Molecular and patho-physiological analysis of the G protein-coupled receptor GPR84

G蛋白偶联受体是跨质膜蛋白，允许荷尔蒙和神经递质编码的信息转移到身体的细胞和组织中，并通过这样做来控制生理反应。它们都是这类信号转导中最大的一组，并且被证明在作为新药的分子靶标方面最有用。尽管如此，许多GPCR尚未以这种方式成为目标，因为我们目前对其在机构中的具体作用以及促进或阻止其行动的潜在用处或后果知之甚少。受体GPR84就是一个很好的例子。众所周知，它由一系列关键的免疫细胞亚型表达，而且在许多与炎症相关的情况下，其水平在这些细胞中可以显著增加。此外，已知血液中免疫细胞上的GPR84水平可以作为治疗低度肠道炎症条件下溃疡性结肠炎的可能有效性的有用指标。也有建议认为，刺激或阻断GPR84可能是治疗从神经性疼痛到动脉粥样硬化等各种疾病的有用方法。然而，到目前为止，这些建议都没有真正得到实质性的处理。这在很大程度上反映了直到最近还没有可用的工具化合物来阻断GPR84的作用，尽管我们知道某些脂肪酸可以激活GPR84，但要做到这一点，需要非常高的浓度，而循环血液中可能不会正常存在。这表明GPR84的激活可能是由脂肪酸以外的配体产生的，而且我们也知道，我们吃了西兰花和相关蔬菜后在体内产生的一个分子能够激活GPR84。我们计划采用一种全面的方法来了解这种受体的生物学功能，它将使用我们已经确定和表征的每一种新的化学配体，以及每一种基于计算、结构和分子生物学的研究，旨在了解这些配体如何激活或阻断该受体。这些信息将告诉我们如何利用这些信息来开发更有效的配体。我们还将开发和使用缺乏GPR84表达的小鼠，或者我们将用相当于人类受体的GPR84替换小鼠版本的GPR84。在初步鉴定之后，我们将使用这些小鼠品系来研究GPR84的激活剂和阻断剂预防或改变疾病表型特征的能力。这些研究将确定是否有可能将这一工作计划的结果转化为预测GPR84活性的调节是否有助于开发人类疾病的新疗法。

G protein-coupled receptors are trans-plasma membrane proteins that allow the transfer of information encoded by hormones and neurotransmitters into cells and tissues of the body and, by so doing, act to control physiological responses. They are both the largest group of such signal transducers and have proved to be the most useful in acting as the molecular targets for new medicines. Despite this, many GPCRs have not yet been targeted in this way because we currently know too little about their specific roles in the body and the potential usefulness or consequences of promoting or blocking their actions. The receptor GPR84 is a good example of this. It is known to be expressed by a range of key immune cell subtypes and also that its levels can be increased dramatically in such cells in many situations associated with inflammation. Moreover, it is known that levels of GPR84 on immune cells in the blood can be a useful indicator of the likely effectiveness of treatment of the lower gut inflammatory condition ulcerative colitis. There are also suggestions that either stimulating or blocking GPR84 might be useful approaches to treat conditions ranging from neuropathic pain to atherosclerosis. However, to date none of these suggestions have really been addressed in a substantive way. In very large part this reflects that until very recently no tool compounds have been available to block the action of GPR84 and, although it is known than certain fatty acids can activate GPR84 it requires very high concentrations that are probably not present normally in the circulating blood to do so. This suggests that activation of GPR84 may be produced by ligands other than fatty acids and it is also known that a molecule we generate in the body after eating broccoli and related vegetables is able to activate GPR84. We plan a comprehensive approach to understand the biological functions of this receptor that will employ each of novel chemical ligands that we have identified and characterised, and each of computational, structural and molecular biology-based studies designed to understand how such ligands activate or block the receptor. These will inform how such information can be used to develop ligands that are even more effective. We will also develop and use mice which either lack expression of GPR84 or in which we will replace the mouse version of GPR84 with the equivalent human receptor. Following initial characterisation we will use these mouse lines to study the capacity of activators and blockers of GPR84 to prevent or modify features of disease phenotypes. These studies will determine the likely potential to translate the outcomes from this programme of work to predict whether regulation of the activity of GPR84 may be useful in efforts to develop novel treatments for diseases in humans.