Developing new tools and technologies to study calcium signalling in the brain's immune system

开发新工具和技术来研究大脑免疫系统中的钙信号传导

基本信息

  • 批准号:
    2815099
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Studentship
  • 财政年份:
    2023
  • 资助国家:
    英国
  • 起止时间:
    2023 至 无数据
  • 项目状态:
    未结题

项目摘要

Calcium (Ca2+) is a universal and diverse second messenger critical for general and specific cellular function, with its intracellular (IC) concentration finely maintained by a cell-specific toolkit of pumps, channels, and buffers. The cell and context specific expression pattern of these enables spatially and temporally heterogeneous changes in intracellular Ca2+ concentration, exploited for diverse phenotypic outputs.In neuroscience, Ca2+ signalling is vital for information processing via action potential propagation and neurotransmission in electrically excitable neuronal cells, coupled to changes in voltage. However, intracellular Ca2+ changes are also associated with activation of non-excitable cells of the central nervous system (CNS), particularly microglia, CNS resident surveillant innate immune cells activation of which occurs during neuroinflammation. Neuroinflammation is broadly defined as the set of CNS-localised and coordinated immunovascular responses to cell damage, and is associated with distinct changes in microglial morphology alongside a spectrum of "pro-inflammatory" phenotypes such as secretion of cytokines and chemokines, phagocytosis, and inflammasome activation. Although increases in calcium signalling in microglia with a range of characterised inflammatory stimuli have been measured in vitro and in vivo, and correlation with other microglial and neuronal phenotypes identified, stimuli specific thresholds and mechanistic details including the precise calcium mobilisation mechanisms and downstream phenotypically relevant signalling events involved remain ill-defined.Broadly, this PhD project aims to develop to generate a new understanding of how IC calcium signalling links to microglial activation states via generating microglial 'fingerprints' using high content imagine (HCI) approaches. These fingerprints will multiplex reports of intracellular calcium signalling with other physical, chemical, and functional readouts without assumption of which properties will correlate. A suite of novel in vitro assays in human microglia (HMC3) and neuronal (SH-SY5Y) immortalised cell lines will be developed and optimised in parallel. Initially, assays will benchmark of a broad spectrum of characterised "pro" and "anti" inflammatory stimuli associated with microglial activation covering a broad range of microglial expressed receptors, as well as treatment with novel tool compounds synthesised in house by chemists in the Madden lab. Some of the most amenable and powerful phenotypic assays will be upscaled for screening pre-annotated compound libraries using HCI (automated microscopy imaging of multiple endpoints (Lilly, 2018)) with the aim of identifying novel neuroinflammatory modulators and targets without prior knowledge of the molecular pathways involved. Image acquisition will likely use the CellDiscover for end-point and the IncuCyte for kinetic assays. Identified hits will then be taken forward for downstream target deconvolution, potentially discovering novel targets for treatment of neuroinflammatory associated diseases. Dysregulation of neuroinflammation is implicated in aetiology and/or pathogenesis of a range of brain disorders including dementias, neuropsychiatric conditions, and traumatic brain injury complications.
钙(Ca~(2+))是一种普遍而多样的第二信使,对一般和特定的细胞功能至关重要,其细胞内(IC)浓度由泵、通道和缓冲液组成的细胞特有的工具箱很好地维持。这些细胞和上下文特定的表达模式使得细胞内钙离子浓度在空间和时间上的异质性变化,被用于不同的表型输出。在神经科学中,钙离子信号在信息处理中至关重要,通过动作电位的传播和神经传递,在电兴奋的神经元细胞,再加上电压的变化。然而,细胞内钙离子的变化也与中枢神经系统(CNS)中不可兴奋的细胞,特别是小胶质细胞的激活有关,小胶质细胞是中枢神经系统固有免疫细胞在神经炎症过程中被激活的监控者。神经炎被广泛地定义为一组中枢神经系统对细胞损伤的局部和协调的免疫血管反应,与小胶质细胞形态的明显变化以及一系列促炎症表型有关,如细胞因子和趋化因子的分泌、吞噬和炎性小体激活。虽然已经在体外和体内测量了一系列特征性炎症刺激下小胶质细胞钙信号的增加,并与其他小胶质细胞和神经元表型识别的相关性,但刺激的特定阈值和机制细节,包括精确的钙动员机制和下游涉及的表型相关信号事件仍未确定。总的来说,该PHD项目旨在通过使用高含量成像(HCI)方法产生小胶质细胞的指纹,以产生对IC钙信号如何与小胶质细胞激活状态相联系的新的理解。这些指纹将细胞内钙信号的报告与其他物理、化学和功能读数多路传输,而不假设哪些特性将相关。在人类小胶质细胞(HMC3)和神经元(SH-SY5Y)永生化细胞系中,一套新的体外分析方法将被开发和优化。最初,化验将以一系列与小胶质细胞激活相关的广泛的“亲”和“抗炎”刺激为基准,涵盖广泛的小胶质细胞表达的受体,以及使用由马登实验室的化学家在室内合成的新型工具化合物进行治疗。一些最具适应性和最强大的表型分析将被扩大,用于使用HCI(多个端点的自动显微成像(Lilly,2018))筛选预先注释的化合物文库,目的是在不事先了解所涉及的分子通路的情况下识别新的神经炎性调节剂和靶点。图像采集可能会使用CellDiscover作为终点,IncuCyte用于动力学分析。然后,确定的靶点将被用于下游靶点去卷积,潜在地发现治疗神经炎性相关疾病的新靶点。神经炎症调节失调与一系列脑部疾病的病因学和/或发病机制有关,包括痴呆、神经精神疾病和创伤性脑损伤并发症。

项目成果

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其他文献

Internet-administered, low-intensity cognitive behavioral therapy for parents of children treated for cancer: A feasibility trial (ENGAGE).
针对癌症儿童父母的互联网管理、低强度认知行为疗法:可行性试验 (ENGAGE)。
  • DOI:
    10.1002/cam4.5377
  • 发表时间:
    2023-03
  • 期刊:
  • 影响因子:
    4
  • 作者:
  • 通讯作者:
Differences in child and adolescent exposure to unhealthy food and beverage advertising on television in a self-regulatory environment.
在自我监管的环境中,儿童和青少年在电视上接触不健康食品和饮料广告的情况存在差异。
  • DOI:
    10.1186/s12889-023-15027-w
  • 发表时间:
    2023-03-23
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
  • 通讯作者:
The association between rheumatoid arthritis and reduced estimated cardiorespiratory fitness is mediated by physical symptoms and negative emotions: a cross-sectional study.
类风湿性关节炎与估计心肺健康降低之间的关联是由身体症状和负面情绪介导的:一项横断面研究。
  • DOI:
    10.1007/s10067-023-06584-x
  • 发表时间:
    2023-07
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
  • 通讯作者:
ElasticBLAST: accelerating sequence search via cloud computing.
ElasticBLAST:通过云计算加速序列搜索。
  • DOI:
    10.1186/s12859-023-05245-9
  • 发表时间:
    2023-03-26
  • 期刊:
  • 影响因子:
    3
  • 作者:
  • 通讯作者:
Amplified EQCM-D detection of extracellular vesicles using 2D gold nanostructured arrays fabricated by block copolymer self-assembly.
使用通过嵌段共聚物自组装制造的 2D 金纳米结构阵列放大 EQCM-D 检测细胞外囊泡。
  • DOI:
    10.1039/d2nh00424k
  • 发表时间:
    2023-03-27
  • 期刊:
  • 影响因子:
    9.7
  • 作者:
  • 通讯作者:

的其他文献

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{{ truncateString('', 18)}}的其他基金

An implantable biosensor microsystem for real-time measurement of circulating biomarkers
用于实时测量循环生物标志物的植入式生物传感器微系统
  • 批准号:
    2901954
  • 财政年份:
    2028
  • 资助金额:
    --
  • 项目类别:
    Studentship
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  • 财政年份:
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    2908918
  • 财政年份:
    2027
  • 资助金额:
    --
  • 项目类别:
    Studentship
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质子、α 和 γ 辐照辅助应力腐蚀开裂:了解燃料-不锈钢界面
  • 批准号:
    2908693
  • 财政年份:
    2027
  • 资助金额:
    --
  • 项目类别:
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Field Assisted Sintering of Nuclear Fuel Simulants
核燃料模拟物的现场辅助烧结
  • 批准号:
    2908917
  • 财政年份:
    2027
  • 资助金额:
    --
  • 项目类别:
    Studentship
Assessment of new fatigue capable titanium alloys for aerospace applications
评估用于航空航天应用的新型抗疲劳钛合金
  • 批准号:
    2879438
  • 财政年份:
    2027
  • 资助金额:
    --
  • 项目类别:
    Studentship
Developing a 3D printed skin model using a Dextran - Collagen hydrogel to analyse the cellular and epigenetic effects of interleukin-17 inhibitors in
使用右旋糖酐-胶原蛋白水凝胶开发 3D 打印皮肤模型,以分析白细胞介素 17 抑制剂的细胞和表观遗传效应
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    2890513
  • 财政年份:
    2027
  • 资助金额:
    --
  • 项目类别:
    Studentship
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CDT 第 1 年,预计 2024 年 10 月
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  • 资助金额:
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Understanding the interplay between the gut microbiome, behavior and urbanisation in wild birds
了解野生鸟类肠道微生物组、行为和城市化之间的相互作用
  • 批准号:
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  • 财政年份:
    2027
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    --
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