Receptors for Short Chain Fatty Acids in the control of bacterial infection and gut immunity
短链脂肪酸受体控制细菌感染和肠道免疫
基本信息
- 批准号:BB/X001814/1
- 负责人:
- 金额:$ 80.75万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2022
- 资助国家:英国
- 起止时间:2022 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
The human intestine routinely contains an almost unimaginable number of bacteria. In health they perform many key roles and generate a vast number of by-products of their own metabolism that positively affect the cells and tissue of our own body. However, in certain settings invasive bacteria multiply extensively and this can result in ill-health that can range from mild symptoms of an 'upset stomach' to much more serious and life-threatening conditions such as sepsis. The gut has a surveillance system that detects the presence of such invasive bacteria, and a major element of this Gut-Associated Lymphoid Tissue is the so called 'Payer's patches'. These contain a wide range of immune cells involved in both these initial processes and then co-ordinating the response of the body to disable and destroy such bacteria. Two sets of these immune cells are called 'dendritic' cells and 'type 3 innate lymphoid (IL3)' cells. For many years we have been studying cell surface receptors that are activated by short chain fatty acids, such as acetic acid, that are generated in large amounts by the metabolic activity of many of the gut bacteria. These receptors, called Free Fatty Acid Receptor 2 and Free Fatty Acid Receptor 3 are members of a large family of transmembrane proteins called G protein-coupled receptors that are the targets of many successfully used medicines, and we have been exploring in many settings, including diabetes and other metabolic disorders, if activating or blocking one or other of these receptors for short chain fatty acids might be a useful means to treat disease. Within these studies we have developed a number of novel chemical ligands that either mimic the effects of the short chain fatty acids or block their actions. It turns out that both 'dendritic' cells and 'type 3 innate lymphoid (IL3)' cells express very high amounts of Free Fatty Acid Receptor 2 and other cells in the gut express Free Fatty Acid Receptor 3. This implies that Free Fatty Acid Receptor 2, and possibly also Free Fatty Acid Receptor 3, are likely to play important roles in the detection of invasive bacteria and promote both gut and overall whole body immune responses. A number of studies have supported this idea but other studies are contradictory. Initial studies that are designed to understand basic biological processes and whether they can potentially be targeted to treat human disease are often performed in mice. This reflects that as mammals they share many of the same physiological functions and mechanisms of control as humans. However, there are also many differences, and in the case of Free Fatty Acid Receptor 2, potential drug-like like molecules that both we and pharmaceutical companies have developed to block this receptor are very effective at the human form of the receptor but do not work at the mouse form. As we need to fully understand the possible effects of activating or blocking this receptor in mouse before studies in human can be considered we have engineered mice so that they express the human form of the receptor in place of the mouse version. We have also made other genetic modifications to the receptor in these modified mice to allow us to 'see' clearly the cells in which the human receptor is expressed. We plan to use these mice and the variety of drug-like compounds we have developed to assess if activating the modified receptor, or indeed Free Fatty Acid Receptor 3 which is unchanged in these mice, is effective in combatting the ability of invasive bacteria including Salmonella to colonise the gut and potential cause disease. We will also use other genetic strategies to assess if activating Free Fatty Acid Receptor 2 only in dendritic' cells or 'type 3 innate lymphoid (IL3)' cells is able and sufficient to combat infection. These experiments will generate clear understanding if activating free fatty acid receptors can suggest a therapeutic strategy that can be taken forward to human studies.
人类肠道通常含有几乎难以想象数量的细菌。在健康方面,它们发挥着许多关键作用,并产生大量自身代谢的副产品,对我们身体的细胞和组织产生积极影响。然而,在某些情况下,侵入性细菌大量繁殖,这可能导致健康状况不佳,从轻微的“胃部不适”症状到更严重和危及生命的疾病,如败血症。肠道有一个监测系统,可以检测到这种入侵细菌的存在,这种肠道相关的类肉瘤组织的主要成分是所谓的“派耶尔补丁”。这些包含了广泛的免疫细胞参与这两个初始过程,然后协调身体的反应,以禁用和摧毁这些细菌。这些免疫细胞中的两组被称为“树突状”细胞和“3型先天淋巴(IL3)”细胞。多年来,我们一直在研究由短链脂肪酸(如乙酸)激活的细胞表面受体,这些短链脂肪酸由许多肠道细菌的代谢活动大量产生。这些被称为游离脂肪酸受体2和游离脂肪酸受体3的受体是一个名为G蛋白偶联受体的跨膜蛋白大家族的成员,这些受体是许多成功使用的药物的靶点,我们一直在探索许多环境,包括糖尿病和其他代谢疾病,如果激活或阻断这些短链脂肪酸受体中的一种或另一种可能是治疗疾病的有用手段。在这些研究中,我们已经开发了一些新的化学配体,它们要么模仿短链脂肪酸的作用,要么阻断它们的作用。事实证明,“树突状”细胞和“3型先天淋巴(IL 3)”细胞表达非常高的游离脂肪酸受体2,肠道中的其他细胞表达游离脂肪酸受体3。这意味着游离脂肪酸受体2,也可能是游离脂肪酸受体3,可能在入侵细菌的检测中发挥重要作用,并促进肠道和全身免疫反应。一些研究支持这一观点,但其他研究则相互矛盾。最初的研究旨在了解基本的生物学过程,以及它们是否可以潜在地靶向治疗人类疾病,通常在小鼠中进行。这反映了作为哺乳动物,它们与人类共享许多相同的生理功能和控制机制。然而,也有许多差异,在游离脂肪酸受体2的情况下,我们和制药公司开发的用于阻断这种受体的潜在药物样分子对人类形式的受体非常有效,但对小鼠形式无效。由于我们需要充分了解在人类研究之前激活或阻断这种受体在小鼠中可能产生的影响,我们已经改造了小鼠,使它们表达人类形式的受体,而不是小鼠形式。我们还对这些修饰小鼠的受体进行了其他遗传修饰,使我们能够清楚地“看到”表达人类受体的细胞。我们计划使用这些小鼠和我们开发的各种药物样化合物来评估激活修饰的受体,或者在这些小鼠中没有改变的游离脂肪酸受体3,是否能有效地对抗包括沙门氏菌在内的侵入性细菌的能力。我们还将使用其他遗传策略来评估仅在树突状细胞或3型先天淋巴(IL 3)细胞中激活游离脂肪酸受体2是否能够并足以对抗感染。这些实验将产生明确的理解,如果激活游离脂肪酸受体可以提出一种治疗策略,可以采取人类研究。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Phosphorylation bar-coding of free fatty acid receptor 2 is generated in a tissue-specific manner.
- DOI:10.7554/elife.91861
- 发表时间:2023-12-12
- 期刊:
- 影响因子:7.7
- 作者:Barki N;Jenkins L;Marsango S;Dedeo D;Bolognini D;Dwomoh L;Abdelmalik AM;Nilsen M;Stoffels M;Nagel F;Schulz S;Tobin AB;Milligan G
- 通讯作者:Milligan G
Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists.
- DOI:10.1021/acs.jmedchem.2c01935
- 发表时间:2023-05-11
- 期刊:
- 影响因子:7.3
- 作者:Valentini, Alice;Schultz-Knudsen, Katrine;Hansen, Anders Hojgaard;Tsakoumagkou, Argyro;Jenkins, Laura;Christensen, Henriette B.;Manandhar, Asmita;Milligan, Graeme;Ulven, Trond;Ulven, Elisabeth Rexen
- 通讯作者:Ulven, Elisabeth Rexen
Phosphorylation bar-coding of free fatty acid receptor 2 is generated in a tissue-specific manner
游离脂肪酸受体 2 的磷酸化条形码以组织特异性方式生成
- DOI:10.7554/elife.91861.3
- 发表时间:2023
- 期刊:
- 影响因子:7.7
- 作者:Barki N
- 通讯作者:Barki N
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Graeme Milligan其他文献
Gonadotrophin-releasing hormone receptor agonist-mediated down-regulation of Gq alpha/G11 alpha (pertussis toxin-insensitive) G proteins in alpha T3-1 gonadotroph cells reflects increased G protein turnover but not alterations in mRNA levels.
α T3-1 促性腺激素细胞中促性腺激素释放激素受体激动剂介导的 Gq α/G11 α(百日咳毒素不敏感)G 蛋白下调反映了 G 蛋白周转增加,但不影响 mRNA 水平。
- DOI:
10.1073/pnas.92.6.1886 - 发表时间:
1995 - 期刊:
- 影响因子:11.1
- 作者:
Bukhtiar H. Shah;David J Macewan;Graeme Milligan - 通讯作者:
Graeme Milligan
GPR35: from enigma to therapeutic target
GPR35:从谜团到治疗靶点
- DOI:
10.1016/j.tips.2023.03.001 - 发表时间:
2023-05-01 - 期刊:
- 影响因子:19.900
- 作者:
Graeme Milligan - 通讯作者:
Graeme Milligan
Probing Allosteric Binding Site Mapping in the Free Fatty Acid 2 receptor
- DOI:
10.1016/j.bpj.2010.12.483 - 发表时间:
2011-02-02 - 期刊:
- 影响因子:
- 作者:
Irina G. Tikhonova;Nicola J. Smith;Richard J. Ward;Leigh A. Stoddart;Brian D. Hudson;Evi Kostenis;Trond Ulven;Joanne C. Morris;David R. Adams;Graeme Milligan - 通讯作者:
Graeme Milligan
Characterisation of SC332 a novel, non-ROCK inhibitory, stem cell survival agent suitable for large scale culture
- DOI:
10.1016/j.jcyt.2015.03.547 - 发表时间:
2015-06-01 - 期刊:
- 影响因子:
- 作者:
Scott Cowan;David Adams;Graeme Milligan;Joanne Mountford - 通讯作者:
Joanne Mountford
Kinetics of Ternary Complex Formation with Fusion Proteins Composed of the A<sub>1</sub>-Adenosine Receptor and G Protein α-Subunits
- DOI:
10.1074/jbc.274.43.30571 - 发表时间:
1999-10-22 - 期刊:
- 影响因子:
- 作者:
Maria Waldhoer;Alan Wise;Graeme Milligan;Michael Freissmuth;Christian Nanoff - 通讯作者:
Christian Nanoff
Graeme Milligan的其他文献
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{{ truncateString('Graeme Milligan', 18)}}的其他基金
GPR35: mechanisms of action and agonism as a potential therapeutic strategy for non-alcoholic fatty liver diseases
GPR35:作为非酒精性脂肪肝疾病潜在治疗策略的作用和激动机制
- 批准号:
MR/X008827/1 - 财政年份:2024
- 资助金额:
$ 80.75万 - 项目类别:
Research Grant
India Link: Selective interactions between G protein-coupled receptors and conformationally selective arrestin variants
India Link:G 蛋白偶联受体与构象选择性抑制蛋白变体之间的选择性相互作用
- 批准号:
BB/T018720/1 - 财政年份:2023
- 资助金额:
$ 80.75万 - 项目类别:
Research Grant
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 - 财政年份:2020
- 资助金额:
$ 80.75万 - 项目类别:
Research Grant
Defining physiological and pathophysiological roles of the Free Fatty Acid Receptor2 by analysis of novel transgenic mouse models
通过分析新型转基因小鼠模型定义游离脂肪酸受体2的生理和病理生理作用
- 批准号:
BB/S000453/1 - 财政年份:2018
- 资助金额:
$ 80.75万 - 项目类别:
Research Grant
Defining the functional roles of the enigmatic G protein-coupled receptor GPR35
定义神秘的 G 蛋白偶联受体 GPR35 的功能作用
- 批准号:
BB/P000649/1 - 财政年份:2017
- 资助金额:
$ 80.75万 - 项目类别:
Research Grant
GRACE II: new horizons and consolidation
GRACE II:新视野和整合
- 批准号:
MC_PC_16073 - 财政年份:2017
- 资助金额:
$ 80.75万 - 项目类别:
Intramural
Defining signal selection from the free fatty acid receptor FFA4; implications for physiological functions
定义游离脂肪酸受体 FFA4 的信号选择;
- 批准号:
BB/R001480/1 - 财政年份:2017
- 资助金额:
$ 80.75万 - 项目类别:
Research Grant
Proximity to Discovery 2014 - University of Glasgow
接近发现 2014 - 格拉斯哥大学
- 批准号:
MC_PC_14133 - 财政年份:2015
- 资助金额:
$ 80.75万 - 项目类别:
Intramural
The organisational structure of class A GPCRs: Implications for pharmacology, function and therapeutic regulation
A 类 GPCR 的组织结构:对药理学、功能和治疗调节的影响
- 批准号:
MR/L023806/1 - 财政年份:2014
- 资助金额:
$ 80.75万 - 项目类别:
Research Grant
Using a 'Designer Receptor Exclusively Activated by Designer Drug' to define the role of short chain fatty acids in metabolic disease and inflammation
使用“设计药物专门激活的设计受体”来定义短链脂肪酸在代谢疾病和炎症中的作用
- 批准号:
BB/L027887/1 - 财政年份:2014
- 资助金额:
$ 80.75万 - 项目类别:
Research Grant
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