Although Crohn's colitis (CC) and ulcerative colitis (UC) share several clinical features they are different and have different causes and discrete mechanisms of tissue damage and treatment options differ significantly. Therefore the accurate diagnosis of inflammatory bowel disease (IBD) is of paramount importance in terms of medical care, surgical intervention and prognosis. The distinction between UC and CC is made on the basis of clinical, radiologic, endoscopic, and pathologic interpretations, but cannot be differentiated in up to 15% of IBD patients. This is called indeterminate colitis (IC). About 90% o IC is diagnosed at the time of colectomy for fulminant colitis and subsequent management critically depends on the correct diagnosis. We have developed an amenable proteomic methodology that supports the diagnostic feasibility to discriminate molecularly, different inflammatory colitis. Previous research has been variably successful in serum, in stool and in mucosal biopsy biomarker studies to differentiate prognostically active disease and quiescent state. These biomarkers however, were not discriminatory between CC and UC. Specialized matrix assisted laser desorption/ionization mass spectrometry (MALDI MS) offers the possibility of proteomic biomarker assessment of the tissue directly. In our preliminary studies, the histologic layers of colectomy samples from patients with confirmed UC, CC, IC, colon cancer, and associated non inflamed normal tissue used as controls) were analyzed using MALDI MS for proteomic profiling. The results have successfully identified 11 highly significant mass-to-charge ratio (m/z) signals that distinguish UC from CC and from normal controls. These m/z values displays all of which showed greater fold induction in CC. Some of these signatures were only found in the colonic submucosa while others were found in both the mucosa and submucosa. With the R21 funding, in Aim 1, we would like to identify the 11 statistically significant finger prints using Mass spectrometry cutting-edge technology.
The second aim will be to validate the presence of the identified proteins in the colon tissue layers using IHC, Western blot and/ or ELISA assays. This will allow pursuit of further funding (R01) that will allow identification of serum-based markers found and validated in aims 1 and 2 for colitis-specific fingerprint in serum, and eventually develop antibodies for the novel proteins with no available immunoreagents in the market. This will also allow testing our hypothesis of delineating IC into either UC or CC through identifying signatures in endoscopic tissue samples from patients with colitis as well as eventually creating a serum biomarker assay to delineate the inflammatory colitides using same protein(s). This information may provide new avenues for the development of novel diagnostic, prognostic and therapeutic targets.
We anticipate identifying novel molecular biometric fingerprints that will allow delineation of inflammatory bowel disease called ulcerative colitis (UC) and Crohn's colitis (CC) as well as potentially predict indeterminate colitis (IC) eventual differentiation into either UC or CC. We hypothesize that these biological signature candidates that distinguish UC from CC and normals represent identifiable proteins that are able to be sequenced and identified. This will allow pursuit of further larger funding (R01) to test our hypothesis of delineating IC into either UC or CC through endoscopic tissue samples from patients with colitis as well as eventually creating a serum biomarker assay to delineate the inflammatory colitides.
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