Targeting GLP-1 receptor trafficking to improve therapies for type 2 diabetes

靶向 GLP-1 受体转运以改善 2 型糖尿病的治疗

基本信息

  • 批准号:
    MR/R010676/1
  • 负责人:
  • 金额:
    $ 71.58万
  • 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

Type 2 diabetes (T2D) kills around 4 million people worldwide every year and causes ill health in many more. A major underlying problem in T2D is that specialised cells in the pancreas known as beta cells start to fail and do not produce or secrete enough insulin, which is needed to control blood sugar. Beta cells can be stimulated to release more insulin by activating a surface protein known as glucagon-like peptide-1 receptor (GLP-1R). GLP-1R treatments, known as GLP-1R agonists, are already used in T2D. We have found that a process known as "receptor trafficking" limits the effectiveness of GLP-1R agonists. When the agonist activates the receptor, it also "internalises" it into the cell where it is hidden and can no longer be activated by agonists outside the cell. We showed this using a modified version of a GLP-1R agonist currently used in T2D (exendin-4, also known as "Exenatide"), which we engineered to reduce the internalisation process. This new agonist called "Ex-phe1" was much more effective than unmodified exendin-4 in mice with T2D, as it allowed the receptor to remain longer at the cell surface and be continually reactivated, leading to more insulin release. Also, despite being more effective in beta cells, Ex-phe1 did not cause more nausea, a well-known side effect of GLP-1R agonists.This project has two goals. The first is to understand how changes in GLP-1R trafficking modify insulin release from beta cells. The second, to be performed in parallel, is to optimise the compounds we generated in our preliminary work to produce new, better, treatments for T2D. Our approach includes experiments in beta cells and pancreatic tissue ("islets"), which allow us to understand events in molecular detail, and in mice with T2D, which tell us what happens at the whole body level. We place a lot of emphasis on using human islets (provided for research when surplus to requirements for organ donation), as we believe this is essential to understand and treat human disease.We highlight below some key experiments:1) We will use a combination of computer modelling and genetic modification of the GLP-1R to identify specific interactions between the receptor and Ex-phe1 or other biased GLP-1R agonists which underpin their different trafficking and therapeutic effects. This knowledge will be critical for the design of even more effective drugs in the future.2) We will genetically modify human islets to reduce levels of "beta-arrestin-2", a protein in beta cells that we believe is a key link between GLP-1R activation, trafficking, and beneficial insulin release. We will also breed genetically modified mice lacking beta-arrestin-2 in beta cells. We will use these systems to look at complex patterns of protein and gene activation within beta cells in response to GLP-1R agonist treatment. From this we hope to identify molecules that could in the future be targeted as new T2D treatments.3) We will study the long-term effects of our new, improved GLP-1R agonist Ex-phe1 on human islets transplanted into diabetic mice. Importantly, we will use a new approach in which the islets are actually transplanted in the eye, where changes to islet shape, behaviour and overall health can be directly and repeatedly viewed in a microscope. The mice will be treated with a long-lasting formulation of Ex-phe1 or exendin-4 for several months, and we will monitor changes to blood sugar, allowing us to compare the treatments for their effects on overall islet function. Due to well-known differences between mouse and human islets, we believe that using this "humanised" mice is critical to understanding long-term treatment effects.In summary, we have identified an exciting new approach based on GLP-1R trafficking for improving the treatment of T2D. In this project we will establish the molecular details of why this approach works, identify new potential drug targets and demonstrate the long-term effects of this new treatment in unique humanised mice.
2型糖尿病(T2D)每年在全球约400万人丧生,并在更多人中造成不良健康。 T2D中的一个主要潜在问题是,胰腺中的专门细胞被称为β细胞开始失败,不会产生或分泌足够的胰岛素,这是控制血糖所需的。可以通过激活称为胰高血糖素样肽-1受体(GLP-1R)的表面蛋白来刺激β细胞释放更多胰岛素。 T2D已经使用了GLP-1R处理,称为GLP-1R激动剂。我们发现,一种称为“受体运输”的过程限制了GLP-1R激动剂的有效性。当激动剂激活受体时,它也将其“内部化”到隐藏的细胞中,无法再被细胞外的激动剂激活。我们使用当前在T2D中使用的GLP-1R激动剂的修改版本(exendin-4,也称为“ Aceenatide”)展示了这一点,我们为减少内部化过程而设计。在具有T2D的小鼠中,这种称为“ Ex-Phe1”的新激动剂比未修饰的Exendin-4更有效,因为它允许受体在细胞表面保持更长的时间并不断重新激活,从而导致胰岛素释放更多。同样,尽管在β细胞中更有效,但Ex-Phe1并没有引起更多的恶心,这是GLP-1R激动剂的众所周知的副作用。该项目有两个目标。首先是了解GLP-1R运输的变化如何改变β细胞中胰岛素的释放。第二,要同时执行的是优化我们在初步工作中生成的化合物,以产生T2D的新,更好,更好的处理。我们的方法包括在β细胞和胰腺组织(“胰岛”)中进行的实验,这些实验使我们能够以分子细节了解事件,以及在带有T2D的小鼠中,告诉我们整个体内会发生什么。我们非常强调使用人类胰岛(在盈余到器官捐赠的要求时提供研究),因为我们认为这对于理解和治疗人类疾病是必不可少的。我们在某些关键实验下突出显示:1)我们将使用计算机建模和GLP-1R的遗传修改的组合来识别受体和ex-phe1或其他偏见的GLP-1R的特定相互作用,该型号及其差异的销量销量是不同的,该相互作用是不同的beias beias extpin anters anters antert anders anterpect anders anterpect anders blp-1R的销售销量。效果。这些知识对于将来的更有效药物的设计至关重要。2)我们将基因修改人类胰岛以降低“β-arrestin-2”水平,这是β细胞中的蛋白质,我们认为这是GLP-1R激活,运输,运输,有益的胰岛素释放之间的关键联系。我们还将繁殖在β细胞中缺乏β-arrestin-2的转基因小鼠。我们将使用这些系统来研究β细胞内蛋白质和基因激活的复杂模式,以响应GLP-1R激动剂治疗。从中,我们希望确定将来可能将其作为新的T2D处理的分子。3)我们将研究新的,改善的GLP-1R激动剂Ex-Phe1对移植到糖尿病小鼠中的人类小岛的长期影响。重要的是,我们将使用一种新的方法,其中胰岛实际上是在眼睛中移植的,其中可以直接在显微镜中直接且反复观察到胰岛形状,行为和整体健康。几个月以来,将用Ex-Phe1或Exendin-4的长期配方对小鼠进行处理,我们将监测血糖的变化,使我们能够比较它们对它们对整体胰岛功能的影响的处理。由于小鼠和人类胰岛之间的众所周知的差异,我们认为使用这种“人性化”小鼠对于理解长期治疗效果至关重要。总而言之,我们确定了一种基于GLP-1R运输的令人兴奋的新方法,以改善T2D的处理。在这个项目中,我们将建立一个分子细节,说明这种方法为何起作用,确定新的潜在药物靶标,并证明在独特的人类小鼠中这种新治疗的长期影响。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
LUXendins reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics
LUXendins 揭示内源性胰高血糖素样肽-1 受体分布和动态
  • DOI:
    10.1101/557132
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ast J
  • 通讯作者:
    Ast J
An expanded LUXendin color palette for GLP1R detection and visualization in vitro and in vivo
用于体外和体内 GLP1R 检测和可视化的扩展 LUXendin 调色板
  • DOI:
    10.26434/chemrxiv-2021-7rngq
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ast J
  • 通讯作者:
    Ast J
GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo.
  • DOI:
    10.1186/s12915-021-00966-w
  • 发表时间:
    2021-03-03
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Arcones AC;Vila-Bedmar R;Mirasierra M;Cruces-Sande M;Vallejo M;Jones B;Tomas A;Mayor F Jr;Murga C
  • 通讯作者:
    Murga C
Glucagon-like peptide 1 receptor (GLP-1R) expression by nerve fibres in inflammatory bowel disease and functional effects in cultured neurons.
  • DOI:
    10.1371/journal.pone.0198024
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Anand U;Yiangou Y;Akbar A;Quick T;MacQuillan A;Fox M;Sinisi M;Korchev YE;Jones B;Bloom SR;Anand P
  • 通讯作者:
    Anand P
Expanded LUXendin Color Palette for GLP1R Detection and Visualization In Vitro and In Vivo.
  • DOI:
    10.1021/jacsau.2c00130
  • 发表时间:
    2022-04-25
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Ast, Julia;Novak, Alissa N;Podewin, Tom;Fine, Nicholas H F;Jones, Ben;Tomas, Alejandra;Birke, Ramona;RoSSmann, Kilian;Mathes, Bettina;Eichhorst, Jenny;Lehmann, Martin;Linnemann, Amelia K;Hodson, David J;Broichhagen, Johannes
  • 通讯作者:
    Broichhagen, Johannes
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Alejandra Tomas其他文献

Pro-survival role of gelsolin in mouse beta-cells.
凝溶胶蛋白在小鼠β细胞中的促生存作用。
  • DOI:
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Barbara Yermen;Alejandra Tomas;P. Halban
  • 通讯作者:
    P. Halban
Stress-specific p38 MAPK activation is sufficient to drive EGFR endocytosis but not its nuclear translocation
应激特异性 p38 MAPK 激活足以驱动 EGFR 内吞作用,但不能驱动其核转位
  • DOI:
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    4
  • 作者:
    Alejandra Tomas;Sylwia Jones;S. Vaughan;D. Hochhauser;C. Futter
  • 通讯作者:
    C. Futter
Stress reveals new destination for EGF receptor
压力揭示了 EGF 受体的新目的地
  • DOI:
    10.1080/15384101.2015.1093432
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    4.3
  • 作者:
    Alejandra Tomas;C. Futter
  • 通讯作者:
    C. Futter
Expression of mini-G proteins specifically halt cognate GPCR trafficking and intracellular signalling
mini-G 蛋白的表达特异性地阻止同源 GPCR 运输和细胞内信号传导
  • DOI:
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Yusman Manchanda;Zenouska Ramchunder;Maria M. Shchepinova;G. Rutter;A. Inoue;Edward W. Tate;B. Jones;Alejandra Tomas
  • 通讯作者:
    Alejandra Tomas
Receptor Activity-Modifying Protein 2 (RAMP2) alters glucagon receptor trafficking in hepatocytes with functional effects on receptor signalling
受体活性修饰蛋白 2 (RAMP2) 改变肝细胞中胰高血糖素受体的运输,并对受体信号传导产生功能性影响
  • DOI:
    10.1101/2021.05.09.443291
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    8.1
  • 作者:
    E. McGlone;Yusman Manchanda;B. Jones;P. Pickford;A. Inoue;D. Carling;S. Bloom;T. Tan;Alejandra Tomas
  • 通讯作者:
    Alejandra Tomas

Alejandra Tomas的其他文献

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{{ truncateString('Alejandra Tomas', 18)}}的其他基金

Molecular mechanisms underlying divergent incretin receptor responses in alpha versus beta cells
α细胞与β细胞中肠促胰岛素受体反应不同的分子机制
  • 批准号:
    MR/X021467/1
  • 财政年份:
    2023
  • 资助金额:
    $ 71.58万
  • 项目类别:
    Research Grant
Role and regulation of GLP-1 receptor trafficking in pancreatic beta cells
GLP-1 受体运输在胰腺 β 细胞中的作用和调节
  • 批准号:
    MR/M012646/1
  • 财政年份:
    2015
  • 资助金额:
    $ 71.58万
  • 项目类别:
    Research Grant

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  • 批准号:
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Fam3a介导的胰腺GLP-1生成在胰高糖素受体阻断诱导的胰岛再生中的作用及机制
  • 批准号:
    82270843
  • 批准年份:
    2022
  • 资助金额:
    52.00 万元
  • 项目类别:
    面上项目
探究GLP-1受体激动剂通过调控小胶质细胞线粒体动力学改善视网膜缺血再灌注损伤的作用机制
  • 批准号:
    82201226
  • 批准年份:
    2022
  • 资助金额:
    30.00 万元
  • 项目类别:
    青年科学基金项目
Fam3a介导的胰腺GLP-1生成在胰高糖素受体阻断诱导的胰岛再生中的作用及机制
  • 批准号:
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    2022
  • 资助金额:
    52 万元
  • 项目类别:
    面上项目
探究GLP-1受体激动剂通过调控小胶质细胞线粒体动力学改善视网膜缺血再灌注损伤的作用机制
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  • 批准年份:
    2022
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    30 万元
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    青年科学基金项目

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  • 批准号:
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