A novel, two-armed autotherapy for mucosal infectious diseases

一种针对粘膜感染性疾病的新型双臂自疗法

• 批准号: 10229352
• 负责人: MARK C HERZBERG
• 金额: $ 24.35万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229352
• 关键词: Alveolar Bone Loss; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics; Arachidonate 15-Lipoxygenase; Attenuated; Autologous; Bacteria; Bacterial Infections; Cations; Cells; Communicable Diseases; Complex; Development; Disease; Engineering; Epithelial; Exhibits; Flow Cytometry; Food; Gingiva; Immunofluorescence Microscopy; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Learning; Leukocyte L1 Antigen Complex; Ligature; Lipids; Lipoxins; Messenger RNA; Modeling; Monitor; Mucous Membrane; Mus; Natural regeneration; Pathology; Pathway interactions; Periodontitis; Predisposition; Proteins; Resistance; Resolution; S100A8 gene; S100A9 gene; Technology; Testing; Therapeutic; Tissues; Topical application; Transfection; Transgenic Animals; Transition Elements; Whole-Genome Shotgun Sequencing; Wild Type Mouse; Work; alveolar bone; antimicrobial; arm; attenuation; dysbiosis; experimental study; fungus; in vivo; mRNA Expression; metal chelator; microCT; microbial; microbiome; mouse model; novel; overexpression; pathogen; side effect; treatment response; treatment strategy

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.

项目摘要 抗生素和抗炎剂分别给药攻击病原体或破坏性的 炎症反应。这两种药物都是非特异性的，具有非靶向效应， 最佳治疗效果通过设计人体自身的蛋白质来表达或过度表达， 建议开发一种双臂治疗方法，控制细菌和真菌的水平，同时 使感染期间伴随炎症的组织破坏最小化。 牙周炎是一个很好的第一个疾病目标的双重治疗。牙周炎是由 微生物生态失调和组织病理主要归因于所产生的炎症。使用我们 在小鼠的实验性牙周炎模型中，我们假设局部牙龈 应用食品安全的、包装的编码钙卫蛋白的mRNA（复合的S100 A8和S100 A9; S100 A8/A9）将减弱微生物的侵害，而编码15 '-脂氧合酶的mRNA将减轻微生物的侵害。 炎症反应。为了验证我们的假设，我们将： 1.比较单独施用的每种mRNA种类对局部微生物组的影响， 牙周炎模型中的炎症细胞浸润和牙槽骨损失;和 2.表征当两种mRNA种类同时存在时对双重疗法的协同治疗反应。 一起管理。 为了了解所提出的治疗性mRNA的施用如何起作用，内源性mRNA的水平可能会降低。 S100 A8/A9和内源性脂氧素将被确定，并且相应蛋白质的增加将被确定。 得到证实。将比较双重mRNA转染技术的治疗益处， 每一种都单独减弱了生态失调的微生物组、炎性细胞浸润和牙槽骨损失。 通过表达粘膜上皮的天然蛋白质，我们提出这种自我治疗将减少 并作为开发用于其他粘膜炎类似疗法的指导 感染.