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

在天然存在的蛋白质纳米注射器中设计细胞类型特异性，用于细胞内蛋白质递送

• 批准号: 2105853
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2105853
• 关键词: Engineering; cell; type; specificity; naturally

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.

这个由MRC资助的博士培训伙伴关系（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，使学生能够解决以假设为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。生物活性蛋白在生物医学应用中的应用变得越来越重要，因为它们可以表现出高度特异性和有效的活性。好的例子包括基于抗体和精氨酸的疗法。然而，应该注意的是，目前大多数成功的基于多肽的疗法，如这些疗法，在宿主细胞外部起作用或需要内吞加工。一个主要的障碍仍然是让活性多肽穿过生物膜，将它们靶向靶细胞内的特定区室。因此，存在开发用于细胞内纳米医学的更复杂工具的未满足的需求。自然界已经进化出高度多样和有效的分子机制，用于生物活性多肽跨生物膜的易位。特别地，分泌的细菌毒素是能够将活性多肽递送到宿主细胞中的自包含的和高度适应的分子装置。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好处。值得注意的是，昆虫病原细菌Photorhabdus部署了一个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，我们将建立在重新设计这些纳米注射器成为可行的细胞内蛋白质药物输送工具的重大进展。这些工具最终将对解决癌症、免疫学疾病和酶缺乏等一系列人类疾病具有价值。学生将获得合成生物学，高分辨率显微镜，组织培养/细胞生物学技术和先进的分析化学方法的经验。