Mechanisms of Duox2 variants in the pathogenesis of preclinical IBD

Duox2变异在临床前IBD发病机制中的作用

• 批准号: 10752786
• 负责人: Helmut F Grasberger
• 金额: $ 68.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752786
• 关键词: Ablation; Address; Alleles; Biopsy; Cells; Chronic; Colitis; Colon Carcinoma; Defect; Development; Diabetes Mellitus; Disease; Early Diagnosis; Early treatment; Enterocytes; Enzymes; Epithelium; Event; Gastrointestinal tract structure; Genes; Genetic; Genetic Epistasis; Genetic Variation; Gnotobiotic; Gram-Negative Bacteria; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Gut Mucosa; Healthcare; Homeostasis; Homologous Gene; Host Defense; Human; Hydrogen Peroxide; IL17C gene; Immune; Immune response; In Vitro; Individual; Inflammatory; Inflammatory Bowel Diseases; Integration Host Factors; Investigation; Link; M cell; Measures; Mediating; Metabolic syndrome; Microbe; Modeling; Molecular; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Mucous body substance; Mus; NADPH Oxidase; Obesity; Onset of illness; Outcome; Oxidases; Oxidation-Reduction; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Plasma; Population; Population Attributable Risks; Predisposition; Production; Prognosis; Proteins; Regulation; Research; Resources; Risk; Risk Factors; Role; Signal Transduction; System; Testing; Therapeutic Intervention; Variant; Work; autocrine; bacterial fitness; disorder prevention; dysbiosis; fatty liver disease; genetic association; genetic variant; genome-wide; germ free condition; gut bacteria; gut microbes; gut microbiota; improved; interleukin-17C; interleukin-22; intestinal barrier; loss of function; man; microbial colonization; microbiota; multiple omics; new therapeutic target; novel; novel strategies; overexpression; pathobiont; pharmacologic; pre-clinical; prevent; preventive intervention; reconstitution; risk variant; virulence gene

PROJECT SUMMARY/ABSTRACT Inflammatory Bowel Disease (IBD) is a debilitating gut disorder with significant morbidity and healthcare resource utilization. Because early diagnosis and treatment may improve the prognosis of IBD, there is an urgent need to better understand the preclinical incipient disturbance of gut microbe-epithelial homeostasis in at-risk individuals to identify novel therapeutic targets to halt disease onset, which is our long-term objective. A crucial host factor in maintaining a homeostatic relationship with the gut microbiota is Dual Oxidase 2 (DUOX2), an epithelial-specific NADPH oxidase releasing H2O2 into the supra-epithelial mucus layer. DUOX2 is highly inducible by abnormal microbial colonization and among the most robustly and consistently overexpressed genes in mucosal biopsies from patients with preclinical IBD. We previously showed a defect in DUOX2 leads to activation of compensatory epithelial defense systems in specific-pathogen-free mice and loss-of-function alleles in human populations are associated with increased susceptibility to IBD. However, the relevant mechanisms underlying this genetic association remain unclear. The objective here is to determine how DUOX2 loss-of-function genetic variants render an individual susceptible to dysbiosis and a loss of mucosal immune homeostasis leading to IBD. We hypothesize that dysregulation of IL-17C signaling is a critical pathogenic driver of DUOX2-associated IBD. The rationale for the proposed research is that, once it is known how dysregulation of IL-17C signaling in DUOX2 defective hosts contributes to pathogenesis of IBD, novel strategies can be developed to identify at-risk individuals and restore homeostasis to prevent the onset of IBD. We will test our hypothesis and, thereby, accomplish our objective by pursuing the following specific aims: 1. Determine the mechanisms of how DUOX2 loss-of-function results in microbe-dependent activation of the IL17C axis. 2. Assess the function of IL17RE-like protein, a hitherto uncharacterized IBD risk factor. 3. Investigate the role of chronic IL-17C activation in DUOX2 defective hosts as a driver of IBD pathogenesis. The expected outcome of the proposed work is a mechanistic framework of how DUOX2 variants cause an increased risk for IBD, namely by sustained activation of IL17C-mediated immune responses due to abnormal microbe-epithelial interactions. Such results are expected to have an important positive impact because understanding how DUOX2 variants contribute to IBD pathogenesis is highly likely to provide new targets for preventative and therapeutic interventions for diseases associated with dysregulated microbe-intestinal interaction (e.g., IBD, IBS, colon cancer) in addition to fundamentally advancing the fields of gut mucosal immunity.

项目总结/文摘