Junctional multiprotein signaling complexes in sensory neurons

感觉神经元中的连接多蛋白信号复合物

基本信息

  • 批准号:
    BB/R003068/1
  • 负责人:
  • 金额:
    $ 62.49万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2017
  • 资助国家:
    英国
  • 起止时间:
    2017 至 无数据
  • 项目状态:
    已结题

项目摘要

In order to perceive and evaluate the environment mammals are equipped with peripheral nerves (peripheral somatosensory system). These nerves run through our body and collect information about rigidity, warmth and chemical composition of the surrounding milieu and also about our own body's integrity. These nerves are equipped with various molecular sensors that respond to specific external stimuli, transforming these into the uniform electrical impulses ('action potentials') that are then sent to the brain for interpretation. Single somatosensory nerve often expresses a variety of different sensors or sensory mechanisms that respond to distinct stimuli, yet the output signals produced by a nerve are very similar. A major conundrum in the field is how different types of signals are specifically interpreted by a single sensory nerve cells; the main aim of this proposal is to shed light on this question. Based on the wealth of preliminary data and published work from our group and others we hypothesize that one mechanism for such intracellular signal specificity lies in the assembly of different intracellular signaling mechanisms into distinct, physically associated protein complexes. Such physical separation of one signaling machinery from another allows them to use common signaling events and messenger molecules without 'mixing up' the meaning of the message. We will focus on one such multiprotein complex which is responsible for body's detection of tissue inflammation (i.e. inflammatory pain). We have already established that there are intricate multiprotein signaling complexes in some sensory nerves that bring together receptors for chemical mediators of inflammation and some signaling proteins that are targeted by these receptors. However, hardly anything is known about the overall constitution of these complexes, functional arrangements of their components, relationships with other signalling mechanisms, whether these complexes are dynamic or static or whether these can be manipulated for therapeutic benefits. Our project aims to answer these intriguing questions. We have three specific aims: 1) to reveal molecular composition of the inflammatory multiprotein signaling complexes in sensory nerves; 2) to elucidate functional significance of these complexes; 3) to develop strategies for manipulations with complex integrity for scientific and therapeutic purposes. We developed a comprehensive and multidisciplinary approach in which fidelity, specificity and localization of neuronal communication mechanisms will be elucidated in their complexity. This approach combines cutting-edge methods such as Nobel Prize winning super-resolution microscopy, proteomics, molecular and structural biology approaches and in vivo studies. We are confident that this research will bring our understanding of mammalian sensory systems and, particularly, of inflammatory pain mechanisms, to a new level of insight. Importantly, our findings may shape new approaches for analgesic drug development and pain management.
为了感知和评价环境,哺乳动物具有外周神经(外周体感系统)。这些神经贯穿我们的身体,收集关于周围环境的硬度、温度和化学成分的信息,也收集关于我们自己身体完整性的信息。这些神经配备了各种分子传感器,对特定的外部刺激做出反应,将这些刺激转化为均匀的电脉冲(“动作电位”),然后发送到大脑进行解释。单个体感觉神经通常表达多种不同的传感器或感觉机制,对不同的刺激作出反应,但由神经产生的输出信号非常相似。该领域的一个主要难题是,不同类型的信号是如何被单个感觉神经细胞特异性地解释的;这项建议的主要目的是阐明这个问题。基于丰富的初步数据和我们小组和其他人发表的工作,我们假设这种细胞内信号特异性的一种机制在于将不同的细胞内信号机制组装成不同的、物理相关的蛋白质复合物。这种信号机制与另一种信号机制的物理分离允许他们使用共同的信号事件和信使分子,而不会“混淆”信息的含义。我们将重点讨论一种多蛋白复合物,它负责人体对组织炎症(即炎症性疼痛)的检测。我们已经确定,在一些感觉神经中存在复杂的多蛋白信号复合物,它们将炎症化学介质的受体和这些受体靶向的一些信号蛋白结合在一起。然而,对于这些复合物的整体构成、其成分的功能安排、与其他信号机制的关系、这些复合物是动态的还是静态的,或者它们是否可以被操纵以获得治疗益处,几乎一无所知。我们的项目旨在回答这些有趣的问题。我们有三个具体目标:1)揭示炎症多蛋白信号复合物在感觉神经中的分子组成;2)阐明这些复合物的功能意义;3)为科学和治疗目的制定具有复杂完整性的操作策略。我们开发了一种全面的多学科方法,其中神经元通信机制的保真度,特异性和定位将在其复杂性中得到阐明。该方法结合了获得诺贝尔奖的超分辨率显微镜,蛋白质组学,分子和结构生物学方法以及体内研究等尖端方法。我们相信,这项研究将把我们对哺乳动物感觉系统的理解,特别是对炎症性疼痛机制的理解,提高到一个新的水平。重要的是,我们的发现可能会形成镇痛药物开发和疼痛管理的新方法。

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)
Kv7.4 channel is a key regulator of vascular inflammation and remodeling in neointimal hyperplasia and abdominal aortic aneurysms.
  • DOI:
    10.1016/j.freeradbiomed.2021.11.041
  • 发表时间:
    2021-12
  • 期刊:
  • 影响因子:
    7.4
  • 作者:
    Xizhenzi Fan;Ying-Ying Wang-Ying;Zi Y Cui;Zi-Hao Cheng;Hai-lin Zhang;N. Gamper;Fan Zhang;Mei Han
  • 通讯作者:
    Xizhenzi Fan;Ying-Ying Wang-Ying;Zi Y Cui;Zi-Hao Cheng;Hai-lin Zhang;N. Gamper;Fan Zhang;Mei Han
Inferiority complex: why do sensory ion channels multimerize?
Junctophilin-4 is essential for signalling at plasma membrane-endoplasmic reticulum junctions in sensory neurons
  • DOI:
    10.1101/842476
  • 发表时间:
    2019-11
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Alexandra S. Hogea;Shihab S. Shah;F. Jones;Chase M. Carver;Han Hao;Ce Liang;Dongyang Huang;Xiaona Du;N. Gamper
  • 通讯作者:
    Alexandra S. Hogea;Shihab S. Shah;F. Jones;Chase M. Carver;Han Hao;Ce Liang;Dongyang Huang;Xiaona Du;N. Gamper
Junctophilin-4 facilitates inflammatory signalling at plasma membrane-endoplasmic reticulum junctions in sensory neurons
  • DOI:
    10.1113/jp281331
  • 发表时间:
    2021-03-03
  • 期刊:
  • 影响因子:
    5.5
  • 作者:
    Hogea, Alexandra;Shah, Shihab;Gamper, Nikita
  • 通讯作者:
    Gamper, Nikita
A super-resolution protocol to correlate structural underpinnings of fast second-messenger signalling in primary cell types
  • DOI:
    10.1101/2020.09.29.319400
  • 发表时间:
    2020-09
  • 期刊:
  • 影响因子:
    0
  • 作者:
    M. Hurley;T. M. Sheard;R. Norman;Hannah M. Kirton;Shihab S. Shah;E. Pervolaraki;Zhaokang Yang;N. Gamper;Ed White;D. Steele;I. Jayasinghe
  • 通讯作者:
    M. Hurley;T. M. Sheard;R. Norman;Hannah M. Kirton;Shihab S. Shah;E. Pervolaraki;Zhaokang Yang;N. Gamper;Ed White;D. Steele;I. Jayasinghe
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Nikita Gamper其他文献

Optical Superresolution Analysis of Intracellular Calcium Handling Proteins and Correlating Calcium Signal Morphology
  • DOI:
    10.1016/j.bpj.2019.11.1054
  • 发表时间:
    2020-02-07
  • 期刊:
  • 影响因子:
  • 作者:
    Miriam E. Hurley;Thomas M. Sheard;Ruth Norman;Hannah M. Kirton;Shihab S. Shah;Eleftheria Pervolaraki;Zhaokang Yang;Derek S. Steele;Nikita Gamper;Ed White;Izzy Jayasinghe
  • 通讯作者:
    Izzy Jayasinghe
Modulation of KCNQ1/KCNE channel complexes by intracellular zinc
  • DOI:
    10.1016/j.bpj.2023.11.1610
  • 发表时间:
    2024-02-08
  • 期刊:
  • 影响因子:
  • 作者:
    Shuo Zhang;Xinhe Yang;Sai Shi;Haixia Gao;Nikita Gamper
  • 通讯作者:
    Nikita Gamper
Role of Store Operated Calcium Channel Complex in the Inflammatory Signaling in Peripheral Sensory Neurons
  • DOI:
    10.1016/j.bpj.2018.11.2867
  • 发表时间:
    2019-02-15
  • 期刊:
  • 影响因子:
  • 作者:
    Alexandra S. Hogea;Shihab Shah;Nikita Gamper
  • 通讯作者:
    Nikita Gamper
Regulation Of Kcnq2/3 Channels By The Transcriptional Repressor REST In Nociception
  • DOI:
    10.1016/j.bpj.2008.12.815
  • 发表时间:
    2009-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Lezanne Ooi;Kirstin E. Rose;John E. Linley;Mariusz Mucha;Ian C. Wood;Nikita Gamper
  • 通讯作者:
    Nikita Gamper
Substance P and Bradykinin Activate Alternative Gq/11-Coupled Signalling Cascades and Impose Opposite Effects on M Current in DRG Neurons
  • DOI:
    10.1016/j.bpj.2009.12.732
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    John E. Linley;Boyi Liu;Lezanne Ooi;Hailin Zhang;Nikita Gamper
  • 通讯作者:
    Nikita Gamper

Nikita Gamper的其他文献

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{{ truncateString('Nikita Gamper', 18)}}的其他基金

Unravelling dorsal root ganglion as an intrinsic filtering device
揭开背根神经节作为内在过滤装置的神秘面纱
  • 批准号:
    MR/V012738/1
  • 财政年份:
    2021
  • 资助金额:
    $ 62.49万
  • 项目类别:
    Research Grant
Divide and rule: localised Ca2+ signalling in sensory neurons
分而治之:感觉神经元中的局部 Ca2 信号传导
  • 批准号:
    BB/V010344/1
  • 财政年份:
    2021
  • 资助金额:
    $ 62.49万
  • 项目类别:
    Research Grant
China Partnering Award: Emerging Approaches to Intracellular Signaling
中国合作奖:细胞内信号转导的新兴方法
  • 批准号:
    BB/R02104X/1
  • 财政年份:
    2018
  • 资助金额:
    $ 62.49万
  • 项目类别:
    Research Grant
Regulation of M-type K+ channel expression in sensory neurones as a novel mechanism contributing to chronic pain states
感觉神经元中 M 型 K 通道表达的调节作为导致慢性疼痛状态的新机制
  • 批准号:
    G1002183/1
  • 财政年份:
    2011
  • 资助金额:
    $ 62.49万
  • 项目类别:
    Research Grant
Probing G protein coupled receptor signaling networks in trigeminal nociception
探讨三叉神经伤害感受中的 G 蛋白偶联受体信号网络
  • 批准号:
    G0700966/1
  • 财政年份:
    2008
  • 资助金额:
    $ 62.49万
  • 项目类别:
    Research Grant

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