Lay Summary

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a serious and chronic inflammatory condition that affects individuals throughout life. The etiology and pathogenesis of IBD are not fully defined. Animal models of colitis have provided an excellent opportunity to study the pathogenesis of IBD. 

 

We recently identified that a protein called chitinase 3-like-1 (CHI3L1) was significantly upregulated in several murine colitis models and human IBD, but completely absent the expression in normal individuals. In the previous study, we have identified that CHI3L1 plays a pathogenic role in colitis by enhancing the intestinal bacterial attachment and the following internalization in colonic epithelial cells (CECs) and promoting the perpetuation and exacerbation of intestinal inflammation. In addition, a significantly increased level of CHI3L1 protein is observed in the serum of patients with IBD as well as colon cancer positively associated with the severity of disease and bad prognosis.

 

We, therefore, propose to investigate if CHI3L1 is involved in the initiation and perpetuation of IBD as well as colitis-associated carcinogenic change of CECs, and hypothesize that the inhibition or neutralization of CHI3L1 may have a potential therapeutic effect to ameliorate intestinal inflammation and colitis-associated cancer. We aim to answer this question by investigating if expressions of CHI3L1 and the other mammalian chitinases in colonic mucosa are altered in IBD and colitis-associated cancer. In addition, we will utilize a chronic DSS-induced cancer model to identify whether the CHI3L1 protein plays a pivotal and critical role in initiation and/or exacerbation of chronic colitis-associated carcinogenic change in CECs. Identification of the CHI3L1-mediated alteration in CECs may highly improve the transfer of knowledge gained at the bench to the bedside. Furthermore, we want to investigate the effect of CHI3L1-mediated signaling pathways on CECs in vitro.

 

Our proposed project will strongly help to understand the biological role of mammalian chitinases as in the mechanisms of development of chronic colitis and the following colitis-associated carcinogenesis. We do hope to identify a new type of therapeutic strategy to completely inhibit the development of chronic colitis and colitis-associated cancer, and it will be beneficial for helping to reduce the extreme burden from patients who are suffering from IBD and IBD-associated carcinoma.