DFG Research Training Group "TJ-Train" (GRK 2318)
Tight junctions and their proteins
Molecular features and actions in health and disease
Hypotheses and Aims: Bacterial toxins can either directly
permeabilize tight junctions e.g. by cleavage of tight junction proteins or (much more common) can induce signaling in
epithelial cells which dysregulates tight junctions. Signaling can be via Ca2+ influx
through pores formed by toxins or receptor activation and results in tight junction disassembly (often via endocytosis
of tight junction proteins). Depending on the respective tight junction alterations either bacterial translocation,
leak flux diarrhea as the result of barrier changes against ions and water or inflammatory responses due to increased
antigen uptake are the consequences.
Methods: The working plan is to
perform infection experiments in cell and animal models including co-cultures of epithelial (HT-29/B6) and immune
cells (M1-macrophages) for characterizing signaling mechanisms and functionality. The panel of methods includes
electrophysiological measurements, morphological studies as EM and confocal laser scanning microscopy, and molecular
techniques like immunoblotting with densitometry and mRNAseq for expression analysis with subsequent Upstream
Regulator Analysis for signaling events.
Work plan: For a toxin of a
food-borne pathogen with barrier effects and induction of chronic inflammation which is also discussed in the context
of IBD permission, the signaling pathways leading to tight junction alterations, the contribution of immune cells and
the functional consequences of the toxin exposure to the intestinal barrier will be investigated. Pro-inflammatory
functionality is investigated using an inflammation mouse model, the IL-10-/- mouse, under the influence of
the toxin produced by inoculating wild type bacteria in comparison to a toxin-negative mutant strain. Cell and animal
model results will be confirmed in a small number of biopsies from infected patients and/or normal colon biopsies
exposed to the bacterium.
PhD doctoral student
Note to TJ-Train students: If a paper is not accessible, please mail to
Escherichia coli: a potentiator of inflammatory
activity in the colon. Gut
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
Schumann M, Günzel D, Buergel N, Richter JF,
Troeger H, May C, Fromm A,
Sorgenfrei D, Daum S, Bojarski C, Heyman M, Zeitz M, Fromm M, Schulzke JD (2012)
Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial
tight junction defects in celiac disease.
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. Cell Sci.
Amasheh M, Fromm A, Krug SM, Amasheh S, Andres S, Zeitz M, Fromm M,
Schulzke JD (2010) TNFalpha-induced and berberine-antagonized tight junction barrier
impairment via tyrosine kinase, pAkt, and NFkB signaling.
J. Infect. Dis.
Bücker R*, Troeger H* (*shared first authorship), Kleer J, Fromm M,
Schulzke JD (2009) Arcobacter butzleri induces barrier dysfunction in intestinal
Epple HJ, Schneider T, Troeger H, Kunkel D, Allers K, Moos V, Amasheh M,
Loddenkemper C, Fromm M, Zeitz M, Schulzke JD (2009) Impairment of the
intestinal barrier is evident in untreated but absent in suppressively treated
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.
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.
alpha-hemolysin induces focal leaks in colonic epithelium
– a novel mechanism of
bacterial translocation. Cell.
Troeger H*, Richter JF* (*shared first authorship), Beutin L, Günzel D,
Dobrindt U, Epple HJ, Gitter AH, Zeitz M, Fromm M, Schulzke JD (2007)
Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD (2001). Celiac
disease-like abnormalities in a subgroup of patients with irritable bowel