RTG 2408 - Maladaptive processes across physiological barriers in chronic diseases

Key goals of RTG 2408

Chronic diseases constitute a major health threat and pose an increasing burden on health systems. Central mechanistic aspects in chronic diseases are cellular maladaptation and misdirected cellular communication at physiological barriers. Highly specialized cells, such as endothelial or epithelial cells, define physiological barriers. Dysregulation and -function of these cellular barriers may result in a disease-promoting micromilieu. The latter is characterized by a specific secretome and the activation and maladaptation of local and inflammatory cells. Moreover, important to disease chronification is the perpetuation of the maladaptive process. Mechanistically, perpetuated disease processes depend on altered cellular signalling, resulting in molecular fixation of the disease process. Currently, our understanding of the molecular changes underlying maladaptation at physiological barriers and leading to chronic diseases is limited.

Within our RTG we aim to characterize disease-defining maladaptive processes at endothelial and epithelial barriers. In systematic approaches, we analyze gene expression, molecular signalling and molecular networks (e.g. NF-κB system) in endothelial and epithelial cells and their impact on barrier function.

The comparative studies of these two barrier-defining cell-types provide the opportunity to exchange ideas and to combine experimental tools (e.g. animal models, organoids, co-culture systems) and technical approaches (e.g. high resolution 3D-imaging, intravital 2-photon-microscopy, mass spectrometry), thus, generating an added value for the young researchers. Additionally, the involvement of medical students and clinicians generates an environment fostering translational research. Thus, we train young scientists in a highly relevant research area and by exposing them to timely methodology and state-of-the-art approaches our RTG prepares the young scientists for their independent research careers.


Maladaptive response at physiological barriers in chronic diseases. Pathologic stimuli (1) impair adaptive cellular processes (e.g. unfolded protein response, UPR, 2). These changes promote protein modifications and regulation of histones (3), transcription factors (4) and other regulators of key cellular functions (e.g. proteostasis, 5), perpetuating the maladaptive response. The resulting dysfunction of endothelial or epithelial cells at physiological barriers generates a disease promoting micromilieu (6), characterized by cellular dysfunction of barrier-defining cells (yellow to brown; dark colouring reflecting an altered cellular phenotype, 7) and recruited inflammatory (green, 8) cells. These changes may dispose to cellular dysplasia.


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Individual Projects of Cohort 2

 P1-2   Michael Naumann   USP48-dependent regulation of NF-κB and cell survival in the infected gastric mucosa
 P2-2   Dunja Bruder   Relevance of epigenetic changes in intestinal epithelial cells for per-turbation of inflammation and response to pathogens
 P4-2   Anne Dudeck   Characterization of the specific functional relevance of perivascular mast cells in skin inflammation
 P8-2   Peter Mertens   Determining the role of cold shock proteins on mitochondrial homeostasis and tubular cell phenotypes during cell stress
 P11-2   Verena Keitel-Anselmino   Bile acid receptors and their role for maladaptive processes in cholangiocytes and biliary diseases
 P12-2   Sascha Kahlfuß   Th2 cell-dependent effects on the airway epithelial barrier during chronic asthma
 P13-2   Dimitrios Mougiakakos   Endothelial cell-triggered metabolic maladaptation of CLL cells controls therapeutic resistance and immune escape
 P14-2   Dunja Bruder
Dimitrios Mougiakakos
  Interleukin-7 dependent infiltration of acute lymphoblastic leukemia across the testicular endothelial barrier
 P15-2   Michael Naumann   Exploitation of epithelial/endothelial microenvironment crosstalk
 Associated Projects
 AP10   Michael Naumann   Modes of Helicobacter pylori-induced NF-κB activity in the gastric mucosa
AP11   Verena Keitel-Anselmino   Characterization of the genotype underlying hereditary forms of intrahepatic cholestasis
Characterization of the genotype underlying hereditary forms of intrahepatic cholestasis Medical Doctor Projects
 MD5   Peter Mertens   Characterization of kidney organoids as a model system to analyze bacterial colonization
 MD6   Sascha Kahlfuß   Molecular interplay of Th2 cells and the airway epithelium on the transcriptome of alveolar type II cells during asthma
 MD7   Sascha Kahlfuß   Epigenetic perpetuation of chronic asthma in alveolar type II cells
 MD8   Michael Naumann   H. pylori-induced stress response signaling in the gastric mucosa
 MD9   Sascha Kahlfuß   Direct and indirect intercellular communication between alveolar epithelium type 2 cells and T cells during chronic exposure to house dust mite allergens
 MD10   Peter Mertens  

Excessive sodium chloride ingestion promotes immune cell infiltration and kidney fibrosis in aging mice

 Clinician Scientist Projects
 CS5   Verena Keitel-Anselmino   Characterisation of the cellular expression pattern of bile acid receptors in intrahepatic cholangiocellular carcinoma



Individual Projects of Cohort 1

 P1-1   Michael Naumann   Helicobacter pylori infection and gastric barrier function
 P2-1   Dunja Bruder   Impact of epigenetic imprinting on the perpetuation of intestinal inflammation and dysplasia
 P4-1   Anne Dudeck   Relevance of mast cells in maladaptation of the epidermal and endothelial barrier during chronic skin inflammation
 P5-1   Khurrum Shahzad   Maladaptive unfolded protein response (UPR) and senescence at the vascular barrier in diabetes mellitus
 P6-1   Rüdiger Braun-Dullaeus   Normoxic HIF stabilization at the vascular barrier in atherosclerosis
 P7-1   Berend Isermann   Maladaptive cross-talk at the glomerular filtration barrier
 P8-1   Peter Mertens  

DNA binding protein A is a key regulator of mitochondrial function that promotes renal ischemia/reperfusion injury

 P9-1   Berend Isermann
Michael Naumann
  TEM-1 as a novel regulator of renal and gastric barrier function
 P10-1   Borna Relja   Maladaptation of the hepatic barrier in alcohol-induced liver injury
 Associated Projects
 AP2   Michael Naumann   Role of STAMBPL1 in cell survival in gastric mucosa
 AP4   Berend Isermann   Role of platelets and transcription factor p45-NFE2 for renal barrier function in diabetic nephropathy
 AP5   Dunja Bruder   Insight into the regulation of innate immune responses in Streptococcus pneumoniae-induced COPD exacerbation
 AP6   Dunja Bruder   Effects of respiratory infections and microbial carriage on the induction and shape of allergic asthma
 AP7   Anne Dudeck   The role of Syndecan-4 in the development of Osteoarthritis
 Medical Doctor Projects
 MD1   Peter Mertens   Depletion of DbpA (DNA binding protein-A) affects the inflammatory response and outcome of experimental kidney diseases
 MD2   Anne Dudeck   The capacity of mast cells to translate skin inflammation into systemic effects
 MD3   Borna Relja   Role of A20 in lung barrier breakdown after trauma
 MD4   Anne Dudeck   Investigating the mode of mast cell-driven translation of local inflammation into systemic effects - impact mobilization or emergency myelopoiesis?
 Clinician Scientist Projects
 CS1   Berend Isermann   Uremia-induced microglial activation occurs via P-38-MAPK and Cathepsin C and mediates neuronal dysfunction via Il1β
 CS2   Rüdiger Braun-Dullaeus   The role of VAMP3-IKKg/NEMO interaction in inflammation of atherosclerosis
 CS3   Peter Mertens   The role of the cold shock protein YB-1 and its autoantibodies in the disease process of Alzheimer's disease
 Start-up Funding
 SF1   Shruthi Krishnan   SF1: Role of CD248 in mTORC1-mediated unfolded protein response (UPR) in diabetic kidney disease




Mechanisms of induction of classical NF-κB by H. pylori

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