Investigating the interaction between Photorhabdus Virulence Cassette nanosyringes with immune cells.

生物活性蛋白质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性和有效的活性。好的例子包括基于抗体和甘氨酸的方法。然而，应该注意的是，目前大多数成功的基于多肽的工具，例如这些工具在宿主细胞外部起作用或需要内吞加工。一个主要的挫折仍然是让活性多肽穿过生物膜，并将它们靶向到靶细胞内的特定区室。对于开发用于细胞内生物医学应用的更复杂的工具存在未满足的需求。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。分泌的细菌毒素代表了用于将活性多肽递送到宿主细胞中的自包含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，以便使它们适应替代的理想功能。昆虫病原细菌Photorhabdus部署了惊人的纳米级蛋白质注射器，将有效载荷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设备成为可行的细胞内蛋白质药物递送工具的重大进展。这些工具最终将作为生命科学的研究工具而具有价值，并有可能解决各种人类或动物疾病，如癌症，免疫学疾病和酶缺乏症。

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 approaches. It should be noted however that the majority of current successful polypeptide-based tools such as these act externally to host cells or require endocytic processing. A major frustration remains in getting active polypeptides across biological membranes and targeting them into specific compartments within target cells. There is an unmet need to develop more sophisticated tools for intracellular biomedical applications. Nature has evolved highly diverse and efficient molecular mechanisms for the translocation of biologically active polypeptides across biological membranes. Secreted bacterial toxins represent self-contained and highly adapted molecular devices for the delivery of active polypeptides into host cells. Advanced synthetic biology techniques now afford the opportunity to re-engineer toxin systems in order to adapt them for alternative desirable functions. The insect pathogenic bacterium Photorhabdus deploys astonishing nanoscale protein syringes to deliver payload toxins into host cells. In this project we will build upon significant previous progress in re-engineering these devices into viable intracellular protein drug delivery tools. These tools will ultimately be valuable as both research tools in life sciences and have the potential to address a huge range of human or animal diseases such as cancer, immunology disorders and enzyme deficiencies.