Prof. Dr. Udo Oppermann
Udo Oppermann obtained a Diploma in Human Biology in 1990 and PhD in Pharmacology and Toxicology in 1994, both with distinctions from Philipps University Marburg, Germany. He went on to become Associate Professor at Karolinska Institutet, Stockholm, in the Department of Medical Biochemistry and Biophysics where he stayed until 2004. After a sabbatical stay at Yale University, he has been a Principal Investigator of the Structural Genomics Consortium (SGC) in Oxford since its inception in 2003. In 2008 he became Professor of Molecular Biology at NDORMS, and he is now Deputy Director of the Institute of Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, as well as a Fellow of St Catherine's College. The research in the Oppermann group focuses on the biology and structure-activity relationships of human metabolic protein families of all types but with emphasis on oxidoreductases such as short - or medium chain dehydrogenases / reductases (SDR, MDR), or oxidative enzymes such as the ketoglutarate dependent oxygenases.The use of chemical biology to understand human biology is a major focus of the group and is currently applied to the field of epigenetic mechanisms in stem cell biology, as well as chronic inflammatory and metabolic diseases.
Nowak RP, Tumber A, Johansson C, Che KH, Brennan P, Owen D, Oppermann U. Advances and challenges in understanding histone demethylase biology. Curr Opin Chem Biol. 2016 Jun 29;33:151-159.
Johansson C, Velupillai S, Tumber A, Szykowska A, Hookway ES, Nowak RP, Strain-Damerell C, Gileadi C, Philpott M, Burgess-Brown N, Wu N, Kopec J, Nuzzi A, Steuber H, Egner U, Badock V, Munro S, LaThangue NB, Westaway S, Brown J, Athanasou N, Prinjha R, Brennan PE, Oppermann U. Structural analysis of human KDM5B guides histone demethylase inhibitor development. Nat Chem Biol. 2016 Jul;12(7):539-45.
Wagner T, Greschik H, Burgahn T, Schmidtkunz K, Schott AK, McMillan J, Baranauskienė L, Xiong Y, Fedorov O, Jin J, Oppermann U, Matulis D, Schüle R, Jung M. Identification of a small-molecule ligand of the epigenetic reader protein Spindlin1 via a versatile screening platform. Nucleic Acids Res. 2016 May 19;44(9):e88.
Korczynska M, Le DD, Younger N, Gregori-Puigjané E, Tumber A, Krojer T, Velupillai S, Gileadi C, Nowak RP, Iwasa E, Pollock SB, Ortiz Torres I, Oppermann U, Shoichet BK, Fujimori DG. Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors. J Med Chem. 2016 Feb 25;59(4):1580-98.
Bavetsias V, Lanigan RM, Ruda GF, Atrash B, McLaughlin MG, Tumber A, Mok NY, Le Bihan YV, Dempster S, Boxall KJ, Jeganathan F, Hatch SB, Savitsky P, Velupillai S, Krojer T, England KS, Sejberg J, Thai C, Donovan A, Pal A, Scozzafava G, Bennett JM, Kawamura A, Johansson C, Szykowska A, Gileadi C, Burgess-Brown NA, von Delft F, Oppermann U, Walters Z, Shipley J, Raynaud FI, Westaway SM, Prinjha RK, Fedorov O, Burke R, Schofield CJ, Westwood IM, Bountra C, Müller S, van Montfort RL, Brennan PE, Blagg J. 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors. J Med Chem. 2016 Feb 25;59(4):1388-409.
Understanding the role of histone demethylase LSD1 in mesenchymal stem cell biology and musculosketal ageing
Epigenetic mechanisms control gene transcription by integrating modifications on DNA and chromatin. Current drug development efforts aim to utilise the potential that epigenetics offer to address unmet needs in various areas of human disease including inflammatory disorders such as rheumatoid arthritis.
We have previously identified epigenetic mechanisms that control the complex stem cell and inflammatory environment that leads to destruction of bone tissue in arthritis and other musculoskeletal conditions. One of the identified critical factors that regulates osteoblast development from mesenchymal stem cells is the histone demethylase LSD1; this field has been subject of intensive research of Professor R Schuele in Freiburg. LSD1 knockdown in human mesenchymal stem cells resulted in significant increases in osteoblast properties when stem cells are directed towards this lineage. This has potential therapeutic implications in several areas of medicine including rheumatology, ageing and regenerative medicine.
We now wish to further evaluate LSD1 as possible therapeutic intervention point, by performing initial proof of concept studies in model systems which are available at the host laboratory. In particular, we will investigate the effect of small molecule inhibitors how LSD1 regulates chromatin function and osteoblast differentiation. It is anticipated that results from this project will increase our understanding of possible bone anabolic effects of LSD1 inhibitors.