Regulation of colonic stem cell proliferation: A novel role for redox signaling

Dysregulation of colon epithelial barrier integrity can lead to inflammatory bowel disease (IBD) including ulcerative colitis and Crohn´s disease.

Redox biology and reactive oxygen species (ROS) play an important role in maintaining colonic barrier function, with ROS predominantly thought to protect against bacterial invasion. NADPH oxidase 1 (NOX1), a ROS producer with no other known function is uniquely expressed in the colon.

NOX1 is important to colon health exemplified by reduced mucosal wound healing in NOX1-/- mice and the association of NOX1 loss-of-function SNPs with the development of very early onset IBD.

However, it remains unclear exactly how NOX1-derived ROS contribute to colon health since NOX1-derived ROS are too low to be directly bactericidal.

My research finds that NOX1 is a novel and specific marker of proliferating colon stem cells and participates in the quiescent-proliferative transition via NOX1-derived ROS activated EGFR signaling to potentiated proliferation.

Important questions remain that are the focus of this proposal. "How does NOX1-derived ROS activate EGFR-dependent signaling?, "Why is NOX1 highly and uniquely expressed in proliferating colonic stem cells?, "Do very early onset IBD associated NOX1 mutations lead to disease via stem cell dysfunction?.

Combined the results from the proposed experiments will contribute to a more complete understanding of how of redox signaling effects stem cell proliferation in the colon in health and disease.