DFG Research Unit FOR 721/2
Molecular Structure and Function of the Tight Junction
  Project 1   

Michael Fromm, Prof. Dr. ,   Salah Amasheh, Dr. 

Institute of Clinical Physiology, Campus Benjamin Franklin,
Charité, Freie Universität and Humboldt-Universität, Berlin

Characterization of tight junction proteins as barrier- or channel-formers

This project deals with the fundamental characterization of transmembranal tight junction proteins by means of molecular biological, iimunofluorescence confocal microscopical, freeze fracture electron microscopical, and last not least electrophysiological techniques. Depending on the suitability, overexpression and silencing methods are applied. In addition, tight junction proteins are analyzed regarding the paracellular permeation of water.

Aims are to investigate the barrier or channel properties for solutes and water of distinct tight juntion prteins. This includes to explore the mechanisms of size-dependent barrier properties of the tricellular tight junction, the meeting point of three cells.

A sub-project deals with the effect of therapeutics in inflammatory bowel diseases on barrier function and tight junction proteins of renal and intestinal cells. In cooperation with project 2 therapeutic effects of biopsy specimens from Crohn's disease and ulcerative colitis patients are investigated.

In endothelial cells, the effect of circulation and hypoxy on tight junction protein expression and signal transduction is investigated. Finally, potential absorption enhancers which temporarily open the paracellular pathway for solute passage in epithelial and endothelial tissues is studied.

Granted by project 1

Participation with project 1

Publications 2010 - present(FOR 721/2)
 

2015

  • Conrad MP*, Piontek J* (*shared first authorship), Günzel D, Fromm M, Krug SM (2016, online 2015) Molecular basis of claudin-17 anion selectivity. Cell. Mol. Life Sci. 73(1): 185-200 (°IF 5.8) [PubMed] [WebPage] [PDF] [Supplement] TP1+TP6+TP7+TPZ{FFEM}

2014

  • Bücker R, Schulz E, Günzel D, Bojarski C, Lee IM, John LJ, Wiegand S, Janßen T, Wieler LH, Dobrindt U, Beutin L, Ewers C, Fromm M, Siegmund B, Troeger H, Schulzke JD (2014) α-Haemolysin of Escherichia coli: a potentiator of inflammatory activity in the colon. Gut 63(12): 1893-1901 (IF 14.7) [PubMed] [WebPage] [PDF] [Supplements]

  • TP2+TP7+TP1
  • Dittmann I, Amasheh M, Krug SM, Markov AG, Fromm M, Amasheh S (2014) Laurate permeabilizes the paracellular pathway for small molecules in the intestinal epithelial cell model HT-29/B6 via opening the tight junctions by reversible relocation of claudin-5. Pharm. Res. 31(9): 2539–2548 {Erratum about Title misprint: Pharm. Res. 32(2): 737} (IF 3.4) [PubMed] [WebPage] [PDF] TP1+TP2+TPZ

  • Hering NA*, Richter JF* (*shared first authorship), Fromm A, Wieser A, Hartmann S, Günzel D, Bücker R, Fromm M, Schulzke JD° (°corresponding author), Troeger H (2014) TcpC protein from E. coli Nissle improves epithelial barrier function involving PKCζ and ERK1/2 signalling in HT-29/B6 cells. Mucosal Immunol. 7(2): 369-378 (IF 7.0) [PubMed] [WebPage] [PDF] TP2+TP1+TP7+TPZ{2PI}

    • Review

  • Krug SM, Schulzke JD, Fromm M (2014) Tight junction, selective permeability, and related diseases. Semin. Cell Devel. Biol. 36: 166-176 (IF 6.3) [PubMed] [WebPage] [PDF] TP1+TP2

    • Invited Editorial

  • Rosenthal R, Fromm M (2014) Significant water absorption goes paracellular in kidney proximal tubules. Am. J. Physiol. Renal Physiol. 306(1): F51-F52 (IF 3.3)  [PubMed] [WebPage] [PDF] TP1

2013

2012

2011

  • Bücker R, Krug SM, Rosenthal R, Günzel D, Fromm A, Zeitz M, Chakraborty T, Fromm M, Epple HJ, Schulzke JD (2011) Aerolysin from Aeromonas hydrophila perturbs tight junction integrity and cell lesion repair in intestinal epithelial HT-29/B6 cells. J. Infect. Dis. 204 (8): 1283-1292 [PubMed] [WebPage] [PDF] TP2+TP1+TP7+TPZ

  • Hering NA*, Andres S* (*shared first authorship), Fromm A, van Tol EA, Amasheh M, Mankertz J, Fromm M, Schulzke JD (2011) Transforming growth factor b, a whey protein component, strengthens the intestinal barrier by upregulating claudin-4 in HT-29/B6 cells. J. Nutr. 141(5): 783-789 [PubMed] [WebPage] [PDF] TP2+TP1

  • Hering NA, Richter JF, Krug SM, Günzel D, Fromm A, Bohn E, Rosenthal R, Bücker R, Fromm M, Troeger H, Schulzke JD (2011) Yersinia enterocolitica induces epithelial barrier dysfunction through regional tight junction changes in colonic HT-29/B6 cell monolayers. Lab. Invest. 91: 310-324 [PubMed] [WebPage] [PDF] [Supplement DOC] TP2+TP1+TP7

  • Markov AG, Voronkova MA, Volgin GN, Yablonsky PK, Fromm M, Amasheh S (2011) Tight junction proteins contribute to barrier properties in human pleura. Resp. Physiol. Neurobiol. 175(3): 331-335 [PubMed] [WebPage] [PDF] TP1

  • Nielsen HL, Nielsen H, Ejlertsen T, Engberg J, Günzel D, Zeitz M, Hering N, Fromm M, Schulzke JD, Bücker R (2011) Oral and fecal Campylobacter concisus strains perturb barrier function by apoptosis induction in HT-29/B6 intestinal epithelial cells. Plos One 6(8): e23858 (print pages 1-8) [PubMed] [WebPage] [PDF] TP2+TP7+TP1

  • Stumpff F, Georgi MI, Mundhenk L, Rabbani I, Fromm M, Martens H, Günzel D (2011) Sheep rumen and omasum primary cultures and source epithelia: Barrier function aligns with expression of tight junction proteins. J. Exp. Biol. 214: 2871-2882 [PubMed] [WebPage] [PDF] [Supplement] TP7+TP1

    • Reviews

  • Amasheh S, Fromm M, Günzel D (2011) Claudins of intestine and nephron - a correlation of molecular tight junction structure and barrier function. Acta Physiol. 201(1): 133-140 [PubMed] [WebPage] [PDF] (Review) TP1+TP7

  • John LJ, Fromm M, Schulzke JD (2011) Epithelial barriers in intestinal inflammation. Antioxid. Redox Signal. 15(5): 1255-1270 (IF 8.2) [PubMed] [WebPage] [PDF for printing] [PDF with links] (Review) TP2+TP1

2010

  • Amasheh M, Fromm A, Krug SM, Amasheh S, Andres S, Zeitz M, Fromm M, Schulzke JD (2010) TNFa-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, pAkt, and NFkB signaling. J. Cell Sci. 123(23): 4145-4155 [PubMed] [WebPage] [PDF] [Supplements]

  • Becker S*, Wandel E* (*shared first authorship), Wobus M, Schneider R, Amasheh S, Sittig D, Kerner C, Naumann R, Hamann J, Aust G (2010) Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions. Plos One 5(1): e8507 [PubMed] [WebPage] [PDF]

  • Bücker R, Schumann M, Amasheh S, Schulzke JD (2010) Claudins in intestinal function and disease. Curr. Top. Membr. 65: 195-227 [Directory] [WebPage] [PDF] (Review / book chapter)

  • Epple HJ, Allers K, Tröger H, Kühl A, Erben U, Fromm M, Zeitz M, Loddenkemper C*, Schulzke JD*, Schneider T* (*shared last authorship) (2010) Acute HIV infection induces mucosal infiltration with CD4+ and CD8+ T cells, epithelial apoptosis, and a mucosal barrier defect. Gastroenterology 139(4): 1289-1300 [PubMed] [WebPage] [PDF] [Supplement PDF]

  • Kirschner N, Houdek P, Fromm M, Moll I, Brandner JM (2010) Tight junctions form a barrier in human epidermis. Eur. J. Cell Biol. 89(11): 839-842 (IF 3.6) [PubMed] [WebPage] [PDF]

  • Markov AG*, Veshnyakova A* (*shared first authorship), Fromm M, Amasheh M, Amasheh S (2010) Segmental expression of claudin proteins correlates with tight junction barrier properties in rat intestine. J. Comp. Physiol. B 180(4): 591-598 [PubMed] [WebPage] [PDF]

  • Milatz S, Krug SM, Rosenthal R, Günzel D, Müller D, Schulzke JD, Amasheh S*, Fromm M* (*shared last authorship) (2010) Claudin-3 acts as a sealing component of the tight junction for ions of either charge and uncharged solutes. Biochim. Biophys. Acta Biomembr. 1798: 2048-2057 [PubMed] [WebPage] [PDF]

  • Rosenthal R, Milatz S, Krug SM, Oelrich B, Schulzke JD, Amasheh S, Günzel D, Fromm M (2010) Claudin-2, a component of the tight junction, forms a paracellular water channel.. J. Cell Sci. 123(11): 1913-1921 [PubMed] [WebPage] [PDF] [Supplement]

  • Westphal JK, Dörfel MJ, Krug SM, Cording JD, Piontek J, Blasig IE, Tauber R, Fromm M, Huber O (2010) Tricellulin forms homomeric and heteromeric tight junctional complexes. Cell. Mol. Life Sci. 67(12): 2057-2068 [PubMed] [WebPage] [Supplement] [PDF]

    • Reviews

  • Günzel D, Krug SM, Rosenthal R, Fromm M (2010) Biophysical methods to study tight junction permeability. Curr. Top. Membr. 65: 39-78 [Directory] [WebPage] [PDF] (Review / book chapter)

    • Award

  • Krug SM, Bojarski C, Fromm A, Schulzke JD, Fromm M (2010) The tight junction protein tricellulin in Crohn's disease and ulcerative colitis. Posterpreis der European Intestinal Transport Group (EITG), Salerno, Italy

 Publications 2007 - 2009 (FOR 721/1)

  • Amasheh M, Grotjohann I, Amasheh S, Fromm A, Söderholm JD, Zeitz M, Fromm M, Schulzke JD (2009) Regulation of mucosal structure and barrier function in rat colon exposed to tumor necrosis factor alpha and interferon gamma in vitro: A novel model for studying the pathomechanisms of inflammatory bowel disease cytokines. Scand. J. Gastroent. 44: 1226-1235 [PubMed] [WebPage] [PDF]

  • Amasheh S, Dullat S, Fromm M, Schulzke JD, Buhr HJ, Kroesen AJ (2009) Inflamed pouch mucosa possesses altered tight junctions indicating recurrence of inflammatory bowel disease. Int. J. Colorectal Dis. 24(10): 1149-1156 [PubMed] [WebPage] [PDF] 

  • Günzel D, Amasheh S, Pfaffenbach S, Richter JF, Kausalya PJ, Hunziker W, Fromm M (2009) Claudin-16 affects transcellular Cl- secretion in MDCK cells. J. Physiol. (Lond.) 587(15): 3777-3793 [PubMed] [WebPage] [PDF] [Supplement]

  • Krug SM, Amasheh S, Richter JF, Milatz S, Günzel D, Westphal JK, Huber O, Schulzke JD, Fromm M (2009) Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol. Biol. Cell 20: 3713-3724 [PubMed] [WebPage] [PDF] [Supplement text] [Supplement video]

  • Krug SM, Fromm M, Günzel D (2009) Two-path impedance spectroscopy for measuring paracellular and transcellular epithelial resistance. Biophys. J. 97(8): 2202-2211 [PubMed] [WebPage] [PDF] [Supplement]

  • Amasheh S*, Milatz S* (*shared first authorship), Krug SM, Bergs M, Amasheh M, Schulzke JD, Fromm M (2009, Epub 08.11.2008) Na+ absorption defends from paracellular back-leakage by claudin-8 upregulation. Biochem. Biophys. Res. Comm. 378(1): 45-50 [PubMed] [WebPage] [PDF]

  • Bücker R*, Troeger H* (*shared first authorship), Kleer J, Fromm M, Schulzke JD (2009) Arcobacter butzleri induces barrier dysfunction in intestinal epithelial cells. J. Infect. Dis. 200(5): 756-764 [PubMed] [WebPage] [PDF]

  • Günzel D, Stuiver M, Kausalya PJ, Haisch L, Krug SM, Rosenthal R, Meij IC, Hunziker W, Fromm M, Müller D (2009) Claudin-10 exists in six alternatively spliced isoforms which exhibit distinct localization and function. J. Cell Sci. 122: 1507-1517 [PubMed] [WebPage] [PDF]

  • Mankertz J*, Amasheh M* (*shared first authorship), Krug SM, Fromm A, Amasheh S, Hillenbrand B, Tavalali S, Fromm M, Schulzke JD (2009) TNFalpha up-regulates claudin-2 expression in epithelial HT-29/B6 cells via phosphatidylinositol-3-kinase signaling. Cell Tiss. Res. 336(1): 67-77 [PubMed] [WebPage] [PDF]

  • Troeger H, Loddenkemper C, Schneider T, Schreier E, Epple HJ, Zeitz M, Fromm M, Schulzke JD (2009) Structural and functional changes of the duodenum in human norovirus infection. Gut 58: 1070-1077 [PubMed] [WebPage] [PDF]

  • Yu ASL, Cheng MH, Angelow S, Günzel D, Kanzawa SA, Schneeberger EE, Fromm M, Coalson RD (2009) Molecular basis for cation selectivity in claudin-2-based paracellular pores: Identification of an electrostatic interaction site. J. Gen. Physiol. 133(1): 111-127 [PubMed] [WebPage] [PDF]

  • Amasheh M, Schlichter S, Amasheh S, Mankertz J, Zeitz M, Fromm M, Schulzke JD (2008) Quercetin enhances epithelial barrier function and increases claudin-4 expression in Caco-2 cells. J. Nutr. 138(6): 1067-1073 [PubMed] [WebPage] [PDF]

  • Epple HJ, Schneider T, Troeger H, Kunkel D, Allers K, Moos V, Amasheh M, Loddenkemper C, Fromm M, Zeitz M, Schulzke JD (2009, Epub 04.11.2008) Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients. Gut 58: 220-227 [PubMed] [WebPage] [PDF]

  • Kroesen AJ, Dullat S, Schulzke JD, Fromm M, Buhr HJ (2008) Permanently increased mucosal permeability in patients with backwashileitis after ileoanal pouch for ulcerative colitis. Scand. J. Gastroent. 43(6): 704-711 [PubMed] [WebPage] [PDF]

  • Schumann M, Richter JF, Wedell I, Moos V, Zimmermann-Kordmann M, Schneider T, Daum S, Zeitz M, Fromm M, Schulzke JD (2008) Mechanisms of epithelial translocation of the a2-gliadin-33mer in celiac sprue. Gut 57(6): 747-754 [PubMed] [WebPage] [PDF]

  • Will C, Fromm M, Müller D (2008) Claudin tight junction proteins: novel aspects in paracellular transport. Periton. Dialysis Int. 28(6): 577-584 [PubMed] [PDF]

  • Markov AG, Veshnyakova A, Krug SM, Milatz S (2007) Expression of tight junction proteins in the epithelium of small intestine of the rat. Russ. J. Physiol. (Ross. Fiziol. Zh. Im. I. M. Sechenova) 93(9): 1043-1054 [PubMed]

  • Troeger H, Epple HJ, Schneider T, Wahnschaffe U, Ullrich R, Burchard GD, Jelinek T, Zeitz M, Fromm M, Schulzke JD (2007) Effect of chronic Giardia lamblia infection on epithelial transport and barrier function in human duodenum. Gut 56(3): 328-335 [PubMed] [WebPage] [PDF]

  • Zeissig S, Bürgel N, Günzel D, Richter JF, Mankertz J, Wahnschaffe U, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD (2007) Changes in expression and distribution of claudin-2, -5 and -8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn's disease. Gut 56(1): 61-72 [PubMed] [WebPage] [PDF]

Ann. N.Y. Acad. Sci. 1165   [Contents and Full Papers]

  • Fromm M, Schulzke JD, Volume Editors (2009) Molecular structure and function of the tight junction. Ann. N.Y. Acad. Sci. 1165: pp 1-346 [Contents and Full Papers] [Cover]

  • Amasheh M, Andres S, Amasheh S, Fromm M, Schulzke JD (2009) Barrier effects of nutritional factors. Ann. N.Y. Acad. Sci. 1165: 267-273 [PubMed] [WebPage] [PDF]

  • Amasheh S, Milatz S, Krug SM, Markov AG, Günzel D, Amasheh M, Fromm M (2009) Tight junction proteins as channel formers and barrier builders: claudin-2, -5, and -8. Ann. N.Y. Acad. Sci. 1165: 211-219 [PubMed] [WebPage] [PDF]

  • Fromm M, Krug SM, Zeissig S, Richter JF, Rosenthal R, Schulzke JD, Günzel D (2009) High resolution analysis of barrier function. Ann. N.Y. Acad. Sci. 1165: 74-81 [PubMed] [WebPage] [PDF]

  • Günzel D, Haisch L, Pfaffenbach S, Krug SM, Milatz S, Amasheh S, Hunziker W, Müller D (2009) Claudin function in the thick ascending limb of Henle's loop. Ann. N.Y. Acad. Sci. 1165: 152-162 [PubMed] [WebPage] [PDF]

  • Schulzke JD, Fromm M (2009) Tight junctions: Molecular structure meets function. Ann. N.Y. Acad. Sci. 1165: 1-6 [PubMed] [WebPage] [PDF]

  • Schulzke JD*, Ploeger S* (*shared first authorship), Amasheh M, Fromm A, Zeissig S, Troeger H, Richter JF, Bojarski C, Schumann M, Fromm M (2009) Epithelial tight junctions in intestinal inflammation. Ann. N.Y. Acad. Sci. 1165: 294-300 [PubMed] [WebPage] [PDF]

Doctoral thesis

  • Krug SM (2009) Tricellulin and its function in the tricellular tight junction of epithelial cells. Biochemistry, Freie Universitaet Berlin. Dr. rer. nat., summa cum laude

Previous work

  • Amasheh S, Meiri N, Gitter AH, Schöneberg T, Mankertz J, Schulzke JD, Fromm M (2002) Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J. Cell Sci. 15(24): 4969-4976 [PubMed] [WebPage] [PDF]

  • Amasheh S, Barmeyer C, Koch CS, Tavalali S, Mankertz J, Epple HJ, Gehring MM, Florian P, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD (2004) Cytokine-dependent transcriptional down-regulation of epithelial sodium channel (ENaC) in ulcerative colitis. Gastroenterology 126: 1711-1720 [PubMed] [WebPage] [PDF]

  • Amasheh S, Schmidt T, Mahn M, Florian P, Mankertz J, Tavalali S, Gitter AH, Schulzke JD, Fromm M (2005) Contribution of claudin-5 to barrier properties in tight junctions of epithelial cells. Cell Tiss. Res. 321(1): 89-96  [PubMed] [WebPage] [PDF]

  • Bürgel N, Bojarski C, Mankertz J, Zeitz M, Fromm M, Schulzke JD (2002) Mechanisms of diarrhea in collagenous colitis. Gastroenterology 123(2): 433-443 [PubMed] [WebPage] [PDF]

  • Gitter AH, Bendfeldt K, Schulzke JD, Fromm M (2000) Leaks in the epithelial barrier caused by spontaneous and TNFa-induced single-cell apoptosis. FASEB J. 14: 1749-1753  [PubMed] [WebPage] [PDF]

  • Günzel D*, Florian P* (*shared first authorship), Richter JF, Troeger H, Schulzke JD, Fromm M, Gitter AH (2006) Restitution of single-cell defects in the mouse colon epithelium differs from that of cultured cells. Am. J. Physiol. - Reg. Integ. Comp. Physiol. [Supplemental videos] 290: R1496-R1507.

  • Kausalya PJ*, Amasheh S* (*shared first authorship), Günzel D, Wurps H, Müller D, Fromm M, Hunziker W (2006) Disease-associated mutations affect intracellular traffic and paracellular Mg2+ transport function of claudin-16. J. Clin. Invest. 116(4): 878-891.

  • Saitou M, Furuse M, Sasaki H, Schulzke JD, Fromm M, Takano H, Noda T, Tsukita S (2000). Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell 11: 4131-4142.

  • Schmitz H, Fromm M, Bentzel CJ, Scholz P, Bode H, Epple HJ, Riecken EO, Schulzke JD (1999) Tumor necrosis factor-alpha (TNFa) regulates the epithelial barrier in the human intestinal cell line HT-29/B6. J. Cell Sci. 112: 137-146.

  • Schmitz H, Barmeyer C, Fromm M, Runkel N, Foss HD, Bentzel CJ, Riecken EO, Schulzke JD (1999) Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology 116: 301-309.

  • Schulzke JD, Gitter AH, Mankertz J, Spiegel S, Seidler U, Amasheh S, Saitou M, Tsukita S, Fromm M (2005) Epithelial transport and barrier function in occludin-deficient mice. Biochim. Biophys. Acta - Biomembranes 1669(1): 34-42.

  • Welsh MJ, Smith PL, Fromm M, Frizzell RA (1982) Crypts are the site of intestinal fluid and electrolyte secretion. Science 218: 1219-1221.