Role of IL-23 in the Immunopathogenesis of C. difficile colitis

描述(由申请人提供)：我们建议测试IL-23介导对艰难梭菌感染(CDI)的破坏性炎症反应的假设。在目标1中，我们进一步假设炎性树突状细胞(DC)在结肠中产生IL-23，(目标2)IL-23继而引起破坏肠道上皮屏障的炎症，(目标3)IL-23作用的靶点是表达IL-23R的天然淋巴样细胞(IL-23R)，产生IL-17、IL-22和/或干扰素γ。这些研究的成功完成将勾勒出IL-23介导的CDI加重的机制和途径，并为治疗干预提供几个潜在的部位。意义：艰难梭菌是北美头号医院获得性感染，尽管接受抗生素治疗，死亡率仍为10%-15%，10%-35%的患者复发。该提案的创新方面包括，它探索了免疫调节剂在艰难梭菌治疗中的潜力。这项工作的环境包括首席研究员实验室的一组研究生团队，他们为感染性结肠炎研究做出了超过25年的贡献，以及一名外部顾问Brian Kelsall博士，他带来了树突状细胞生物学方面的专门知识。R21：这个范围适合R21，因为这项工作处于CDI中IL-23理解的最早概念阶段，并提出了对其作用机制的高风险/高回报研究。

DESCRIPTION (provided by applicant): We propose to test the hypothesis that IL-23 mediates a destructive inflammatory response to C. difficile infection (CDI). We further hypothesize in Aim 1 that inflammatory dendritic cells (DCs) produce IL-23 in the colon, and (Aim 2) that IL-23 in turn causes inflammation that disrupts the gut epithelial barrier, and that (Aim 3) the targets of IL-23 action are IL-23R expressing innate lymphoid cells (ILCs) that produce IL-17, IL- 22, and/ or IFNγ. Successful completion of these studies will delineate the mechanism and pathways of IL-23 mediated exacerbation of CDI and provide several potential sites for therapeutic intervention. Significance: C. difficile is the number one hospital-acquired infection in North America and despite antibiotic therapy has a mortality of 10-15%, with relapses in 10-35% of patients. Innovative aspects of the proposal include that it explores the potential for immune modulators in the treatment of C. difficile. The environment for the work includes a team of graduate students in the lab of the Principal Investigator who has contributed to infectious colitis research for over 25 years, and an external advisor, Dr. Brian Kelsall, who brings special expertise in dendritic cell biology. R21: The scope is appropriate for an R21 as the work is at the earliest conceptual stages of understanding of IL-23 in CDI, and proposes a high risk/high reward study of its mechanisms of action.