Lay Summary

Proposal No. IBD-0259
Principal Investigator: David Boone, M.D.
Applicant Organization: The University of Chicago (Illinois, U.S.A.)
Project Title: Functional consequences of autophagy mutations in Crohn’s disease 
Period of Award: December 1, 2008 – February 28, 2010

Many new gene mutations that increase susceptibility to Crohn’s disease (CD) are being discovered. The next step is to determine what these genes do and how changes in these genes might lead to CD. In the past we have learned a lot about the pathology of CD by using mouse models involving gene targeting. In these models, the function of a gene is determined by deleting the gene in a whole mouse and examining the effect. This “knockout” approach is akin to removing parts from a car to find out what each part does. If you “knockout” the steering wheel of a car, you will find out what the steering wheel normally does when you reach your first corner. Similarly, if one knocks out a gene in a mouse and the mouse develops IBD, then one can assume that the gene normally controls inflammation in the intestine. This powerful approach is hampered somewhat by the simple fact that mice are not humans and so some genes have unique functions in humans that are not the same in mice. We have recently developed the ability to “knockout” genes in human cells and this will allow us to directly test the function of human genes in human cells. We can also “knockin” the exact mutations that have recently been discovered in human populations and study the effects of these mutations in human cells. This will rapidly advance our research efforts to link the expanding list of human gene mutations to gene functions in human cells.