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

基本信息

  • 批准号:
    BB/S000453/1
  • 负责人:
  • 金额:
    $ 74.53万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2018
  • 资助国家:
    英国
  • 起止时间:
    2018 至 无数据
  • 项目状态:
    已结题

项目摘要

Development of new medicines is a long term ambition and challenge. Initial efforts are often based on observations and analysis of effects in rodents of either activating or blocking a specific protein or a signal transduction pathway that is believed to contribute to or influence the development of a disease in humans. Means to do this include elimination of expression of specific genes in mouse or treatment of animals with synthetic drug-like molecules with the hope that responses produced will inform or mimic those that might occur in humans. Although it is true that many important physiological process are controlled and regulated in equivalent ways between mice and humans there are also many differences that reflect the 90 million years of evolution separating the species. One common aspect of this is that there are often differences in sequence between the equivalent proteins from different species and in a number of cases this is known to markedly effect the ability of a synthetic drug to produce effects. This is the situation for the receptor FFA2 that is activated by short chain fatty acids produced by the bacteria that are present in the intestine. Antagonists of this receptor that were identified by finding ligands that block the human form simply don't work at rodent orthologues and, because of this, it has been difficult to perform preliminary studies in mice that might predict their effects in humans. To overcome this we have generated mice in which we replaced the mouse version of FFA2 with the human form, and have shown that in tissues from these animals the identified antagonists are now able to block FFA2-mediated effects. We have also taken this one step further. As there are at least two receptors in both mouse and human that are activated by short chain fatty acids we further adapted human FFA2 such that it NOT activated by short chain fatty acids but is activated instead by a set of synthetic molecules that don't activate the normal forms of FFA2. We have also generated mice in which this modified human receptor is expressed instead of the mouse form. With this underpinning knowledge we now plan to fully investigate the roles that are controlled by FFA2 in mouse. We will pay particular attention to actions in both the intestine where our preliminary studies have shown that FFA2 is a key regulator of release of a hormone called GLP-1 that after its release plays a central role in promoting insulin production from the pancreas when blood glucose levels rise after a meal. There have also been conflicting reports from other groups as to whether activating or blocking FFA2 might be an effective approach to either prevent the development of, or to treat, diseases such as ulcerative colitis that are based on inflammation of the lower intestine. We will now be able to address these questions in mouse models of this and related diseases, something that has hitherto been impossible. Another key area where there has been debate and contradictory views is whether direct activation or blockade of FFA2 would be able to enhance or limit release of insulin in humans, and specifically in type II diabetics. There are reasons to believe the control mechanisms in mouse are different from in humans and now, using both the animal models described above and detailed molecular studies on both mouse and human forms of the receptor protein we plan to assess this question. This is likely to influence thinking with the pharmaceutical industry as to the most appropriate strategy to consider as a therapeutic treatment and whether studies that have been performed in wild type mice might actually be pointing in the wrong direction for therapy in humans.
开发新药是一项长期的雄心和挑战。最初的努力通常基于对啮齿动物激活或阻断特定蛋白质或信号转导途径的影响的观察和分析,这些蛋白质或信号转导途径被认为有助于或影响人类疾病的发展。做到这一点的方法包括消除小鼠特定基因的表达,或者用合成的类药物分子治疗动物,希望产生的反应将通知或模仿可能在人类身上发生的反应。尽管许多重要的生理过程确实在老鼠和人类之间以相同的方式受到控制和调控,但也存在许多差异,反映了将物种分开的9000万年的进化。其中一个共同的方面是,来自不同物种的等量蛋白质之间往往存在序列差异,在许多情况下,这已知会显着影响合成药物产生效果的能力。这就是受体FFA2的情况,它被肠道中存在的细菌产生的短链脂肪酸激活。这种受体的拮抗剂是通过寻找阻止人类形状的配体来鉴定的,在啮齿动物的同源基因中根本不起作用,因此,很难在老鼠身上进行初步研究,以预测它们对人类的影响。为了克服这一点,我们产生了小鼠,在其中我们用人的形式取代了小鼠版本的FFA2,并表明在这些动物的组织中,已识别的拮抗剂现在能够阻断FFA2介导的效应。我们也进一步推进了这一步。由于在老鼠和人类中都有至少两种受体被短链脂肪酸激活,我们进一步改造了人类FFA2,使其不被短链脂肪酸激活,而是由一组不激活正常形式的FFA2的合成分子激活。我们还产生了表达这种修饰的人类受体的小鼠,而不是小鼠的形式。有了这些基础知识,我们现在计划全面研究FFA2在小鼠体内所控制的角色。我们将特别关注FFA2在肠道中的作用,我们的初步研究表明,FFA2是一种名为GLP-1的激素释放的关键调节因子,当餐后血糖水平上升时,GLP-1释放后在促进胰腺产生胰岛素方面发挥核心作用。对于激活或阻断FFA2是否是预防或治疗溃疡性结肠炎等疾病的有效方法,其他研究小组也有相互矛盾的报告。溃疡性结肠炎是基于下肠的炎症。我们现在将能够在这种疾病和相关疾病的小鼠模型中解决这些问题,这是到目前为止还不可能做到的。另一个存在争论和相互矛盾的观点的关键领域是,直接激活或阻断FFA2是否能够增强或限制人类胰岛素的释放,特别是在II型糖尿病患者中。有理由相信小鼠的控制机制与人类不同,现在,利用上述动物模型以及对小鼠和人类两种形式的受体蛋白的详细分子研究,我们计划评估这个问题。这可能会影响制药业的想法,即考虑作为治疗方法的最合适策略,以及在野生型小鼠身上进行的研究是否真的指向了人类治疗的错误方向。

项目成果

期刊论文数量(9)
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
G protein-coupled receptors not currently in the spotlight: free fatty acid receptor 2 and GPR35.
Metabolic and inflammatory functions of short-chain fatty acid receptors.
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
Chemogenetic analysis of how receptors for short chain fatty acids regulate the gut-brain axis
短链脂肪酸受体如何调节肠脑轴的化学遗传学分析
  • DOI:
    10.1101/2020.01.11.902726
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 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。
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:
    $ 74.53万
  • 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:
    $ 74.53万
  • 项目类别:
    Research Grant
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
  • 批准号:
    BB/X001814/1
  • 财政年份:
    2022
  • 资助金额:
    $ 74.53万
  • 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:
    $ 74.53万
  • 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:
    $ 74.53万
  • 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:
    $ 74.53万
  • 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:
    $ 74.53万
  • 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:
    $ 74.53万
  • 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:
    $ 74.53万
  • 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:
    $ 74.53万
  • 项目类别:
    Research Grant

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生理/病理应激差异化调控肝再生的“蓝斑—中缝”神经环路机制
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使用芯片肺平台和常见病理生理机制的多组学分析来表征化学威胁剂暴露
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