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Klinik für Dermatologie und VenerologieHautklinik

Research

Center for Excellence "Fragile Skin"

Director:
Prof. Dr. Dr. h.c. Leena Bruckner-Tuderman, MD
E-mail: leena.bruckner-tuderman@uniklinik-freiburg.de
Phone: +49 (0)761 270-67160

Clinical Investigators:
Prof. Dr. Cristina Has, MD
Dr. Dr. Johannes Kern, MD, PhD
PD Dr. Dimitra Kiritsi, MD
Dr. Hauke Schumann, MD (external collaboration partner)

The Center of Excellence “Fragile Skin” combines clinical patient care, molecular diagnostics and experimental research. The term “Fragile Skin” was coined for disorders of the skin and mucous membranes, which manifest with blister formation, easy bruisability or tearing, slow or disturbed wound healing, and reduced resistance against external mechanical forces. The Center is hosted by the Department of Dermatology, Medical Center - University of Freiburg. Its functions are based on intensive interactions of research and clinical medicine and encompass the following:

  • high standards in interdisciplinary medical care and nursing 
  • modern molecular diagnostics of skin fragility disorders 
  • internationally competitive experimental research 
  • development of novel molecular and cellular therapeutic strategies.

The lab members are an international group comming from Germany, Finland, France, Greece, Romania, Sweden, China, India, Gabon and Sudan. The center participates in several international networks for basic and clinical research. Below, the different areas of research in the center are introduced:

    

Molecular basis of skin fragility and mechanisms of genetic skin fragility associated with anomalies of proteins of focal adhesions

Prof. Dr. Cristina Has, MD
E-mail: cristina.has@uniklinik-freiburg.de
Phone: +49 (0)761 270-67850

Dr. Yinghong He, MD
Awardee of the Else Kröner-Fresenius-Stiftung
E-mail: yinghong.he@uniklinik-freiburg.de
Phone:+49 (0)761 270-67210 

Our group was involved in the identification of new genes for genetic skin fragility disorders - the Kindler syndrome, the acantholytic epidermolysis bullosa and junctional epidermolysis bullosa with renal and respiratory involvement. We have characterized large cohorts of patients with different types of epidermolysis bullosa, established genotype-phenotype correlations and explored the underlying disease mechanisms. In particular, we aim to understand the molecular mechanisms of disorders due to genetic defects of proteins associated with focal adhesions, kindlin-1 and the integrin a3 subunit, and the interactions between kindlins in the skin.

Former members: Dr. Anja Heinemann, PhD; Dr. Corinna Herz, PhD; Dr. Johannes S. Kern, MD, PhD; Dr. Dimitra Kiritsi, MD; Dr. Kristin Maier; Dr. Chiara Pazzagli, PhD; Dr. Manuela Pigors, PhD; Dr. Elena Zimina PhD

    

Somatic mosaicism in skin fragility disorders: mechanisms and therapeutic perspectives

PD Dr. Dimitra Kiritsi, MD
E-mail: dimitra.kiritsi@uniklinik-freiburg.de
Phone: +49 (0)761 270-67100

Dr. Kiritsi works as a physician scientist both in the clinical patient care and in the laboratory. Her work focuses on a special form of mosaicism, so called revertant mosaicism or “natural gene therapy” in genetic skin diseases. The group has described the presence of segmental mosaicism and characterized the underlying molecular mechanisms in patients with keratinization and skin fragility disorders, especially different subtypes of epidermolysis bullosa (EB). Since the skin in the mosaic areas has spontaneously converted to normal, cells from these areas may have therapeutic potential. To this end, the group cultivates and characterizes revertant cells with the objective of developing of cell-based therapies for EB patients using spontaneously-corrected, patient-own cells.

In addition, Dr. Kiritsi is involved in the identification of novel genetic skin fragility disorders and characterization of rare EB subtypes. Recently, genotype-phenotype correlations were established for patients with junctional EB, acral peeling skin syndrome and EB simplex-Ogna.

In conclusion, Dr. Kiritsi combines clinical expertise and laboratory research with the goal of disclosing pathogenetic disease mechanisms resulting in skin fragility, promoting the understanding of disease variability, and improving the diagnostic and therapeutic possibilities for genetic skin diseases.

    

    

Basement membranes in health and disease, and new therapies for dystrophic EB

Dr. Alexander Nyström, PhD
Group leader
E-mail: alexander.nystroem@uniklinik-freiburg.de
Phone: +49 (0)761 270 67850

Career
PhD in Developmental biology at Lund University, Lund, Sweden
Postdoc Renato Iozzo laboratory, Thomas Jefferson University, Philadelphia, PA, USA
Postdoc, Group leader Molecular dermatology lab, Medical Center – University of Freiburg, Freiburg, Germany

The extracellular matrix is not merely a scaffold providing organs with mechanical support, but it also actively determines cell faith by direct signaling and modulation of growth factor availability. Our research is focused on basement membranes, thin specialized extracellular matrix structures underlying epithelia and endothelia and surrounding many other tissues, and their individual components (Nystrom et al., 2016). Specifically, we study how changes such as limited proteolytic processing or complete loss of function of individual components impact the microenvironment during homeostasis and regenerative or pathological events (Mittapalli et al, 2016, Nystrom et al., 2009; Nystrom et al., 2013, Nystrom et al., 2016). Collagen VII is a specific focus of our research. It is a large basement membrane-associated protein that anchors the basement membrane to the interstitial matrix in many squamous epithelia. Deficiency in collagen VII leads to dystrophic epidermolysis bullosa (DEB), an inherited skin fragility disorder. The disorder, which is manifested by mechanosensitive skin that heals with excessive scarring, has wide spectra in degree of severity depending on partially retained or non-functional collagen VII due to its mutations.  In the case of complete loss of collagen VII, DEB is severely disabling and patients have a high propensity to develop aggressive squamous cell carcinoma at scarred sites. No causative therapy exists. We unravel the mechanistic consequences of collagen VII loss to gain further knowledge about its function and the function of its interaction partners that would first of all explain the phenotypic changes specific to DEB skin. Importantly, this knowledge can also be applied to construct new therapies for skin-related pathologies such as impaired wound healing (Nyström et al., 2013). Thus, our second interest is to develop and test new therapies (causal and symptomatic) for DEB (e.g. Bornert et al., 2016, Kühl et al., 2015, Kühl et al., 2016, Nyström et al., 2016, Wenzel et al., 2014).  

Dr. Oliver Bornert, PhD, Postdoc working on splice-based and other novel therapies for DEB
E-mail: olivier.bornert@uniklinik-freiburg.de
Phone: +49 (0)761 270-67100

Dr. Tobias Kühl, PhD
, Postdoc working on novel causal and antifibrotic therapies for DEB
Email: tobias.kuehl@uniklinik-freiburg.de
Phone:  +49 (0)761 270 67100  

Rocco Bernasconi, MSc, PhD student working on mechanisms of soft tissue fibrosis in DEB.  E-mail: rocco.bernasconi@uniklinik-freiburg.de
Phone: +49 (0)761 270 67100

Daniel Kruppa, MSc, PhD student working on proteases in wound healing pathologies.
E-mail: daniel.kruppa@uniklinik-freiburg.de
Phone: +49 (0)761 270 67210

Former member: Dr. Venugopal Rao Mittapalli, PhD

Selected publications

  • Bornert O, Kühl T, Bremer J, van den Akker PC, Pasmooij AM, Nyström A (2016). Analysis of the functional consequences of targeted exon deletion in COL7A1 reveals prospects for dystrophic epidermolysis bullosa therapy. Mol Ther. 24:1302-1311.
  • Kühl T, Mezger M, Hausser I, Guey LT, Handgretinger R, Bruckner-Tuderman L, Nyström A (2016). Collagen VII Half-Life at the Dermal-Epidermal Junction Zone: Implications for Mechanisms and Therapy of Genodermatoses. J Invest Dermatol. 136:1116-1123.
  • Kühl T, Mezger M, Hausser I, Handgretinger R, Bruckner-Tuderman L, Nyström A (2015). High Local Concentrations of Intradermal MSCs Restore Skin Integrity and Facilitate Wound Healing in Dystrophic Epidermolysis Bullosa. Mol Ther. 23:1368-1379.
  • Mittapalli VR, Madl J, Löffek S, Kiritsi D, Kern JS, Römer W, Nyström A, Bruckner-Tuderman L (2016). Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression. Cancer Res76:940-51.
  • Nyström A, Bornert O, Kühl T (2016). Cell therapy for basement membrane-linked diseases. Matrix Biol. S0945-053X(16)30068-3.
  • Nyström A, Thriene K, Mittapalli V, Kern JS, Kiritsi D, Dengjel J, Bruckner-Tuderman L (2015). Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms. EMBO Mol Med7:1211-1228.
  • Nyström, A., Z.P. Shaik, D. Gullberg, T. Krieg, B. Eckes, R. Zent, A. Pozzi, and R.V. Iozzo (2009). Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity. Blood. 114:4897-4906.
  • Nyström, A., D. Velati, V.R. Mittapalli, A. Fritsch, J.S. Kern, and L. Bruckner-Tuderman (2013). Collagen VII plays a dual role in wound healing. J Clin Invest. 123:3498-3509.
  • Wenzel D, Bayerl J, Nyström A, Bruckner-Tuderman L, Meixner A, Penninger JM (2014). Genetically corrected iPSCs as cell therapy for recessive dystrophic epidermolysis bullosa. Sci Transl Med 6(264):264ra165.

The main objective of our work is to understand the molecular mechanisms leading to the development of highly invading skin cancers in the patients of Recessive Dystrophic Epidermolysis Bullosa (RDEB).  We are using immune-competent models and advanced 2D, 3D in vitro methods as well as state-of-the -art imaging techniques, to elucidate the intricate signaling processes involved in rapid progression of RDEB cancers. Preclinical studies are also being carried out in suitable models to evaluate the efficiency of certain ‘molecular therapeutics’ which are targeted against specific signaling pathways involved in inflammation, skin fibrosis and cancer.   Our studies will help understand the mechanisms of several clinical manifestations of RDEB patients and may help to provide efficient therapeutic strategies in future.  

    

Physiological and pathological role of cell surface proteolysis in the skin

Prof. Dr. Claus-Werner Franzke, PhD
Group Leader
E-mail: claus-werner.franzke@uniklinik-freiburg.de
Phone: +49 (0)761 270-67850

Dr. Jasmin Kroeger, PhD
E-mail: jasmin.kroeger@uniklinik-freiburg.de
Phone: +49 (0)761 270-67210

Former member: Dr. Célimène Galiger, PhD

Our group uses transgenic mouse models, cell biological and biochemical approaches to study the regulatory functions of proteases, especially disintegrin-metalloproteinases (ADAMs), in epidermal homeostasis, re-epithelization of skin wounds, and squamous cell cancer invasion. We have previously shown that ADAM 9- and 10-dependent collagen XVII ectodomain shedding modulates keratinocyte motility and that ADAM17 is crucial for the maintenance of the epidermal skin barrier by regulating EGFR ligand dependent terminal keratinocyte differentiation. Our current focus is to investigate the in vivo role of the cell surface proteolysis by ADAMs in keratinocyte migration and invasion during wound healing or carcinogenesis by using ADAM knockout mouse models and mice expressing the cleavage resistant ADAM substrate collagen XVII. Our studies aim to identify specific ADAMs and their substrates as suitable targets of new therapeutic approaches to atopic dermatitis, chronic wounds, and skin cancer.

Former members: Dr. Cristina Cobzaru, PhD; Dr. Joanna Jacków, PhD; Dr. vet. Sonja Huttenlocher, DVM

    

Autoimmune Skin Diseases
Cassian Sitaru

Prof. Dr. Cassian Sitaru, MD
E-mail: cassian.sitaru@uniklinik-freiburg.de
Phone: +49 (0)761 270-69920

Helper T (Th) cell-regulated development of antigen-specific B and plasma cells resulting in the production of pathogenic autoantibodies underpins the pathology of several autoimmune diseases. These include pemphigus, pemphigoid, myasthenia gravis, Guillan-Barre syndrome, autoimmune hemolytic anemia, immune thrombocytopenia, autoimmune dilative cardiomyopathy, Goodpasture’s syndrome, systemic lupus erythematosus, anti-phospholipid syndrome, and rheumatoid arthritis. Our research focuses on the mechanisms governing the coupling of autoantibody specificity to effector cell response, with special emphasis on autoantibodies against structural skin proteins in autoimmune blistering diseases. These diseases are clinically and immunopathologically well-defined entities where both the autoantigen and the pathogenic autoantibodies are well characterized. However, the complex pathogenic and regulatory mechanisms of pathogenic autoantibody production and several aspects of blister formation are still poorly understood. A major focus of our research is to investigate these pathogenetic mechanisms using in vitro and in vivo models of autoimmunity against structural skin proteins. In parallel projects, we study the structure and function of skin proteins, including collagens VII and XVII of the dermoepidermal junction such as collagen XVII (BP180) or p200, which are targets of the autoimmune response in a group of acquired blistering diseases. Ongoing patient-centered studies address the pathogenesis of pemphigus, a severe bullous dermatosis with intraepidermal blistering, with the aim of improving diagnosis and therapy.

Medical Proteome Research

Prof. Dr. Joern Dengjel, PhD
Group leader
E-mail: joern.dengjel@medizin.uni-freiburg.de
Phone: +49 (0)761 270-68930

Kerstin Thriene, PhD student
E-mail: kerstin.thriene@uniklinik-freiburg.de
Phone: +49 (0)761 270-67740

Former members
Postdocs: Veronica Dumit, Rudolf Engelke, Mostafa Zarei
PhD students: Andrea Becker, Britta Dietrich, Sven Eiselein, Marta Kischel, Victoria Küttner,  Adrian Sprenger
Diploma student: Fabian Metzger
Master student: Julia Donauer, Michal Rackiewicz
Bachelor students: Julia Riede, Lea Bühler,  Jakob Käppler  

Klinik für Dermatologie und Venerologie

Hauptstraße 7
79104 Freiburg
Telefon: 0761 270-67010
Telefax: 0761 270-68290
E-Mail: sabine.acker-heinig
@uniklinik-freiburg.de