Scientific Abstract

Proposal No.  IBD-0051R2
Principal Investigator:  Shukti Chakravarti, Ph.D.
Applicant Institution:  Johns Hopkins University (Baltimore, Maryland, U.S.A.)
Project Title:  Molecular classification of Crohn’s disease subtypes by gene expression profiling
Award Period:  July 1, 2003 – February 28, 2005

Crohn's disease (CD) is a heterogeneous chronic inflammatory bowel disease (IBD) with subgroups characterized by distinct disease site, symptoms and response to therapy.  Clearly effective diagnosis, an understanding of the pathobiology, prognosis and tailored therapies require better molecular classification of Crohn's disease subtypes.

We hypothesize that the ileocolonic (ICD) and colonic (CCD) forms of Crohn’s disease represent separate disease subtypes, characterized by distinctive gene expression patterns arising from different biological pathways.  To test this hypothesis, we will elucidate changes in gene expression patterns of ileocolonic CD and colonic CD (stratified for NOD2 genotype), compared to normal control (routine screening) and ulcerative colitis as another non-CD inflammatory control.  The gene expression data will be used to address the following questions:

a)      What is the distinctive gene expression pattern for clinically defined ICD and CCD?  Genes differentially expressed in ICD and CCD will be identified by the significance analysis of microarrays (SAM).

b)      Is there a reliable smaller subset of genes that best characterize ICD and CCD?  The prediction analysis of microarrays (PAM) methods will be used to identify a subset of genes that best characterize ICD and CCD.  This smaller set of genes will be used in future for subtype prediction of Crohn's disease involving the colon.

The current study will identify underlying differences in the pathogenesis of two clinical subtypes, ICD and CCD.  This study will establish a molecular classification of two major CD subtypes and lead to future studies that may develop subtype-predicting markers.  Gene expression profiling of biopsy tissues can form the basis of follow-up profiling of the same individual for prospective studies to elucidate changes that precede a flare-up or response to specific therapies.