Role of IL-18 in Crohn's Disease (CD)

IL-18 在克罗恩病 (CD) 中的作用

• 批准号: 7489430
• 负责人: Theresa Torres Pizarro
• 金额: $ 27.87万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489430
• 关键词: Accounting; Acute; Address; Affect; Alleles; Animal Model; Autoimmune Diseases; Automobile Driving; Binding; Biological Assay; Biological Models; Biopsy; Blood specimen; Bone Marrow; Bone Marrow Transplantation; CCL2 gene; Candidate Disease Gene; Cell Line; Cells; Characteristics; Chimera organism; Chronic; Chronic Phase; Chronic Phase of Disease; Classification; Colitis; Complex; Crohn' s disease; DNA Probes; Dendritic Cells; Development; Disease; Disease susceptibility; Dose; Electrophoretic Mobility Shift Assay; Environmental Risk Factor; Epithelial; Epithelial Cells; Etiology; Evaluation; Experimental Animal Model; Experimental Models; Family; Foundations; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; Haplotypes; Human; IL18 gene; Ileitis; Immune; Immune response; Immune system; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Insulin-Dependent Diabetes Mellitus; Interleukin-11; Interleukin-18; Intestines; Knowledge; Laboratories; Linkage Disequilibrium; Measures; Mediating; Messenger RNA; Modality; Modeling; Molecular; Molecular Biology Techniques; Mouse Strains; Mucosal Immune Responses; Mucous Membrane; Multiple Sclerosis; Mus; Organ; Pathogenesis; Patients; Pattern; Phase; Plasma; Play; Population; Population Control; Predisposition; Production; Promoter Regions; Proteins; Quantitative Trait Loci; Range; Regulation; Regulator Genes; Reporter; Reporting; Research Personnel; Research Proposals; Rheumatoid Arthritis; Role; Sarcoidosis; Screening procedure; Severity of illness; Single Nucleotide Polymorphism; Site-Directed Mutagenesis; Sodium Dextran Sulfate; Source; Specificity; Staging; Subgroup; Susceptibility Gene; Testing; Thinking; Time; Tissues; Transcriptional Regulation; Transfection; Ulcerative Colitis; Variant; Virginia; Whole Blood; Wild Type Mouse; Work; base; cell type; chemokine; clinical phenotype; cytokine; design; disorder control; genetic association; genetic linkage; genetic variant; human study; in vivo; macrophage; mouse model; novel; programs; promoter; repaired; research study; response; transcription factor; transmission process

Although the precise etiology is unknown, inflammatory bowel disease (IBD) is thought to occur as a result of a dysregulated mucosal immune response to environmental factors in a genetically predisposed individual. IL-18 is a cytokine that plays an important role in the pathogenesis of several chronic Thl-mediated disorders, including Crohn's disease (CD). In fact, a dramatic shift in IL-18 expression occurs during CD from intestinal epithelial cells (IEC) to mucosal immune cells (i.e. macrophages and dendritic cells), as the severity of disease increases. In addition, recent evidence supports the role of IL-18 as a protective factor during the acute phase of mucosal immune responses, when IEC are the primary source of IL-18. This novel function for IL-18 contrasts with the pathogenic role IL-18 is believed to play in more chronic phases of Thl-mediated inflammation. A genetic basis for differences in IL-18 regulation and expression observed in IBD may exist since recent studies have reported the association of specific single nucleotide polymorphisms (SNPs) in the IL-18 promoter region and several autoimmune diseases. Therefore, using genetic and molecular biology techniques as well as experimental models intestinal inflammation, the present study is designed to investigate the specific genetic factors that regulate IL-18 synthesis and to determine the precise function of epithelial and immune cell-derived IL-18 in the acute versus chronic phases of IBD. The central hypothesis of the present proposal is that IL-18plays a key role in regulating normal innate immune responses in the gut mucosa and dysregulation of IL-18 may result in chronic intestinal inflammation characteristic of IBD. The following three specific aims are proposed to test this hypothesis: 1) Determine the relationship between polymorphisms in the IL-18 promoter region and IBD. The role of IL-18 in IBD susceptibility will be defined using an association approach by screening for recently described IL-18 promoter polymorphisms and performing case association studies of these genetic markers in well-characterized IBD and control populations. IBD multiplex families will also be used to test linkage disequilibrium between these marker loci and putative disease susceptibility loci in order to further characterize the transmission pattern of allelic variants. 2) Define the mechanismCs) of polymorphic IL-18 gene regulation in different mucosal cell populations. The functional relevance of IL-18 promoter polymorphisms will be achieved by creation of reporter constructs, site-directed mutagenesis experiments, and in vitro transfection assays in epithelial and macrophage cell lines. In addition, differential transcription factor binding and subsequent transcriptional regulation will be assessed in order to determine how the IL- 18 gene is differentially regulated by IL-18 promoter polymorphisms, and if transcriptional control varies among different intestinal cell types. 3) Evaluate the specific role of IL-18 derived from different gut mucosal cell populations in an in vivo setting using experimental models of intestinal inflammation. The extent and severity of disease will be assessed in mice genetically- and immunologically-manipulated to produce IL-18 in either hemopoietic- (i.e. immune cells) or non-hemopoietic-cells (i.e. epithelial cells) following the induction of acute or chronic intestinal inflammation. These experiments will mechanistically address, in an in vivo setting, if IL-18 derived from specific mucosal cell populations and expressed during the acute versus chronic phases of disease, are involved in the pathogenesis of IBD. The ultimate goal of the present research proposal is to define the precise role of IL-18 in CD in order to develop specific treatment modalities aimed at modifying the natural course of this devastating disease.

虽然确切的病因尚不清楚，但炎症性肠病（IBD）被认为是由于一个失调的