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 抗生素和抗炎药分别攻击病原体或破坏性 炎症反应。两种代理都是非特异性的，并且具有脱靶效应 治疗上最佳。通过工程化人体自己的蛋白质要表达或表达过表达，我们 提议开发双臂治疗，控制细菌和真菌的水平，并同时 最大程度地减少伴随感染期间炎症的组织破坏。 牙周炎是拟议双重疗法的极好的第一个疾病靶标。牙周炎由 微生物营养不良和组织病理学主要归因于产生的炎症。使用我们的 在小鼠中，特征良好的实验性牙周炎模型，我们假设牙线牙龈 使用编码钙蛋白酶的食物安全，包装的mRNA（复合的S100A8和S100A9； S100A8/A9）将减轻微生物的侮辱，编码15'-脂氧酶的mRNA将减轻 炎症反应。为了检验我们的假设，我们将： 1。比较单独施用的每个mRNA物种，以影响局部微生物组， 牙周炎模型中的炎性细胞浸润和肺泡骨质流失；和 2。当两个mRNA物种都是双重疗法的协同治疗反应 一起管理。 要了解拟议的治疗mRNA的给药如何起作用，内源性水平 S100A8/A9和内源性脂蛋白将确定，相应蛋白质的增强将 被确认。将双重mRNA转染技术的治疗益处与 每个人都单独减轻了不良生物微生物组，炎性细胞浸润和肺泡骨质流失。 通过表达粘膜上皮的天然蛋白质，我们建议这种自动疗法将减少 牙周炎的迹象，并作为开发其他粘膜类似疗法的指导 感染。