Inflammatory bowel diseases are characterized by intestinal inflammation, increased mucosal cytokines and compromised epithelial barrier function. Epithelial barrier function is regulated by a series of intercellular junctions that encompass the tight junction (TJ), adherens junction (AJ) and desmosomes (DMs). It is now evident that intercellular junctions are highly dynamic structures and their component proteins actively participate in regulating epithelial homeostasis. Mucosal inflammation perturbs intercellular junctions and epithelial homeostatic properties thereby resulting in epithelial barrier compromise. Our knowledge of the molecular basis of intercellular junction protein cross-talk, epithelial homeostasis and compromised epithelial barrier in intestinal inflammation is however very limited. Thus the overall goals of this proposal are to identify mechanisms by which intercellular junction proteins control epithelial homeostasis and barrier function and determine the influence of inflammation on epithelial barrier compromise. We will specifically examine the role of DM cadherins and TJ claudin proteins in regulating the intestinal epithelial barrier. The influence of pro- inflammatory cytokines, IFNg and TNFa on such regulatory processes will be determined. In addition to gaining insights into the molecular basis of intestinal epithelial barrier regulation, these studies will provide new ideas for the development of therapeutic agents that promote the intestinal epithelial barrier function and reduce mucosal inflammation. These studies will also provide insight into strategies of transiently perturbing the epithelial barrier for therapeutic drug/vaccine delivery and cancer therapy.
The epithelial lining of the gastrointestinal tract forms a regulated selective-permeable barrier permitting the uptake of luminal nutrients while restricting pathogen and toxin access to underlying tissue compartments. Intercellular junctions play a pivotal role in this barrier regulation. This proposal seeks to identify the molecular basis by which intercellular junction proteins control barrier function in health and disease. These studies will not only advance our understanding of barrier regulation, but will aid in the development of therapeutic agents that promote barrier function and reduce inflammation or on the converse increase permeability for drug/vaccine delivery.
|Monteiro, Ana C; Luissint, Anny-Claude; Sumagin, Ronen et al. (2014) Trans-dimerization of JAM-A regulates Rap2 and is mediated by a domain that is distinct from the cis-dimerization interface. Mol Biol Cell 25:1574-85|
|Capaldo, Christopher T; Farkas, Attila E; Hilgarth, Roland S et al. (2014) Proinflammatory cytokine-induced tight junction remodeling through dynamic self-assembly of claudins. Mol Biol Cell 25:2710-9|
|Neumann, Philipp-Alexander; Koch, Stefan; Hilgarth, Roland S et al. (2014) Gut commensal bacteria and regional Wnt gene expression in the proximal versus distal colon. Am J Pathol 184:592-9|
|Kamekura, R; Kolegraff, K N; Nava, P et al. (2014) Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling. Oncogene 33:4531-6|
|Jiang, Kun; Rankin, Carl R; Nava, Porfirio et al. (2014) Galectin-3 regulates desmoglein-2 and intestinal epithelial intercellular adhesion. J Biol Chem 289:10510-7|
|Laury, Adrienne M; Hilgarth, Roland; Nusrat, Asma et al. (2014) Periostin and receptor activator of nuclear factor ?-B ligand expression in allergic fungal rhinosinusitis. Int Forum Allergy Rhinol 4:716-24|
|Wise, Sarah K; Laury, Adrienne M; Katz, Elizabeth H et al. (2014) Interleukin-4 and interleukin-13 compromise the sinonasal epithelial barrier and perturb intercellular junction protein expression. Int Forum Allergy Rhinol 4:361-70|
|Nava, Porfirio; Kamekura, Ryuta; Quirós, Miguel et al. (2014) IFN?-induced suppression of ?-catenin signaling: evidence for roles of Akt and 14.3.3?. Mol Biol Cell 25:2894-904|
|Luissint, Anny-Claude; Nusrat, Asma; Parkos, Charles A (2014) JAM-related proteins in mucosal homeostasis and inflammation. Semin Immunopathol 36:211-26|
|Rahman, Khalidur; Sasaki, Maiko; Nusrat, Asma et al. (2014) Crohn's disease-associated Escherichia coli survive in macrophages by suppressing NF?B signaling. Inflamm Bowel Dis 20:1419-25|
Showing the most recent 10 out of 73 publications