Porfirio Nava, PhD
|Versión en Español|
MY LABORATORY IS INTERESTED IN UNDERSTANDING THE REGULATION OF INTESTINAL HOMEOSTASIS AND INTESTINAL EPITHELIAL BARRIER DURING INFLAMMATORY BOWEL DISEASE (IBD).
Epithelial cells lining the intestinal tract function as a selective barrier that regulates nutrient uptake. In addition, the epithelial barrier protects underlying tissue compartments from pathogens and toxins in the lumen of the intestine. The intestinal epithelium is highly dynamic and actively turned over. Regulated intestinal stem cell proliferation and differentiation are required for normal intestinal homeostasis and repair after injury. Many gastrointestinal diseases including IBD are characterized by unbalanced proliferation and differentiation of intestinal epithelial cells. In fact, accumulating evidence implicates the maintenance of intestinal homeostasis as a fundamental regulator of intestinal protein expression and epithelial barrier regulation. Patients with IBD clinically present with relapsing diarrhea that has been attributed in part to aberrant epithelial barrier function, the epithelial leaks appear early due to micro-erosions resulting from upregulated epithelial apoptosis (homeostasis disruption) and changes in protein expression (epithelial barrier dysregulation). Thus, for example, increased paracellular permeability across epithelial cells has been observed in IBD patients. In addition, enhanced paracellular permeability across intestinal epithelium has also been observed in a proportion of first-degree relatives of patients with Crohn’s disease. In animal models a link between epithelial barrier dysfunction and development of colitis has been proposed. The increased paracellular permeability in turn enhances antigenic exposure of underlying immune cells thereby further compromising epithelial barrier function. It is now evident that impaired epithelial barrier function is an important underlying pathophysiologic event in IBD.
Intercellular junctions in epithelial cells are important in the formation of a functional epithelial barrier. The polarity and stability of the intestinal epithelium is established by the formation of distinct intercellular junctions that include Tight Junctions (TJs), Adherens Junctions (AJs), and Desmosomes (DMs). Permeability changes have, in turn, been attributed to defective intercellular junction function. Therefore the studies carried out in my lab are aimed to understand the regulation of the different components of the cell junctions in the pathobiology to mucosal inflammation. An improved understanding of proteins that contribute to establishment of the intestinal epithelial barrier will allow us to identify additional components in the barrier that could contribute to the intestinal epithelial barrier defect observed in IBD.
Selected peer-reviewed publications (in chronological order):
- Desmoglein-2: A Novel Regulator of Apoptosis in the Intestinal Epithelium. Nava P, Laukoetter MG, Hopkins AM, Laur O, Gerner-Smidt K, Green KJ, Parkos CA, Nusrat A. Mol Biol Cell. 2007Nov;18(11):4565-78.
- JAM-A regulates permeability and inflammation in the intestine in vivo. Laukoetter MG, Nava P, Lee WY, Severson EA, Capaldo CT, Babbin BA, Williams IR, Koval M, Peatman E, Campbell JA, Dermody TS, Nusrat A, Parkos CA. J Exp Med. 2007 Dec 24;204(13):3067-76. Equal contribution.
- Formyl peptide receptor-1 activation enhances intestinal epithelial cell restitution through phosphatidylinositol 3-kinase-dependent activation of Rac1 and Cdc42. Babbin BA, Jesaitis AJ, Ivanov AI, Kelly D, Laukoetter M, Nava P, Parkos CA, Nusrat A. J Immunol. 2007 Dec 15;179(12):8112-21.
- Annexin A1 regulates intestinal mucosal injury, inflammation, and repair. Babbin BA, Laukoetter MG, Nava P, Koch S, Lee WY, Capaldo CT, Peatman E, Severson EA, Flower RJ, Perretti M, Parkos CA, Nusrat A. J Immunol. 2008 Oct 1;181(7):5035-44.
- IFN-gamma regulates intestinal epithelial homeostasis through converging Beta-catenin signaling pathways. Nava P, Koch S, Laukoetter MG, Lee WY, Kolegraff K, Capaldo CT, Beeman N, Addis C, Gerner-Smidt K, Neumaier I, Skerra A, Li L, Parkos CA, and Nusrat A. Immunity. 2010 Mar 26;32(3):392-402. Equal contribution.
- Junctional Adhesion Molecule Regulates epithelial proliferation through AKT/beta-catenin signaling. Nava P, Capaldo CT, Koch S, Addis C, Kolegraff K, Li L, Parkos CA, and Nusrat A. Embo reports. EMBO Rep. 2011 Apr;12(4):314-20. Equal contribution.
- The tumor suppressor Desmocollin-2 Regulates epithelial proliferation through PTEN/AKT signaling pathway. Kolegraff K, Nava P, Lin M, Parkos CA, and Nusrat A. 2011 Apr 15;22(8):1121-34. Equal contribution.
- The Wnt antagonist Dkk1 regulates intestinal epithelial homeostasis and wound repair. Koch S, Nava P, Addis C, Kim W, Denning TL, Li L, Parkos CA, and Nusrat A. Gastroenterology. 2011 Jul;141(1):259-68, 268.
- Characterization of full-length and proteolytic cleavage fragments of desmoglein-2 in native human colon and colonic epithelial cell lines. Kolegraff K, Nava P, Laur O, Parkos CA, and Nusrat A. Cell Adh Migr. 2011 Jul 1;5(4):306-14. Equal contribution. Journal cover.
- IFN-γ and TNF-α-induced GBP-1 inhibits epithelial cell proliferation through suppression of β-catenin/TCF signaling. Capaldo CT, Beeman N, Hilgarth RS, Nava P, Louis NA, Naschberger E, Stürzl M, Parkos CA, Nusrat A. Mucosal Immunol. 2012 Jun 13. doi: 10.1038/mi.2012.41. In Press. Journal cover.
- Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis. Khounlotham M, Kim W, Peatman E, Nava P, Medina-Contreras O, Addis C, Koch S, Fournier B, Nusrat A, Denning TL, Parkos CA. Immunity. 2012 Sep 21;37(3):563-73.
- Tight Junction Proteins. (2003). González-Mariscal, L., Betanzos, A., Nava, P. and Jaramillo, B. E. Progress in Biophysics and Molecular Biology. 81; 1-44.
- Commentary. Tight junctions, from tight intercellular seals to sophisticated protein complexes involved in drug delivery, pathogens interaction and cell proliferation. González-Mariscal, L. and Nava, P. Advanced Drug delivery Reviews. 2005 Apr 25;57(6):811-4. Review.
- Critical Role of Tight Junctions in Drug Delivery across Epithelial and Endothelial Cell Layers. Gonzalez-Mariscal, L. Nava, P and Hernandez, S. J. Membr. Biol. 2005 Sept: 207(2):55-68.
- Role of the intestinal barrier in inflammatory bowel disease. Laukoetter MG, Nava P, Nusrat A. World J Gastroenterol. 2008 Jan 21;14(3):401-7.
- Kolegraff, K., Nava, P. and Nusrat, A. (2011) Specialized Intercellular Junctions in Epithelial Cells: The Tight Junction and Desmosome, in Cellular Domains (ed I. R. Nabi), John Wiley & Sons, Inc., Hoboken, NJ, USA doi: 10.1002/9781118015759.ch19.
Review articles / Book Chapters (in chronological order):
Departamento de Fisiología Biofísica y Neurociencias
Centro de Investigación y Estudios Avanzados del IPN,
Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, Del. GAM C.P. 07360 México D.F.
Teléfono 5747 3800(Oficina 3361 Lab. 5172), Fax 5747 3754