Visualizing Filamentous Actin Using Synthetic Biology and Click Chemistry

项目：从细菌到人类的所有细胞中细胞形态和形式的组织基础是其骨架（称为细胞骨架）。已经描述了许多细胞骨架系统，非常重要的一个是肌动蛋白细胞骨架，其在肌肉收缩和癌症转移中的作用是众所周知的。研究细胞骨架及其如何促进细胞功能（如细胞分裂、细胞迁移等过程）的最佳方法之一。是使用先进的显微镜工具使其可视化，这使我们能够看到甚至百万分之一毫米大小的生物分子。然而，构成肌动蛋白细胞骨架的关键蛋白质，肌动蛋白（形成聚合物轨道），很难用灯泡（荧光标记）标记，这将使其在显微镜下可视化。我们计划使用合成生物学方法在肌动蛋白细胞骨架的检测和成像方面进行一步改变，在合成生物学方法中，我们将以非天然氨基酸的形式将超小手柄引入肌动蛋白。这些手柄将通过有机化学方法钩在荧光分子上。灯泡将被引入肌动蛋白的多个位置，一次一个，那些不干扰肌动蛋白功能的灯泡将被用于先进的成像实验。一旦建立了方法，学生将在体外（在试管中，通过纯化细胞中产生的肌动蛋白）和体内（使用先进的显微镜技术在活生物体中）研究肌动蛋白行为的许多方面。这些研究应该提供对基础生物学以及癌症转移，心血管疾病等疾病的主要见解。计划概述：这个MRC资助的博士生培养伙伴关系（DTP）将尖端的分子和分析科学与数据分析中的创新计算方法结合在一起，使学生能够解决假设主导的生物医学研究问题。这是一个为期4年的计划，其第一年涉及一系列教学模块和两个基于实验室的研究项目，导致跨学科生物医学研究硕士学位。前两个学期包括一系列教学模块，让学生在多学科科学中获得坚实的基础。学生还参加了一系列由学术和行业专家领导的大师班，这些专家在分子，细胞和组织动力学，微生物学和感染，应用生物医学技术以及人工智能和数据科学领域。在第三和夏季学期，学生在他们选择的实验室进行两个为期11周的研究项目。

Project:Fundamental to the organization of cell morphology and form in all cells ranging from bacteria to human is its skeleton (termed the cytoskeleton). A number of cytoskeletal systems have been described, a very important one being the actin cytoskeleton, which is well known for its role in muscle contraction and cancer metastasis. One of the best ways to investigate the cytoskeleton and how it promotes cell function (in processes such as cell division, cell migration etc.) is to visualize it using advanced microscopic tools, which can enable us to see biological molecules even a millionth of a millimetre in size. However, the key protein that makes up the actin cytoskeleton, actin (which forms polymeric tracks), is difficult to label with light bulbs (fluorescent tags) that will enable its visualization in microscopy. We plan to make a step change in the detection and imaging of the actin cytoskeleton using synthetic biology approaches in which we will introduce ultra small handles in the form of unnatural amino acids into actin. These handles will be hooked onto fluorescent molecules through organic chemistry approaches. Light bulbs will be introduced at a number of locations in actin, one at a time, and the ones that do not perturb function of actin will be used in advanced imaging experiments. Once the methodology is established, the student will investigate many aspects of actin behaviour in vitro (in a test tube, through purification of the actin protein that was made in cells) and in vivo (in living organisms using advanced microscopic techniques). These studies should provide major insight into basic biology as well as diseases such as cancer metastasis, cardiovascular disorders, and more.Programme overview:This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.