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，可以将激素和神经递质编码的信息转移到身体的细胞和组织中，从而控制生理反应。它们都是最大的一类此类信号转导子，并且已被证明是最有用的作为新药的分子靶点。尽管如此，许多GPCR尚未以这种方式成为目标，因为我们目前对它们在体内的具体作用以及促进或阻止其行动的潜在有用性或后果知之甚少。受体GPR84就是一个很好的例子。已知它由一系列关键免疫细胞亚型表达，并且在与炎症相关的许多情况下，它的水平可以在这些细胞中急剧增加。此外，已知血液中免疫细胞上的GPR84水平可以是治疗下肠道炎症性病症溃疡性结肠炎的可能有效性的有用指标。也有人建议，刺激或阻断GPR84可能是治疗从神经性疼痛到动脉粥样硬化的疾病的有用方法。然而，迄今为止，这些建议都没有得到实质性的处理。在很大程度上，这反映了直到最近还没有工具化合物可用于阻断GPR84的作用，并且尽管已知某些脂肪酸可以激活GPR84，但它需要非常高的浓度才能这样做，而这些浓度通常可能不存在于循环血液中。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，我们在吃西兰花和相关蔬菜后在体内产生的一种分子能够激活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，该方法将采用我们已经鉴定和表征的每种新型化学配体，以及旨在了解此类配体如何激活或阻断受体的每种基于计算，结构和分子生物学的研究。这些将告知如何使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，或者我们将用等效的人类受体替换小鼠版本的GPR84。在初步表征之后，我们将使用这些小鼠系来研究GPR84的激活剂和阻断剂预防或改变疾病表型特征的能力。这些研究将确定将该工作计划的结果转化为预测GPR84活性调节是否有助于开发人类疾病的新疗法的可能性。

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.