Final Progress Report
Proposal No. IBD-0210R2
Principal Investigator: Xiaojing Ma, Ph.D.
Applicant Organization: Weill Medical College of Cornell University (New York, New York, U.S.A.)
Project Title: The Crohn’s disease-associated NOD23020insC mutant has an acquired activity as an inhibitor of IL-10 production
Period of Award: October 1, 2007 - March 31, 2009
The work supported by the BMRP grant (IRB-0210R2) explored the molecular mechanism of the pathoetiology of the inflammatory bowel disorder Crohn’s disease (CD). Specific mutations in the nucleotide-binding oligomerization domain 2 (Nod2) render certain individuals highly susceptible to CD, including an insertion and frame shift mutation at amino acid residue 1007, designated 1007fs. This mutation results in the deletion of the terminal leucine-rich repeats (LRR) of the protein, but the mechanism of its influence on CD has been controversial ever since its identification in 2001. Three high profile studies that used animal models of the disease were published in 2004-05 in Science and Nature Immunology; these suggested that 1007fs was a loss of function mutation, a finding that influenced the perception of others in the field. The study by our group, however, suggested that 1007fs caused a novel “gain of function” change that influenced endogenous IL-10 levels and thereby altered the immune homeostasis. Our findings strongly challenge current research paradigms by calling into question of the relevance of the Nod2-null mouse model and the model targeting an artificial mouse version of the human Nod2 mutant for mimicking the human disease. Because of its significance to CD research, our study received widespread attention: Nature commented on it in its “Research Highlights” [458, 683 (9 April 2009)], Cell discussed it in “A NOD to Unraveling Crohns Disease” (137, May 15, 2009, 593), it was reviewed at length in a Nature Immunology editorial: “Crohn's disease-associated Nod2 mutants reduce IL10 transcription”, [2009 May;10(5):455-7], and it was highlighted by Nature Medicine (2009, 15:5, 501). This work also demonstrated our persistence, as the study took us a total of 3.5 years to complete and we spent 1.5 years addressing the reviewers’ critiques. It involved 3 successive postdocs with different expertise, as well as clinicians from the Netherlands and New York. We did all the work with the one year funding by BMRP, and we persisted despite three consecutive failures with R01 applications that would have funded this project.
Lay summary
The work supported by the BMRP grant (IRB-0210R2) explored the molecular mechanism of the development and pathology of the inflammatory bowel disorder Crohn’s disease (CD). Specific mutations in a host defense gene called nucleotide-binding oligomerization domain 2 (Nod2) render certain individuals highly susceptible to CD. One of these mutants of Nod2 is designated 1007fs. How this mutant of Nod2 causes CD has been controversial ever since its initial identification in 2001. Several high profile studies that used animal models of the disease were published in 2004-05 in Science and Nature Immunology; these suggested that 1007fs was a loss of function mutation, i.e., it is simply a “dead” protein. This perception has had a strong influence over the thinking of the field. The study by our group, however, suggested that 1007fs caused a novel “gain of function” change, i.e., the protein is not “dead”. Instead, it has an altered function from the non-mutated protein in that it can inhibit the production of an important immune regulatory molecule called interleukin-10 (IL-10), which controls the balance between inflammation and tissue repair. Interestingly, this novel property of 1007fs is unique to humans, not observed in mice.
Our findings strongly challenge current paradigms by calling into question of the relevance of the Nod2-deficient mouse models for mimicking the human disease. The study also provides the rationale for therapeutically targeting the process in which IL-10 is produced by immune cells in the treatment of CD. Because of its significance to CD research, our study received widespread attention: Nature commented on it in its “Research Highlights” [458, 683 (9 April 2009)], Cell discussed it in “A NOD to Unraveling Crohns Disease” (137, May 15, 2009, 593), it was reviewed at length in a Nature Immunology editorial: “Crohn's disease-associated Nod2 mutants reduce IL10 transcription”, [2009 May;10(5):455-7], and it was highlighted by Nature Medicine (2009, 15:5, 501).