Engineering cell-type specificity in a naturally occurring protein nanosyringe for intracellular protein delivery

这一由MRC资助的博士培训伙伴关系(DTP)将尖端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引导的生物医学研究问题。这是一个为期4年的课程，第一年包括一系列的教学模块和两个基于实验室的研究项目，这些项目导致了跨学科生物医学研究的硕士学位。前两个学期包括精选的教学模块，使学生能够在多学科的科学中获得坚实的基础。学生们还参加了由学术和行业专家主持的一系列大师课程，这些专家涉及分子、细胞和组织动力学、微生物学和传染病、应用生物医学技术以及人工智能和数据科学等领域。在第三学期和暑期，学生们在他们选择的实验室里进行两个为期十一周的研究项目。项目：生物活性蛋白在生物医学应用中的应用正变得越来越重要，因为它们可以表现出高度特异和有效的活性。很好的例子包括抗体和基于细胞因子的治疗。然而，应该注意的是，目前大多数成功的基于多肽的疗法，如这些，作用于宿主细胞外部或需要内吞处理。一个主要的障碍仍然是通过生物膜将活性多肽靶向靶向靶细胞内的特定间隔。因此，开发更复杂的细胞内纳米医学工具的需求尚未得到满足。自然界已经进化出了高度多样化和高效的分子机制，用于生物膜上生物活性多肽的转移。特别是，分泌型细菌毒素是一种自给自足的高度适应性的分子装置，可以将活性多肽输送到宿主细胞中。先进的合成生物学技术现在提供了重新设计毒素系统的机会，以便使它们适应生物医学的利益。值得注意的是，昆虫致病细菌Photorhabdus部署了一种纳米级的蛋白质注射器，将毒素输送到宿主细胞中。在这个项目中，我们将以最近的重大进展为基础，将这些纳米级的注射器重新设计成可行的细胞内蛋白质药物输送工具。这些工具最终将对解决一系列人类疾病，如癌症、免疫学疾病和酶缺乏症具有重要价值。学生将获得合成生物学、高分辨率显微镜、组织培养/细胞生物学技术和高级分析化学方法方面的经验。

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. Project:The use of biologically active proteins for biomedical applications is becoming increasingly important as they can exhibit highly specific and potent activities. Good examples include antibody and cytokine-based therapies. It should be noted, however, that the majority of current successful polypeptide-based therapies, such as these, act externally to host cells or require endocytic processing. A major hurdle remains in getting active polypeptides across biological membranes to target them to specific compartments within target cells. As such there is an unmet need to develop more sophisticated tools for intracellular nanomedicines. Nature has evolved highly diverse and efficient molecular mechanisms for the translocation of biologically active polypeptides across biological membranes. In particular, secreted bacterial toxins are self-contained and highly adapted molecular devices that can delivery active polypeptides into host cells. Advanced synthetic biology techniques now afford the opportunity to re-engineer toxin systems in order to adapt them for biomedical benefit. Notably, the insect pathogenic bacterium, Photorhabdus, deploys a nanoscale protein syringes to deliver toxins into host cells. In this project we will build upon significant recent progress in re-engineering these nanoscale syringes into viable intracellular protein drug delivery tools. These tools will ultimately be valuable for addressing a huge range of human diseases such as cancer, immunology disorders and enzyme deficiencies. The student will gain experience in synthetic biology, high resolution microscopy, tissue culture/cell biology techniques and advanced analytical chemistry methodologies.