Karsten Seeger's research group

Our research focuses on two main areas: the elucidation of type VII collagen interactions within the extracellular matrix of the skin, and the investigation of metabolic changes associated with inflammation, autoimmune processes, and cellular aging. By studying how collagen VII interacts with other matrix components, we seek to better understand the molecular mechanisms underlying epidermolysis bullosa acquisita (EBA), an autoimmune disease characterized by autoantibodies against collagen VII. In parallel, we explore metabolic alterations in diseased, inflammatory, or senescent cells using NMR-based metabolomics.

To address these topics, we apply a range of biophysical approaches, including NMR spectroscopy and Biacore surface plasmon resonance, and we have extensive experience in protein biochemistry. Together, these methods allow us to characterize protein–protein interactions, metabolic profiles, and disease-associated structural changes at high molecular resolution.

Previous and current research

Metabolomics

In a disease state different proteins are newly synthesized while the expression of other proteins is repressed. However, not only the protein composition and levels are changed during a disease, there are also changes in metabolite concentrations. The usage of metabolic profiles in an “omics” setting is emerging since a few years. In a clinical setting it is used for improved diagnosis and for prediction of therapy outcome. In basic research it allows identification of pathways that are involved in or influenced by a certain (organismal) state. This will provide clues to diagnosis as well as to a deeper understanding of the disease itself.

Our group used NMR spectroscopy for metabolic investigations. We have determined metabolic changes in a mouse model of an inflammatory autoimmune skin disease [1] and identified a metabolic marker for cellular senescence in human fibroblasts [2] and skin melanocytes [3].

We participate with a project on metabolomics in the research training group GRK1727/2 "Modulation of Autoimmunity".

References

  1. Schönig S, Recke A, Hirose M, Ludwig R, Seeger K. Metabolite analysis distinguishes between mice with epidermolysis bullosa acquisita and healthy mice. Orphanet Journal of Rare Diseases 2013, 8(1):93. DOI: 10.1186/1750-1172-8-93
  2. Gey C, Seeger K. Metabolic changes during cellular senescence investigated by proton NMR-spectroscopy. Mech Ageing Dev 2013, 134(3-4): 130-138. DOI: 10.1016/j.mad.2013.02.002
  3. Windler C, Gey C, Seeger K.: Skin melanocytes and fibroblasts show different changes in choline metabolism during cellular senescence. Mech Ageing Dev 2017 164:82-90. DOI: 10.1016/j.mad.2017.05.001

Further literature

  • Seeger K.: Metabolic changes in autoimmune diseases. In Curr. Drug Discov. Technol. 6 (2009), 256-261. DOI: 10.2174/157016309789869074
  • Gey, C. and Seeger, K., 2017. Metabolic changes investigated by proton NMR spectroscopy in cells undergoing oncogene-induced senescence, in: Nikiforov, M.A. (Ed.), Oncogene-Induced Senescence: Methods and Protocols. Springer New York, New York, NY, pp. 155-163. DOI: 10.1007/978-1-4939-6670-7_15

Type VII collagen & autoimmunity

Autoimmune diseases a characterized by a misled response to endogenous proteins. Why an endogenous protein present in the human body for a long time is suddenly recognized as exogenous is not yet understood.

Epidermolysis bullosa acquisita (EBA) is an autoimmune disease of the skin which is characterized by autoantibodies directed against type VII collagen. Type VII collagen links different skin layers together. Autoantibody binding to type VII collagen results in skin blistering and skin lesions.

Our group has characterized interactions of type VII collagen subdomains with e.g. other extracellular matrix proteins [1, 2]. We could show that type VII collagen has a cystine knot with an hitherto unknown topology [3] and that the hinge region of type VII collagen is intrinsically disordered [4]. We recently showed that a mutation in a type VII collagen subdomain results in thermolability of this domain which renders it susceptible to proteases [5].

References

  1. Wegener H, Leineweber S, Seeger K. The vWFA2 domain of type VII collagen is responsible for collagen binding. Biochem Biophys Res Commun 2013, 430(2): 449-453. DOI: 10.1016/j.bbrc.2012.11.119
  2. Leineweber S, Schönig S, Seeger K. Insight into interactions of the von-Willebrand factor-A-like domain 2 with the FNIII like domain 9 of collagen VII by NMR and SPR. FEBS Lett 2011, 585: 1748-1752. DOI: 10.1016/j.febslet.2011.04.071
  3. Wegener H, Paulsen H, Seeger K. The cysteine rich region of type VII collagen is a cystine knot with a new topology. J Biol Chem. 2014, 289(8): 4861-4869. DOI: 10.1074/jbc.M113.531327
  4. Richer BC, Seeger K.: The hinge region of type VII collagen is intrinsically disordered. Matrix Biol. 2014, 36: 77-83. DOI: 10.1016/j.matbio.2014.04.006
  5. Windler C, Hermsdorf U, Brinckmann J, Seeger K.: A type VII collagen subdomain mutant is thermolabile and shows enhanced proteolytic degradability – implications for the pathogenesis of recessive dystrophic epidermolysis bullosa?, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2017 1863: 52-59. DOI: 10.1016/j.bbadis.2016.10.023

Further literature

  • Hermsdorf U, Seeger K.: Chemical shift assignments of the fibronectin III like domains 7-8 of type VII collagen. Biomol NMR Assign 2016 10: 53-55. DOI: 10.1007/s12104-015-9636-9
  • Iwata H, Witte M, Samavedam UK, Gupta Y, Shimizu A, Ishiko A, Schröder T, Seeger K, Dahlke M, Rades D, Zillikens D, Ludwig RJ.: Radiosensitive hematopoietic cells determine the extent of skin inflammation in experimental epidermolysis bullosa acquisita. J Immunol. 2015, 195(5):1945-54. DOI: 10.4049/jimmunol.1501003
  • Iwata H, Bieber K, Tiburzy B, Chrobok N, Kalies K, Shimizu A, Leineweber S, Ishiko A, Vorobyev A, Zillikens D, K hl J, Westermann J, Seeger K, Manz R, Ludwig RJ.: B Cells, Dendritic Cells, and Macrophages Are required to induce an autoreactive CD4 helper T cell response in experimental epidermolysis bullosa acquisita. J Immunol. 2013, 191(6): 2978-2988. DOI: 10.4049/jimmunol.1300310
  • Schönig S, Recke A, Hirose M, Ludwig R, Seeger K.: Metabolite analysis distinguishes between mice with epidermolysis bullosa acquisita and healthy mice. Orphanet Journal of Rare Diseases 2013, 8(1):93. DOI: 10.1186/1750-1172-8-93