Atypical PKC (aPKC): A Novel Therapeutic Target for Treatment of Inflammatory Bowel Disease

Nova Southeastern University, Davie, Florida, USA

Objective. The goal of our research is to unravel the pathophysiological mechanisms that underlie the development of Inflammatory Bowel Disease (IBD). Background. It is widely accepted that the loss of integrity of intestinal barrier is the major factor that perpetuates the disease, facilitating the diffusion of pro-inflammatory molecules into the body’s fluids. We study the cellular signaling proteins that set and control the permeability of the intestinal epithelium, in particular the atypical protein kinase C (aPKC). Our previous results have confirmed an essential anti-inflammatory role of this molecule. The normal expression of aPKC is destabilized under pro-inflammatory conditions, as indicated by decrease of aPKC in biopsy samples from IBD patients. We have shown before that reduction of aPKC levels observed in inflamed intestine is mediated by a member of Bag1 protein family Bag-1M. Our central hypothesis is that inhibition of Bag-1M interaction with intermediate filaments-based Hsp70 chaperoning machinery will restore physiological levels of aPKC. Methods. We have developed a decoy synthetic N-terminal Bag-1M domain peptide (K-Bag peptide), which interferes with Bag-1M binding to intermediate filaments. We have administered this peptide to the cultured intestinal epithelial cells to test its effect on aPKC expression. Results. The data we acquired demonstrate that Bag1-M inhibition results in reduction of expression of pro-inflammatory cytokines and restores the normal levels of aPKC. Conclusion. Bag1-M inhibition has a potential to reduce intestinal inflammation and is indeed the promising starting point to design a novel pharmacological intervention. Grants. This work is supported by PFRDG awarded to AM.