DFG Research Training Group "TJ-Train" (GRK 2318)
Tight junctions and their proteins
Molecular features and actions in health and disease
& Prof. Dr.
Med. Klinik m.S.
Gastroenterologie, Infektiologie & Rheumatologie,
Campus Benjamin Franklin,
Charité - Universitätsmedizin Berlin
Epithelial dyspolarity in chronic intestinal
It is well established that
polarity processes in epithelial cells are central to the barrier function
these cells impose. A set of polarity complex proteins regulates the
molecular composition of the apical junctional complex that includes the
tight junction (TJ) and the adherens junction. We and others have shown that
inflammatory conditions induce dyspolarities in intestinal epithelia that
might precede the emergence of barrier defects. Mucosal barrier defects are
central to the development of inflammatory bowel diseases (IBD), as Crohn´s
disease (CD) or ulcerative colitis. Thus, we ask for the role of polarity
regulation in IBD.
will be the action of interleukin-22 (IL-22), a TH17 cytokine being central
in the immune reaction leading to CD and with its receptor being expressed
on epithelia. Preliminary data reveal a strong activity of IL-22 in
regulation of epithelial polarity but also in colitis-associated
We hypothesize that
IBD-associated mucosal inflammation can cause polarity defects of intestinal
epithelia. Thus, we are going to examine polarity complex in IBD and will
associate this with determining paracellular permeability. Moreover, we
hypothesize that certain cytokines are responsible for this polarity
phenotype by inducing a mis-trafficking of certain polarity proteins.
Candidates from preliminary experiments are Par-3, Dlg1 and Crb-3.
Central techniques of this
project will include standard molecular biology and cell biology techniques
(i.e. immunostaining, confocal microscopy, Western blotting) as well as
physiological techniques to characterize barrier function (using Ussing
chambers, i.e. impedance spectroscopy, flux measurements). The newly
developed sandwich assay will be used to spatially correlate polarity
defects and barrier leaks. Trafficking and expression of polarity proteins
(Pard3, Dlg1, Crb3, PIP-binding moieties) will be analyzed by
live-cell-confocal microscopy using a 3D-cyst model of intestinal Caco-2
cells expressing fluorescently-tagged polarity proteins.
In summary, our specific
thesis projects for two doctoral students (1 PhD and 1 MD) are:
(i) Examine establishment and
loss of epithelial polarity in Crohn´s disease and ulcerative colitis by
combining a cell culture-based approach and ex vivo experiments using human
mucosal tissue samples.
Uncovering mechanisms leading to defective intracellular trafficking in
polarity proteins as Par-3 in intestinal epithelial cells under conditions
PhD doctoral student
MD doctoral student
Note to TJ-Train students: If a paper is not accessible, please mail to
Krug SM, Siegmund B, Neurath MF, Becker C (2017)
Mend your fences: The epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease.
Cell. Mol. Gastroent. Hepatol.
4(1): 33-46 [PubMed] [WebPage]
JF, Schmauder R, Krug SM, Gebert A, Schumann M (2016) A novel
method for imaging sites of paracellular passage of macromolecules in
epithelial sheets. J.
Control Release 229: 70-79 [PubMed]
Inflamm. Bowel Dis.
21: 1297-1305 [PubMed]
Lissner D, Schumann M, Batra A, Kredel LI, Kühl AA, Erben U, May C,
Schulzke JD, Siegmund B (2015) Monocyte and M1 macrophage-induced barrier defect
contributes to chronic intestinal inflammation in IBD.
Kredel LI, Batra A, Stroh T, Kühl AA, Zeitz M, Erben U,
Siegmund B (2013)
Adipokines from local fat cells shape the macrophage compartment of the creeping
fat in Crohn’s disease.
Batra A, Heimesaat MM, Bereswill S, Fischer A, Glauben R, Kunkel D,
Scheffold A, Erben U, Kühl A, Loddenkemper C, Lehr HA, Schumann M, Schulzke JD,
Zeitz M, Siegmund B (2012) Mesenteric fat-control site for bacterial
translocation in colitis?
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 coeliac disease.
protein mediates regulatory T cell development via induction of the Foxp3
Schuster M, Glauben R, Plaza-Sirvent C, Schreiber L, Annemann M, Floess S,
Kühl AA, Clayton LK, Sparwasser T, Schulze-Osthoff K, Pfeffer K, Huehn J, Siegmund B, Schmitz I (2012)
Gerling M, Glauben R, Habermann JK, Kühl AA, Loddenkemper C, Lehr HA,
Zeitz M, Siegmund B (2011) Characterization of chromosomal instability in
murine colitis-associated colorectal cancer.
Glauben R, Batra A, Stroh T, Erben U, Fedke I, Lehr HA, Leoni F, Mascagni
P, Dinarello CA, Zeitz M, Siegmund B (2008) Histone deacetylases: novel targets
for prevention of colitis-associated cancer in mice.
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 alpha(2)-gliadin-33mer in coeliac sprue.
Stroh T, Batra A, Glauben R, Fedke I, Erben U, Kroesen A, Heimesaat MM,
Bereswill S, Girardin S, Zeitz M, Siegmund B (2008) Nucleotide oligonerization
domains 1 and 2: regulation of expression and function in preadipocytes.
Batra A, Pietsch J, Fedke I, Glauben R, Okur B, Stroh T, Zeitz M,
B (2007) Leptin-dependent toll-like receptor expression and responsiveness in
preadipocytes and adipocytes.
Siegmund B, Sennello JA, Jones-Carson J, Gamboni-Robertson F, Lehr HA,
Batra A, Fedke I, Zeitz M, Fantuzzi G (2004) Leptin receptor expression on T
lymphocyte modulates chronic intestinal inflammation in mice.
Siegmund B, Lehr HA, Fantuzzi G (2002) Leptin: a pivotal mediator of
intestinal inflammation in mice.