Current Projects
Role of LINGO2 in Suppressing Colitis-Associated Cancer in Intestinal Epithelial Cells
Colitis-associated colorectal cancer represents a dangerous complication of chronic colitis in patients with inflammatory bowel disease (IBD). Patients with IBD develop cancer at a younger age and have worse survival compared to patients with sporadic colorectal cancer. Not surprisingly, colitis-associated cancer accounts for 10-15% of annual IBD deaths. Yet, the underlying mechanisms by which persistent inflammation drives malignant transformation of intestinal epithelial cells (IECs) are not well understood. Further, it is unclear whether there are molecular pathways that specifically protect IECs against malignant transformation in the setting of persistent inflammation. Recently published studies reveal that Lingo2 deficient mice have increased basal EGFR phosphorylation in colon tissue. Further, Lingo2 deficient epithelial cell lines have increased EGFR-dependent proliferation (Belle et. al. 2019). We therefore hypothesized that LINGO2 protects against the development of colitis-associated cancer by limiting EGFR signaling in the setting of intestinal inflammation. This work we anticipate will shed new light on cross-talk between epithelial cells and the immune system as it relates to cancer development.
Lingo2's Involvement in Immune Modulation
Host defense at the mucosal interface requires collaborative interactions between diverse cell lineages. Epithelial cells damaged by microbial invaders release reparative proteins such as the Trefoil factor family (TFF) peptides that functionally restore barrier integrity. However, whether TFF peptides and their receptors also serve instructive roles for immune cell function during infection is incompletely understood. We recently published that the intestinal trefoil factor, TFF3, restrains TH1 cell proliferation and promotes host protective Type 2 immunity against the gastrointestinal parasitic nematode Trichuris muris. Accordingly, T cell-specific deletion of the TFF3 receptor, Lingo2, impairs TH2 cell commitment, allows proliferative expansion of IFNγ+CD4+ TH1 cells, and blocks normal worm expulsion through an IFNγ-dependent mechanism. This study indicates that TFF3, in addition to its known tissue reparative functions, drives anti-helminth immunity by controlling the balance between TH1/TH2 subsets. It may be possible that disruption of the TFF3/Lingo2 axis in CD4+ T cells partially underlies human inflammatory bowel diseases driven by excessive IFNγ and other pro-inflammatory cytokines.
Lingo2's Involvement in the Enteric Nervous System
Lingo proteins are highly expressed in neuronal tissue, we are exploring whether Lingo proteins are expressed in and function in the enteric nervous system