The development of antimicrobial peptides delivery using POlyhedrin Delivery System (PODS) to treat mucosal ulceration and inflammation

使用多角体蛋白递送系统（PODS）治疗粘膜溃疡和炎症的抗菌肽递送的开发

• 批准号: 2549439
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2549439
• 关键词: development; antimicrobial; peptides; delivery; using

POlyhedrin Delivery System (PODS) are composed of polyhedrin trimers organized into a three-dimensional stable cubic lattice that shield the internal content from environmental damage. They can serve as the basis for the development of robust and versatile nanoparticles for biotechnological applications capable of delivering bioactive proteins to specific sites and tissues. The project involved the development of PODS that deliver anti-microbial peptides to oral and gut endothelial surfaces in order to accelerate the healing process associated with ulceration and inflammation. There are a number of chronic inflammatory oral and gastrointestinal conditions that present with persistent ulcers, such as, oral lichen planus, recurrent aphthous stomatitis (RAS), recurrent erythema multiforme, Behcet's, Crohn's disease, ulcerative colitis. Currently the treatments for these diseases are suboptimal and predominantly rely on steroids or biologics, which have severe side effects or are very expensive. PODS offer an alternative treatment option, are easy to manufacture and cost effective. The project will initially use PODS that contain anti-inflammatory IL-10 or TGFb and determine protein deliver and biological impact on epithelial and innate immune cells. The rate of release and the influence on cellular functions will be determined under a range of different conditions. Anti-microbial peptides will be selected on the basis of a literature review, available mulitomic data, previous association with the mucosal surfaces and ulcerative diseases of the oral and gastrointestinal tract. Candidate peptides will be cloned into expression plasmids, purified and activity tested against a panel of bacteria, containing both symbiotic and pathogenic stains. Antimicrobials that demonstrate activity against pathogenic bacterial strains will be taken forward and inserted in PODS using an insect expression system. Anti-microbial PODS will be assessed as above. In addition, the ability of the antimicrobial PODS to influence epithelial wound healing will be assessed using scratch assays and live cell imaging in the presence of different bacterial and immunogenic stimuli. As the project develops successful antimicrobial PODS will be adapted and modified to alter the delivery rate of the antimicrobial peptide and improve the wound healing capability. Successful antimicrobial PODS will be advanced in to in vivo models of ulcerative mucosal disease. The Project will initiate the early stages in the development of a new therapy in the treatment of chronic ulcerative diseases and mucosal inflammation.

多角体蛋白递送系统（PODS）由多角体蛋白三聚体组成，其组织成三维稳定的立方晶格，保护内部内容物免受环境损害。它们可以作为开发用于生物技术应用的稳健和多功能纳米颗粒的基础，这些纳米颗粒能够将生物活性蛋白质递送到特定部位和组织。该项目涉及PODS的开发，该PODS将抗菌肽递送到口腔和肠道内皮表面，以加速与溃疡和炎症相关的愈合过程。有许多慢性炎症性口腔和胃肠道病症表现为持续性溃疡，例如口腔扁平苔藓、复发性口疮性口炎（RAS）、复发性多形性红斑、白塞病、克罗恩病、溃疡性结肠炎。目前对这些疾病的治疗是次优的，主要依赖于类固醇或生物制剂，其具有严重的副作用或非常昂贵。PODS提供了一种替代的处理选择，易于制造且具有成本效益。该项目最初将使用含有抗炎IL-10或TGF β的PODS，并确定蛋白质递送和对上皮和先天免疫细胞的生物学影响。将在一系列不同条件下测定释放速率和对细胞功能的影响。抗菌肽将根据文献综述、可用的多组数据、先前与口腔和胃肠道的粘膜表面和溃疡性疾病的相关性来选择。候选肽将被克隆到表达质粒中，纯化并针对一组细菌（含有共生菌和致病菌）进行活性测试。使用昆虫表达系统，将显示出对病原性细菌菌株的活性的抗菌剂向前并插入PODS中。如上所述评估抗微生物PODS。此外，在存在不同细菌和免疫原性刺激的情况下，将使用划痕试验和活细胞成像来评估抗微生物PODS影响上皮伤口愈合的能力。随着该项目的发展，成功的抗菌PODS将被调整和修改，以改变抗菌肽的递送速率并提高伤口愈合能力。成功的抗微生物PODS将在溃疡性粘膜疾病的体内模型中发展。该项目将启动慢性溃疡性疾病和粘膜炎症新疗法开发的早期阶段。