Ruprecht-Karls-Universität Heidelberg
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Lehmann0120 - Scientist (f/m) / PhD position
Project no:
Lehmann0120

Project leader:

Project supervisor:
Lehmann, Lorenz
Application deadline:
31. Oct 2020
Start of PhD project:
1. Dec 2020

Project description:

Title:
Inhibitors of Histone Deacetylases; evaluation and target identification of a cardioprotective combination therapy for cancer
Summary:
Deterioration of myocardial contractile function is a major limitation for successful cancer therapies. Anthracyclines, which are well-established anti-cancer drugs and part of many therapeutic regimes have profound cardiac side effects. On a cellular level, they lead to DNA doubles strand beaks, which seems to be a crucial mechanism of cardiotoxicity. The role of epigenetic modifications and the genomic regions, which are targeted by the anthracycline-poised epigenetic modifiers are widely unknown. Histone deacetylases (HDACs) work as epigenetic repressors. Recent work has shown that HDAC inhibitors (HDACi) are not only successful as therapeutics in various cancer entities but also beneficial for the heart in preclinical models of heart failure. Based on our unpublished work, we propose that HDAC-dependent MEF2 (myocyte enhancer factor 2) inhibition plays an important role in anthracycline-induced cardiotoxicity. This inhibitory effect can be amplified by co-treatment with the HDACi vorinostat. The epigenetic changes caused by vorinostat and potential other downstream targets independent of the transcription factor MEF2 are widely unknown, which is why they require further investigations. We want to Identify the global HDACi-dependent epigenetic changes in the heart and determine the HDACi-targeted genomic regions in cardiomyocytes. We further want to determine the role of MEF2 in the control of pathological gene regulation upon anthracycline treatment and to determine the potential cardioprotective effects of vorinostat upon co-treatment with anthracyclines in vivo.
References:
1. Lehmann LH, Jebessa ZH, Kreusser MM, Horsch A, He T, Kronlage M, Dewenter M, Sramek V, Oehl U, Krebs-Haupenthal J, von der Lieth AH, Schmidt A, Sun Q, Ritterhoff J, Finke D, Volkers M, Jungmann A, Sauer SW, Thiel C, Nickel A, Kohlhaas M, Schafer M, Sticht C, Maack C, Gretz N, Wagner M, El-Armouche A, Maier LS, Londono JEC, Meder B, Freichel M, Grone HJ, Most P, Muller OJ, Herzig S, Furlong EEM, Katus HA and Backs J. A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. Nat Med. 2018;24:62-72.

2. Lehmann, L. H., Worst, B. C., Stanmore, D. A., and Backs, J. (2014) Histone deacetylase signaling in cardioprotection. Cell Mol Life Sci 71, 1673-1690

3. Backs, J., Worst, B. C., Lehmann, L. H., Patrick, D. M., Jebessa, Z., Kreusser, M. M., Sun, Q., Chen, L., Heft, C., Katus, H. A., and Olson, E. N. (2011) Selective repression of MEF2D activity by PKA-dependent proteolysis of HDAC4. J Cell Biol 195, 403-415

4. Hohl, M., Wagner, M., Reil, J. C., Muller, S. A., Tauchnitz, M., Zimmer, A. M., Lehmann, L. H., Thiel, G., Bohm, M., Backs, J., and Maack, C. (2013) HDAC4 controls histone methylation in response to elevated cardiac load. J Clin Invest 123, 1359-1370

5. Lehmann, L. H., Rostosky, J. S., Buss, S. J., Kreusser, M. M., Krebs, J., Mier, W., Enseleit, F., Spiger, K., Hardt, S. E., Wieland, T., Haass, M., Luscher, T. F., Schneider, M. D., Parlato, R., Grone, H. J., Haberkorn, U., Yanagisawa, M., Katus, H. A., and Backs, J. (2014) Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling. Proc Natl Acad Sci U S A 111, 13499-13504
Methods that will be used:
Western Blot, Cell culture of primary neonatal and adult cardiomyocytes, animal work with conditional knockout animals, ChIPseq, ChIP-PCR, HiC, siRNA approaches, Luziferase assays.
Cooperation partners:
Johannes Backs, Director of the Department of Molecular Cardiology and Epigenetics (Internal Medicine VIII); DZHK Partner site Heidelberg/Mannheim
Christoph Dieterich, Head of Group “Computational Cardiology”, Department of internal Medicine III, University Hospital of Heidelberg, Heidelberg; DZHK Partner site Heidelberg/Mannheim
Personal qualifications:
We look for a person with a master or equivalent degree in biology or any related field with a strong background in molecular biology and advanced tissue culture experience. Ideally the person has already worked with animals (FELASA A is helpful but not crucial).
You fit to us if you want to work in a world-class research environment with state-of-the-art equipment and access to comprehensive research facilities. You have the ability to work independently, but also show a strong team spirit.
Keywords:
Cardiotoxicity; Epigenetics; HDAC inhibitor; Heart; ChIP;