Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic and frequently disabling intestinal inflammatory disorders that affect more than a million individuals in the US. One of the most dreaded complications of UC and Crohn's colitis is the greatly increased risk of developing colorectal cancer (CRC), which accounts for approximately 15% of all deaths in IBD patients. So far, while endoscopy remains as the only established and vital tool for IBD diagnosis/prognosis, it is an invasive and highly resource-intensive procedure. Therefore, a less expensive, less laborious, less invasive tool is needed for IBD diagnosis/prognosis. Here, we propose a novel high-throughput proteomic approach to screen and identify new serological biomarkers for IBD. We hypothesize that disease- specific antibodies, either anti-intestinal microorganisms or anti-human endogenous proteins (autoantibodies), are present in the sera of IBD patients, and these specific antibodies can be used as serological biomarkers for either IBD diagnosis, or as indicative of disease prognosis and/or responsiveness to therapy. With a complete access to a large number of sera from normal subjects and IBD patients, serum antibodies will be used directly to screen high-density protein chips (also called protein arrays) to identify IBD-specific protein antigens. Our yeast protein chips that cover the entire yeast proteome (with 5,800 unique proteins) and robotically produced at Johns Hopkins will be used in the initial stage of our proposed screening. We are currently in the developing phase of generating E. coli proteome chips (with 4288 unique proteins) and human protein chips (4,000 unique proteins), which are expected to be ready in 3- 5 months. E. coli and human protein chips will be used in the second phase of biomarker screening. The goal is to identify CD- and UC-specific serological biomarkers and to use these biomarkers to develop a clinically reliable, comprehensive one-step diagnostic protein chip/kit for IBD diagnosis and subtyping. Moreover, identification of IBD-specific antibodies might not only reveal new pathogenic mechanisms of IBD, but also provide potential molecular targets for therapeutic intervention of IBD.