Ulcerative colitis and Crohn's disease, chronic relapsing inflammatory disorders of the gastrointestinal tract, affect an estimated one million individuals in the United States. The cause or causes of these debilitating diseases remain unknown. Progress in our understanding and treatment of inflammatory bowel disease (IBD) remains slowed by our limited knowledge of gene products involved in disease pathogenesis and disease heterogeneity. Identification of markers for the precise characterization of patient subgroups and the identification of those factors involved in the initiation, amplification, and perpetuation of the chronic immune response are priority objectives for future inflammatory bowel disease research. The immune response in inflammatory bowel disease is accompanied by complex changes in mucosal gene expression, including expression of molecules related to cell recruitment, adhesion, cellular activation and differentiation, expression of immunomodulatory molecules like cytokines or chemokines, and molecules involved in tissue remodeling and repair. Genome-wide sequencing projects and the development of microarray techniques have recently provided us with new methods that can provide a global perspective on these mucosal events and permit direct investigation of the gene expression resulting in the inflammatory phenotype. We propose to use microarrays derived from the normalized and well- characterized disease-specific libraries we have constructed to examine the following hypothesis: Analysis of genome-wide mucosal gene expression patterns will identify gene clusters or """"""""signatures"""""""" which distinguish different inflammatory bowel disease groups, reflective of the differences in the underlying genetic and environmental pathogenesis. Genes contained within these clusters will serve as markers for the involvement of specific cellular processes or expression of key immunoregulatory molecules. To begin to address this hypothesis, we will focus our efforts on two specific aims: (1) using disease-specific cDNA microarrays, we will characterize the genome-wide mucosal gene expression in patient groups with presentations of inflammatory bowel disease reflective of the diverse clinical patterns. We will investigate the application of microarrays, using cell-type, activation, and differentiation-specific markers as a method to precisely characterize changes in individual leukocyte populations in the inflammatory mucosa; and (2) we will develop, validate, and apply techniques for utilization of endoscopic biopsy samples as input for gene array analysis. We will also apply microarrays to large, well-characterized groups of IBD patients and apply new data analysis tools to identify gene expression signatures on the array for associations with specific pathologic or clinical phenotypes.
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| Warner, Elaine E; Dieckgraefe, Brian K (2002) Application of genome-wide gene expression profiling by high-density DNA arrays to the treatment and study of inflammatory bowel disease. Inflamm Bowel Dis 8:140-57 |
