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

G蛋白偶联受体GPR84的分子和病​​理生理学分析

• 批准号: BB/T000562/1
• 负责人: Graeme Milligan
• 金额: $ 114.86万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT000562%2F1
• 关键词: Molecular; patho; physiological; analysis; protein

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.

G 蛋白偶联受体是跨质膜蛋白，它允许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，并通过这样做来控制生理反应。它们都是此类信号传感器中最大的一组，并且已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 尚未以这种方式被靶向，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作用的潜在用途或后果知之甚少。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，而且在许多与炎症相关的情况下，其水平在这些细胞中会急剧增加。此外，众所周知，血液中免疫细胞上的 GPR84 水平可以作为治疗下肠道炎症溃疡性结肠炎的可能有效性的有用指标。还有建议认为，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疾病的有用方法。然而，迄今为止，这些建议都没有得到真正的实质性解决。这在很大程度上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，而循环血液中通常可能不存在这种浓度。这表明 GPR84 的激活可能是由脂肪酸以外的配体产生的，而且我们还知道，我们在食用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识别和表征的每一种新型化学配体，以及每一项基于计算、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受体。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品系来研究 GPR84 激活剂和阻断剂预防或改变疾病表型特征的能力。这些研究将确定转化该工作计划结果的可能潜力，以预测 GPR84 活性的调节是否有助于开发人类疾病的新疗法。

项目成果

Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists.

• DOI: 10.1021/acs.jmedchem.2c00804
• 发表时间: 2022-08-25
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Mahindra, Amit;Jenkins, Laura;Marsango, Sara;Huggett, Mark;Huggett, Margaret;Robinson, Lindsay;Gillespie, Jonathan;Rajamanickam, Muralikrishnan;Morrison, Angus;McElroy, Stuart;Tikhonova, Irina G.;Milligan, Graeme;Jamieson, Andrew G.
• 通讯作者: Jamieson, Andrew G.

Therapeutic validation of an orphan G protein-coupled receptor: The case of GPR84.

• DOI: 10.1111/bph.15248
• 发表时间: 2022-07
• 期刊: British journal of pharmacology
• 影响因子: 7.3

Selective phosphorylation of threonine residues defines GPR84-arrestin interactions of biased ligands.

• DOI: 10.1016/j.jbc.2022.101932
• 发表时间: 2022-05
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Marsango, Sara;Ward, Richard J.;Jenkins, Laura;Butcher, Adrian J.;Al Mahmud, Zobaer;Dwomoh, Louis;Nagel, Falko;Schulz, Stefan;Tikhonova, Irina G.;Tobin, Andrew B.;Milligan, Graeme
• 通讯作者: Milligan, Graeme

Discovery and Characterization of Novel Antagonists of the Proinflammatory Orphan Receptor GPR84.

• DOI: 10.1021/acsptsci.1c00151
• 发表时间: 2021-10-08
• 期刊: ACS pharmacology & translational science
• 作者: Jenkins L;Marsango S;Mancini S;Mahmud ZA;Morrison A;McElroy SP;Bennett KA;Barnes M;Tobin AB;Tikhonova IG;Milligan G
• 通讯作者: Milligan G

Structure-Activity Relationship Studies and Optimization of 4-Hydroxypyridones as GPR84 Agonists

• DOI: 10.1021/acs.jmedchem.3c01923
• 发表时间: 2024-02-21
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Ieremias，Loukas;Kaspersen，Mads H.;Ulven，Trond
• 通讯作者: Ulven，Trond