RNase L, an interferon-inducible enzyme, is highly expressed in the intestine and intestinal epithelial cells. However, its roles in intestinal epithelial cells are largely unknown. In this project, we hypothesize that RNase L regulates the expression of proinflammatory genes, mediates the inflammatory responses and apoptosis in epithelial cells of intestinal mucosal surface. Lack of RNase L attenuates inflammatory bowel diseases (IBD). This hypothesis is mainly based on the evidence that RNase L is a regulator of the expression of certain proinflammatory genes such as tumor necrosis factor-alpha (TNF-alpha), IFN-gamma inducible protein-10 (IP-10) and cycloxygenase-2 (Cox-2), and plays an important role in cell apoptosis. Our long-term goal is to elucidate the role of RNase L in the pathogenesis of IBD as a necessary prerequisite to the development of therapeutic methods capable of attenuating the disease process.
Two specific aims are proposed to test our hypothesis. In the first specific aim, the role of RNase L in intestinal inflammatory responses and epithelial cell apoptosis will be assessed, and the contribution of RNase L to the pathogenesis of IBD will be determined by using RNase L null mice. In the second specific aim, the molecular mechanism by which RNase L regulates the expression of TNF-alpha will be elucidated. Studies proposed to understand the role of RNase L in inflammation and apoptosis of intestinal epithelial cells, as well as the mechanisms involved will not only provide new insight into the etiology of IBD, but also critically evaluate the significance of RNaseL as a novel target for prevention and/or treatment of IBD.
The objectives in the proposed study are to determine the role of RNase L in the pathogenesis of inflammatory bowel disease and elucidate the molecular mechanism by which RNase L mediates the expression of inflammatory genes.
|Malathi, Krishnamurthy; Siddiqui, Mohammad Adnan; Dayal, Shubham et al. (2014) RNase L interacts with Filamin A to regulate actin dynamics and barrier function for viral entry. MBio 5:e02012|
|Zeng, Chun; Yi, Xin; Zipris, Danny et al. (2014) RNase L contributes to experimentally induced type 1 diabetes onset in mice. J Endocrinol 223:277-87|
|Yi, Xin; Zeng, Chun; Liu, Hongli et al. (2013) Lack of RNase L attenuates macrophage functions. PLoS One 8:e81269|