性方面，现在我们建议分析这种拮抗剂对奖赏反应的影响。我们还研究了最近发现的两个序列相似的神经肽NPB和NPW，它们与孤儿GPCRGPR7结合。由于对这一新的神经肽系统的功能知之甚少，我们建议首先研究NPB在中枢神经系统中的作用部位，以帮助确定其核心作用。我们已经获得了初步的解剖学和行为学数据，表明NPB可能起到缓解焦虑的作用。由于焦虑是对压力的一种反应，这可能会将NPB/NPW系统设置为一个重要的医学目标。我们建议通过分析NPB在不同焦虑相关分析中的作用来进一步研究这一角色。我们还建议将这些研究扩展到缺乏GPR7受体的小鼠，并分析它们天生的焦虑水平。最后，我们建议通过应用我们用于鉴定MCH拮抗剂的方法来分离GPR7拮抗剂，并使用这些拮抗剂来进一步了解NPB/NPW系统在焦虑和可能的其他行为中的功能。

DESCRIPTION (provided by applicant): Brain functions are regulated by the interactions of neurotransmitters and neuropeptides with their specific receptors. Dysfunction in these interactions is the cause of many neurological and psychiatric disorders. Today, over 100 different neurotransmitters and neuropeptides have been identified. However, genomic sequence analyses show that about 50% of the molecules that mediate brain functions are still unknown. Finding and characterizing these molecules should significantly extend our understanding of brain function. We have developed a strategy, called the orphan receptor strategy, which allows us to discover novel neurotransmitters and neuropeptides. This strategy uses orphan G protein-coupled receptors (GPCRs) as "bait" to isolate their natural ligands. We analyzed two orphan GPCRs and identified the neuropeptides that are their natural ligands: melanin-concentrating hormone (MCH) and urotensin II (UII). We have studied these systems anatomically, pharmacologically and biologically. We have isolated a MCH receptor antagonist and have found that it can inhibit the hedonic aspect of food intake, e now propose to analyze the effects of this antagonist on rewarding responses. We have also studied two recently found equentially-similar neuropeptides, NPB and NPW, that bind to the orphan GPCR, GPR7. Since little is known about the function of this novel neuropeptide system, we propose to help identify its central roles by first study NPB sites of action in the CNS. We have already obtained preliminary anatomical and behavioral data that show that NPB may act as an anxiolytic agent. Because anxiety is a response to stress, this could set the NPB/NPW system as an important medical target. We propose to further study this role by analyzing NPB effect in different anxiety-related assays. We also propose to extend these studies to mice devoid of GPR7 receptor and analyze their innate level of anxiety. Finally we propose to isolate GPR7 antagonists, by applying the methodology that we used to identify MCH antagonists, and use these antagonists to further understand the function of the NPB/NPW system in anxiety and possibly other behaviors.