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

IL-23 在艰难梭菌结肠炎免疫发病机制中的作用

• 批准号: 9057951
• 负责人: William A Petri
• 金额: $ 19.14万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057951
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Therapy; Aspergillus; Bacteria; Biological Assay; Cells; Cellular biology; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical Trials; Clostridium difficile; Colitis; Colon; Colony-forming units; Data; Dendritic Cells; Dependency; Detection; Diarrhea; Disease; Environment; Epithelial; Failure; Feces; Gastrointestinal tract structure; Genetic; Health; Heterogeneity; Histopathology; Hospitals; Human; IRF4 gene; ITGAM gene; ITGAX gene; Immune; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interferon Type II; Interleukin-12; Interleukin-17; Invaded; Knock-out; Laboratories; Lamina Propria; Life; Lymphoid Cell; Measures; Mediating; Mediator of activation protein; Mesentery; Messenger RNA; Monoclonal Antibodies; Morbidity - disease rate; Mus; Names; Nature; Neutrophil Infiltration; North America; Nosocomial Infections; Pathogenesis; Pathology; Pathway interactions; Patients; Population; Prevalence; Principal Investigator; Process; Production; Psoriasis; Relapse; Research; Resistance; Role; Serum; Signal Transduction; Site; Sorting - Cell Movement; Source; Staging; Testing; Therapeutic Intervention; Time; Toxin; Translating; Work; base; collaborative environment; cytokine; differential expression; extracellular; fluorescein isothiocyanate dextran; graduate student; high reward; high risk; inflammatory marker; innovation; interleukin-22; interleukin-23; lymph nodes; monocyte; mortality; neutralizing antibody; novel; novel strategies; predict clinical outcome; research study; response

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.

描述（由申请人提供）：我们建议测试IL-23介导对C的破坏性炎症反应的假设。艰难梭菌感染（CDI）。我们在目标1中进一步假设炎性树突状细胞（DC）在结肠中产生IL-23，并且（目标2）IL-23进而引起破坏肠上皮屏障的炎症，并且（目标3）IL-23作用的靶点是表达IL-23 R的先天淋巴样细胞（ILC），其产生IL-17、IL- 22和/或IFNγ。这些研究的成功完成将描绘IL-23介导的CDI恶化的机制和途径，并提供几个潜在的治疗干预位点。显著性：C.艰难梭菌是北美第一大医院获得性感染，尽管进行了抗生素治疗，其死亡率仍为10- 15%，10-35%的患者复发。该提案的创新方面包括探索免疫调节剂在治疗C。很难工作环境包括主要研究者实验室的研究生团队，他们为感染性结肠炎研究做出了超过25年的贡献，以及外部顾问Brian Kelsall博士，他带来了树突状细胞生物学的特殊专业知识。R21：该范围适用于R21，因为该工作处于了解CDI中IL-23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。