Scientific Abstract

Proposal No.  IBD-0006
Principal Investigator:  M. Bishr Omary, Ph.D., M.D.
Applicant Organization:  Stanford University (California, U.S.A.)
Project Title:  Keratin mutations as a risk factor for inflammatory bowel disease
Period of Award:  April 1, 2002 - September 30, 2003

Our hypothesis is that mutations in the cytoskeletal intermediate filament keratin (K) polypeptides 19 or 20 (K19 or K20) are likely to predispose patients to the development of inflammatory bowel disease (IBD).  Unique keratin compliments are expressed in an epithelial cell-type specific manner, and mutations in several keratins have already been identified as a major cause or predisposition to a wide range of epidermal, ocular, esophageal or liver diseases.  Keratins function to protect cells from mechanical and nonmechanical forms of injury, and identification of keratin-related diseases was facilitated, primarily, by the phenotypes of transgenic mice with ablated or mutant-expressing keratins.

We propose to test our hypothesis by screening for keratin mutations in genomic DNA isolated from IBD patients, as compared with control DNA, and then testing the functional consequences of the identified mutations using in vitro culture systems.  Our hypothesis is based on: (i) the preferential expression of K19 and K20 in the small and large intestine; (ii) the finding that keratin 8 (K8)-null mice develop colitis or liver disease depending on the genetic background of the mice.  Absence of K8 results in degradation of the normally associated partner keratins, including K19 and K20, due to the unique biochemical properties of these keratins.  Hence, diseases caused by a given mutant keratin are also likely to result from other mutant keratins found in the same cell type due to the heteropolymeric interaction of the different keratins within a given cell; and (iii) K8 and K18 mutations were recently identified in liver disease patients, thereby supporting the phenotype of the K8-null mice.

If successful, identification of keratin mutations as a predisposition to IBD unfolds a novel pathway to conceptualize IBD in terms of a primary epithelial cell defect that subsequently triggers an untoward immune response.