MICA: Liverpool Imaging Partnership: Molecular physiology and drug response

MICA：利物浦影像合作伙伴：分子生理学和药物反应

• 批准号: MR/K015931/1
• 负责人: Raphael Levy
• 金额: $ 119.56万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK015931%2F1
• 关键词: MICA; Liverpool; Imaging; Partnership; Molecular

In multicellular organisms, cells are exposed to molecular signals such as inflammatory molecules and stress signals. Cells have to interpret these signals to adapt and respond appropriately. To understand the molecular mechanisms leading to a particular response (e.g. cell death, cell growth, cell migration, etc), biologists have to measure the levels, localisation and modifications of proteins, and the subsequent regulation of specific genes. There is an increasing recognition that in a population of cells, each cell is different and therefore measuring the average behaviour can lead to erroneous conclusions. Live cell imaging coupled with the use of fluorescent and luminescent labels and reporters enables biologists to monitor dynamic events in individual cells in real time. Nanotechnology provides additional tools to visualise single molecules.The aim of our project is to build on our existing imaging capabilities in the Centre for Cell Imaging and our world-leading expertise in the synthesis and imaging of nanoparticles to improve the equipment available with the most up-to-date microscopes. We will also develop new technologies, software and image analysis methods that will allow us to increase the resolution of the images and their interpretation (to better see the detailed structures inside the cells). We will make sure that the equipment is used to the best of its capabilities to answer important biological and biomedical questions. For this purpose, we will select the best projects, in Liverpool, the UK and beyond, and we will support users from the conception of their experiments to the analysis and interpretation of their results.The CCI platform will therefore permit researchers from a broad range of research fields to tackle important 21st century challenges in biomedical research, by investigating in real-time cellular events at the molecular level. To illustrate the breadth of science that will be served by the platform, we briefly present below three exemplar projects that, among many others, will benefit of the improved facility. UNDERSTANDING ACUTE PANCREATITIS ON THE NANOMETRE SCALE. Cells of the pancreas produce the enzymes that digest our food inside the intestine. In acute pancreatitis, instead of being secreted to the intestine, enzymes become active in the pancreas cells themselves and damage the pancreas leading to severe pain, hospitalisation and in some cases, death. The activation of these enzymes involves the formation of dynamic structures that are very difficult to study by conventional microscopy because they are smaller than the resolution of conventional microscopes. The new platform will uniquely allow us to study the response of those structures when pancreatic cells are exposed to molecules that may induce or prevent acute pancreatitis and ultimately develop novel approaches to prevent this from happening.IMAGING THE SUBTLE ROLE OF OXIDATIVE STRESS IN AGEING; Oxidative stress leading to oxidative damage has been implicated in the processes underlying ageing for over 50 years, but recent data demonstrated that rather than gross changes in oxidative stress damage, it is the more subtle changes in regulation of reduction-oxidation reactions that play a fundamental role in ageing processes. The new platform will uniquely allow us to control and measure oxygen level and oxidative stress providing new insights into mechanisms of ageing.PROBING THE MECHANISM FOR INTESTINAL ABSORPTION OF NANOMEDICINES; Insolubility of active pharmaceutical ingredients and the resulting lack of bioavailability is a major concern for the development of new drugs. Approaches based on nanotechnology have proven successful, but very little is known regarding the mechanistic basis. The present application will enable us to study differences in trans-intestinal passage and toxicity of nanomedicines compared to conventional dissolved drugs.

在多细胞生物中，细胞暴露于分子信号，如炎症分子和应激信号。细胞必须解释这些信号，以适应并做出适当的反应。为了了解导致特定反应的分子机制（例如细胞死亡，细胞生长，细胞迁移等），生物学家必须测量蛋白质的水平，定位和修饰，以及随后对特定基因的调控。越来越多的人认识到，在细胞群中，每个细胞都是不同的，因此测量平均行为可能会导致错误的结论。活细胞成像加上使用荧光和发光标记和报告使生物学家能够监测动态事件在个别细胞在真实的时间。纳米技术提供了额外的工具来可视化单个分子。我们项目的目的是建立在我们现有的细胞成像中心的成像能力和我们在纳米颗粒合成和成像方面的世界领先的专业知识，以改进最先进的显微镜设备。我们还将开发新的技术，软件和图像分析方法，使我们能够提高图像的分辨率及其解释（以更好地看到细胞内的详细结构）。我们将确保这些设备能够最大限度地用于回答重要的生物学和生物医学问题。为此，我们将在英国利物浦及其他地区选择最好的项目，并为用户提供从实验概念到结果分析和解释的支持。因此，CCI平台将允许来自广泛研究领域的研究人员通过在分子水平上实时研究细胞事件来应对21世纪生物医学研究的重要挑战。为了说明该平台将服务于科学的广度，我们简要介绍了以下三个示例项目，其中包括将受益于改进后的设施的项目。 在纳米尺度上理解急性胰腺炎。胰腺细胞产生消化我们肠道内食物的酶。在急性胰腺炎中，酶不是被分泌到肠道，而是在胰腺细胞本身中变得活跃并损害胰腺，导致严重疼痛，住院治疗，在某些情况下甚至死亡。这些酶的激活涉及到动态结构的形成，这些动态结构很难通过常规显微镜进行研究，因为它们小于常规显微镜的分辨率。这个新的平台将使我们能够研究胰腺细胞暴露于可能诱导或预防急性胰腺炎的分子时这些结构的反应，并最终开发出新的方法来预防这种情况的发生。50多年来，导致氧化损伤的氧化应激与衰老的潜在过程有关，但最近的数据表明，在衰老过程中起根本作用的不是氧化应激损伤的总体变化，而是还原-氧化反应调节中更微妙的变化。新的平台将使我们能够控制和测量氧气水平和氧化应激，为衰老机制提供新的见解。探索纳米药物的肠道吸收机制活性药物成分的不溶性和由此导致的生物利用度的缺乏是新药开发的主要关注点。事实证明，基于纳米技术的方法是成功的，但关于其机理基础却知之甚少。本申请将使我们能够研究纳米药物与常规溶解药物相比在经肠通过和毒性方面的差异。

项目成果

Dissecting the Native Architecture and Dynamics of Cyanobacterial Photosynthetic Machinery.

• DOI: 10.1016/j.molp.2017.09.019
• 发表时间: 2017-11-06
• 期刊: Molecular plant
• 影响因子: 27.5
• 作者: Casella S;Huang F;Mason D;Zhao GY;Johnson GN;Mullineaux CW;Liu LN
• 通讯作者: Liu LN

Nanoparticles for imaging, sensing, and therapeutic intervention.

• DOI: 10.1021/nn500962q
• 发表时间: 2014-04-22
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Bogart, Lara K.;Pourroy, Genevieve;Murphy, Catherine J.;Puntes, Victor;Pellegrino, Teresa;Rosenblum, Daniel;Peer, Dan;Levy, Raphael
• 通讯作者: Levy, Raphael

Rapid kill of malaria parasites by artemisinin and semi-synthetic endoperoxides involves ROS-dependent depolarization of the membrane potential.

• DOI: 10.1093/jac/dkt486
• 发表时间: 2014-04
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Antoine T;Fisher N;Amewu R;O'Neill PM;Ward SA;Biagini GA
• 通讯作者: Biagini GA

Drosophila USP22/nonstop polarizes the actin cytoskeleton during collective border cell migration.

• DOI: 10.1083/jcb.202007005
• 发表时间: 2021-07-05
• 期刊: The Journal of cell biology
• 作者: Badmos H;Cobbe N;Campbell A;Jackson R;Bennett D
• 通讯作者: Bennett D

SERCA directs cell migration and branching across species and germ layers.

• DOI: 10.1242/bio.026039
• 发表时间: 2017-10-15
• 期刊: Biology open
• 影响因子: 2.4
• 作者: Bower DV;Lansdale N;Navarro S;Truong TV;Bower DJ;Featherstone NC;Connell MG;Al Alam D;Frey MR;Trinh LA;Fernandez GE;Warburton D;Fraser SE;Bennett D;Jesudason EC
• 通讯作者: Jesudason EC