A novel, two-armed autotherapy for mucosal infectious diseases

项目摘要 抗生素和抗炎药分别攻击病原体或破坏性 炎症反应。这两种药物都是非特异性的，具有非特异性的非靶向效应。 治疗效果最佳。通过设计人体自身的蛋白质来表达或过度表达，我们 建议开发一种双臂疗法，控制细菌和真菌的水平，并同时 最大限度地减少感染期间伴随炎症而来的组织破坏。 牙周炎是拟议的双重疗法的一个很好的首发疾病靶点。牙周炎由以下原因引起 微生物失调和组织病理在很大程度上归因于由此产生的炎症。使用我们的 在小鼠实验性牙周炎模型上，我们假设局部牙龈 编码钙保护素的食品安全包装信使核糖核酸(复合S100A8和S100A9； S100A8/A9)将减轻微生物的伤害，而编码15‘-脂氧合酶的mRNA将减轻 炎症反应。为了检验我们的假设，我们将： 1.比较单独给药的每一种信使核糖核酸对当地微生物群的影响， 牙周炎模型中炎性细胞浸润和牙槽骨丢失； 2.表征当两种信使核糖核酸同时存在时对双重治疗的协同治疗反应。 一起给药。 为了了解建议的治疗性mRNAs的管理可能如何发挥作用，内源性 将测定S100A8/A9和内源性脂氧素，并将各自的蛋白质增强 得到确认。将双基因转导技术的治疗效益与 每一种单独作用都能减轻微生物群的失调、炎症细胞的渗透和牙槽骨的丢失。 通过表达粘膜上皮的天然蛋白，我们认为这种自动治疗将减少 牙周炎的体征，并为其他粘膜的类似治疗方法的发展提供指导 感染。

Project Summary Antibiotics and anti-inflammatory agents administered separately attack pathogens or the destructive inflammatory response. Both agents are non-specific and have off-target effects that are not therapeutically optimal. By engineering the body's own proteins to be expressed or over-expressed, we propose to develop a dual-armed therapeutic, controlling levels of bacteria and fungi and simultaneously minimizing the tissue destruction that accompanies the attendant inflammation during infection. Periodontitis is an excellent first disease target for the proposed dual therapy. Periodontitis results from microbial dysbiosis and the tissue pathology is largely attributed to the resulting inflammation. Using our well-characterized experimental periodontitis model in mice, we hypothesize that topical gingival application of food-safe, packaged mRNA encoding calprotectin (complexed S100A8 and S100A9; S100A8/A9) will attenuate the microbial insult and mRNA encoding 15'-lipoxygenase will mitigate the inflammatory response. To test our hypothesis, we will: 1. compare each mRNA species administered alone for impact on the local microbiome, inflammatory cell infiltrate, and alveolar bone loss in the periodontitis model; and 2. characterize the synergistic therapeutic response to dual therapy when both mRNA species are administered together. To learn how administration of the proposed therapeutic mRNAs might work, levels of endogenous S100A8/A9 and endogenous lipoxin will be determined and augmentation of the respective proteins will be confirmed. The therapeutic benefit of the dual mRNA transfection technology will be compared to each alone in attenuating the dysbiotic microbiome, inflammatory cell infiltrate, and alveolar bone loss. By expressing the native proteins of the mucosal epithelium, we propose that this auto-therapy will reduce signs of periodontitis and serve as guidance for development of similar therapeutics for other mucosal infections.