Versatile and high-fidelity optical biosensor platforms for GPCR signaling

用于 GPCR 信号传导的多功能高保真光学生物传感器平台

基本信息

  • 批准号:
    10679863
  • 负责人:
  • 金额:
    $ 35.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-04-01 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

SIGNIFICANCE: G protein-coupled receptors (GPCRs) are a large family of membrane proteins that initiate cellular responses to a wide range of extracellular signals, like neurotransmitters or hormones, by activating heterotrimeric G proteins inside cells. This makes GPCRs critical for many physiological processes and their dysregulation is frequently associated with disease. GPCRs are not only the family of proteins most widely targeted by clinically approved drugs, with an estimated market value of hundreds of billions of dollars per year, but also the subject of many ongoing campaigns towards novel therapeutics. Moreover, many GPCRs still remain understudied and “undrugged”, which has great untapped potential for future drug discovery. Despite the biomedical importance of these receptors in physiology and pharmacology, the methodologies currently used to measure GPCR signaling activity in cells have limitations that hinder progress. One significant limitation is the use of approaches that compromise the fidelity of the readout because they are too indirect and/or distort the natural stoichiometry of signaling components. Another significant limitation is that many of the approaches are only feasible in cells in which gene delivery is easy, limiting their implementation to a few cell lines instead of more physiologically relevant systems like primary cell cultures. GOAL: Here, we propose to develop technologies that will allow to measure GPCR signaling activity directly and in diverse, physiologically-relevant cell systems without introducing major perturbations on the natural stoichiometry of signaling components. The tools and resources generated in this project will be made available to other investigators without restrictions. SYNOPSIS OF AIMS: We will develop two complementary assay platforms based on optical biosensors that directly detect the activity of heterotrimeric G proteins. In Aim1, we will establish a suite of broadly applicable “compact” vectors compatible with simple transfection or with viral packaging for the expression of G protein activity biosensors. In Aim 2, we will validate mouse transgenic lines for the conditional expression of biosensors of endogenous G protein activity. Collectively, these two platforms will allow the direct assessment of GPCR signaling activity under native expression conditions, in physiologically relevant cellular systems, and in formats that enable increased throughput to permit the parallel interrogation of the druggable GPCR-ome. IMPACT: The achievement of our goal could transform how the large field of research interested in GPCR- mediated cell communication approaches something as fundamental as measuring signaling activity. The technologies to be developed here would advance the field by: (i) enabling the direct characterization of GPCR signaling in systems in which it is currently not possible, (ii) revealing mechanisms of GPCR signaling with unprecedented fidelity in diverse contexts, and/or (iii) facilitating pharmacological or mechanistic interrogation in formats compatible with increased throughput.
意义:G蛋白偶联受体(gpcr)是一大家族的膜蛋白

项目成果

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Mikel Garcia-Marcos其他文献

Mikel Garcia-Marcos的其他文献

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{{ truncateString('Mikel Garcia-Marcos', 18)}}的其他基金

Direct chemogenetic control of heterotrimeric G protein signaling
异源三聚体 G 蛋白信号传导的直接化学遗传学控制
  • 批准号:
    10590217
  • 财政年份:
    2022
  • 资助金额:
    $ 35.48万
  • 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
  • 批准号:
    10220082
  • 财政年份:
    2019
  • 资助金额:
    $ 35.48万
  • 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
  • 批准号:
    10461747
  • 财政年份:
    2019
  • 资助金额:
    $ 35.48万
  • 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
  • 批准号:
    9914590
  • 财政年份:
    2019
  • 资助金额:
    $ 35.48万
  • 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
  • 批准号:
    10018921
  • 财政年份:
    2019
  • 资助金额:
    $ 35.48万
  • 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
  • 批准号:
    10581960
  • 财政年份:
    2019
  • 资助金额:
    $ 35.48万
  • 项目类别:
Targeting of non-canonical G protein signaling with small molecules
用小分子靶向非经典 G 蛋白信号传导
  • 批准号:
    10180984
  • 财政年份:
    2018
  • 资助金额:
    $ 35.48万
  • 项目类别:
Next generation G protein activity biosensors
下一代 G 蛋白活性生物传感器
  • 批准号:
    9789949
  • 财政年份:
    2018
  • 资助金额:
    $ 35.48万
  • 项目类别:
Identification of chemical probes that specifically disrupt the GIV-Gi interface
鉴定特异性破坏 GIV-Gi 界面的化学探针
  • 批准号:
    8986801
  • 财政年份:
    2015
  • 资助金额:
    $ 35.48万
  • 项目类别:
Alternative mechanisms of signaling via trimeric G proteins
通过三聚体 G 蛋白传递信号的替代机制
  • 批准号:
    10374905
  • 财政年份:
    2014
  • 资助金额:
    $ 35.48万
  • 项目类别:

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