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Deutsch Intern
Rudolf Virchow Center for Integrative and Translational Bioimaging

Maric Group

About the Maric Group

Proteins are essential components of all known organisms and are involved in practically every process of life. One of the great challenges for the life sciences in the post-genomic age is to read the function and interactions of proteins and to exploit this knowledge for therapy. Innovations in the field of automation and miniaturization enable us to gain new molecular insights into the function of proteins and explore novel therapeutic approaches.

Technology

Our organic-chemical and biological-synthetic biochip technology allows us to study protein interactions with highest throughput and to transform peptide-derived compounds into compact and highly affine binding molecules with optimized selectivity profiles.

 

Peptide Based Markers and Tools

Due to their comparably small size and superior binding properties, the peptide-based compounds - developed and manufactured by us - are both specific inhibitors as well as excellent protein labels. Our newly developed fluorescent probes unleash the full resolution potential of the latest high-end microscopy technologies and thereby help to gain new insights into cellular processes.

 

New Neuropharmacological Approaches

A subgroup of autoimmune neuropathies is caused by autoantibodies against critical nerve structures. Here the severity of the disease correlates with the antibody levels and neutralization or removal of antibodies leads to an immediate recovery of the patient. So far, however, only a small part of the existing autoantigens has been identified. In order to counter this great limitation of diagnostic and therapeutic possibilities, we use our array technology to identify new autoantigens on critical structures of the peripheral nerves.

 

Worldwide, more than 50 million people suffer from epilepsy and over 20 million people are diagnosed with schizophrenia. The therapeutic options for these serious and chronic diseases of the brain are limited and a significant proportion of patients show a poor response to treatment. γ-Aminobutyric acid type A receptors (GABAARs) are the main mediators of phasic and tonic inhibition in the human brain and an important neuropharmacological drug target. Currently used drugs have limited GABAAR subtype specificity and affect receptors across different brain regions and neuronal structures. This inherent lack of specificity causes severe side effects and drastically limits the effectiveness of the active ingredients. We envision a new form of GABAAR-based specific therapy to precisely target certain dysfunctional neural pathways. In particular, we explore GABAAR-associated proteins as a means of influencing disease-related protein complexes in certain brain regions as well as discrete neuronal pathways.

7.October 2020 Two Posters for Eureka!

Violetta Peck et al. and Markus Bayer et al. will present two posters summarizing their works at the international EUREKA! Symposium. Enjoy the talks and posters!


1.October 2020

René Weyer has joined our lab as part of his master thesis in Biochemistry. He will define protein interaction profiles for kinases using microarrays and bioinformatics.


01.October 2020 Paraskevi Samara Erasmus Internship

We welcome Paraskevi Samara from the National and Kapodistrian University of Athens to our lab. She will use microarrays to explore the molecular mechanisms that underly the function of the inhibitory synapse.


1.September 2020 Open PhD Position

We are looking for a PhD student (link = https://www.uni-wuerzburg.de/rvz/aktuelles/jobs-karriere/stellenangebote/) highly motivated to identify and characterize new immune neuropathy autoantigens. The project will encompass the use of synthetic chemistry, biophysical characterisation of biomolecular binding interactions and modern automatization technologies.


23.June 2020 Sarah-Marie Buchmann Master Thesis

Sarah-Marie Buchmann has joined our lab for working on her Master Thesis in Biology. The topic of her Thesis is "On-Chip detection and profiling of anti SARS-nCOV2 antibodies: Human Milk Immunity and profiling of therapeutic antibodies"


8.June 2020 Rafael Worschech Master Thesis

Welcome Rafael! He joins our lab as part of his master thesis. Using high affinity, super-binding peptide (SBP) based fluorescent probes, he will explore the GABAA and glycine receptor subtype specificity of major gephyrin isoforms via high-end microscopy. Good luck!


29.May 2020 Gründl et al 2020

Congratulations to Marco Gründl and Stefan Gaubatz on their successful characterization of the interaction between YAP and Myb-MuvB (MMB) complex revealing its role in the proliferation of cardiomyocytes in Plos Biology (link = https://doi.org/10.1371/journal.pgen.1008818). Props to Clemens who contributed the YAP/MMB complex mapping.


30.April 2020 IZKF

Thank you very much to the IZKF (link = https://www.med.uni-wuerzburg.de/izkf/forschungsfoerderung/izkf-projektfoerderung/) for giving us the opportunity to realize the project with the goal to unravel the molecular pathogenesis of nodal and paranodal autoantibodies in Patients with auto-immune neuropathy. We are looking forward to the collaboration with Katrin Doppler and are very excited for the results to come.


30.April 2020 Langlhofer et al 2020

We are very pleased to see the work of Georg Langlhofer resolving the molecular pathology of a hereditary form of hyperekplexia being published in the Journal of Neuroscience (link =  https://doi.org/10.1523/JNEUROSCI.2490-19.2020). We mapped and characterized syndapin I binding and contributed to show how the mutation leads to this type of startle disease. We are excited to move this further forward!


25. March 2020

The JMU provided 20.000 Euros "Start-up Funding" to support the preparation of our next research initiative.

Die JMU unterstützt die Vorbereitung unserer nächsten Forschungsinitiative mit 20.000 Euro "Start-up Funding" - Vielen Dank!


4.March 2020 Prieto-Garcia et al

Congratulations to Cristian Prieto-Garcia and Markus Diefenbacher on their recent work published in EMBO Molecular Medicine delineating the role of USP 28 in squamosa cell carcinoma (link =  https://doi.org/10.15252/emmm.201911101). We are very glad of being able to have contributed to your work and look forward to future collaborations.


21.January 2020

 

Violetta Peck has joined our lab for working on her medical Phd project. She as well was awarded a GSLS scholarship to characterize receptor-binding-profiles of native gephyrin from mouse-brain-lysates using our microarrays.


10 October 2019

Rico Petermann has joined our lab for working on his Master Thesis in Biology. The topic of his Master Thesis is “Molecular Basis Syndapin’s Interaction with Inhibitory Posts-Synaptic Proteins”.


26 June 2019

Vladimirs`new  article is online. He introduces new strategies to modulate GABAergic signalling. Good job Vladimir! Link to publication


3 June 2019

See you at the ReceptorLight Symposium No.2 in Jena! Clemens, Noah, Vladimir & Hans will present their recent progress in profiling native proteins and developing fluorescent probes.


27 May 2019

Publication in Nature Genetics. The Kubicek lab identified MTHFD1, a folate pathway enzyme, as genetic and physical interactor of the important transcription regulator BRD4. Using our microarray technology we mapped the exact binding interface of the BRD4/MTHFD1 complex.

9 August 2018

David Baumstark and Rico Petermann decided to support us to further develop and apply our peptide microarray technology platform!


7 August 2018

Congratulations to Rochelle and Steven for their great work on the collybistin protein that was just accepted in Nature Communications! We identified an exclusive binding of collybistin to the GABAAR-α2-subunit. - Notably, the first report of a high-affinity protein interaction for both proteins. Based on these results Rochelle created knock-in mice and demonstrated that this interaction is critical for the correct targeting and stabilisation of distinct α2-containing GABAAR clusters. She found that interfering with this protein interaction resulted in spontaneous seizures during development, accompanied by early mortality. Surviving mice have increased anxiety-like behavior and EEG abnormalities that are responsive to α2-selective benzodiazepines, revealing a novel therapeutic potential for these compounds. Publication


30 June 2018

Daniel Otzen just published his recent insight into the mechanism of functional Amyloid Formation. Using our microarray-based approach we identified specific motifs that are implicated in amyloid formation. These could lay the foundation for development of peptide-based amyloid inhibitors. Publication


6 June 2018

Neuroscience conference in Schaffhausen, Switzerland. It was a great pleasure to the emerging mechanisms for inhibitory synapse plasticity!  Shuang-Yan & Hans presented their plans how to use the microarray technology to gain molecular level insight into neurobiological processes.


2 May 2018

We welcome biomedicine student Elisa Speth and senior scientist Dr. Shuang-Yan Wang. Dr. Shuang-Yan Wang joined us from Prof. John Robinsons group in Zürich where he developed highly specific cyclic peptidomimetics antibiotics in close cooperation with Polyphor.

 


Langlhofer G, Schaefer N, Maric HM, Keramidas A, Zhang Y, Baumann P, Blum R, Breitinger U, Strømgaard K, Schlosser A, Kessels MM, Koch D, Qualmann B, Breitinger HG, Lynch JW, Villmann C. "A novel glycine receptor variant with startle disease affects syndapin I and glycinergic inhibition." Journal of Neuroscience. 30 April 2020, doi: 10.1523/JNEUROSCI.2490-19.2020


Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Fischer T, Walz S, Schülein-Völk C, Eilers U, Ade CP, Calzado MA, Orian A, Maric HM, Münch C, Rosenfeldt M, Eilers M, Diefenbacher ME. Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells. EMBO Mol Med. 2020 Mar 4;:e11101. doi: 10.15252/emmm.201911101.


Khayenko, V., and Maric, H.M. (2019). Targeting GABAAR-Associated Proteins: New Modulators, Labels and Concepts. Frontiers in Molecular Neuroscience 12. doi: 10.3389/fnmol.2019.00162


Sdelci, S., Rendeiro, A.F., Rathert, P., You, W., Lin, J.-M.G., Ringler, A., Hofstätter, G., Moll, H.P., Gürtl, B., Farlik, M., Schick, S., Klepsch, F., Oldach, M., Buphamalai, P., Schischlik, F., Májek, P., Parapatics, K., Schmidl, C., Schuster, M., Penz, T., Buckley, D.L., Hudecz, O., Imre, R., Wang, S.-Y., Maric, H.M., Kralovics, R., Bennett, K.L., Müller, A.C., Mechtler, K., Menche, J., Bradner, J.E., Winter, G.E., Klavins, K., Casanova, E., Bock, C., Zuber, J., and Kubicek, S. (2019). MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation. Nature Genetics.  doi: 10.1038/s41588-019-0413-z


Baluapuri A, Hofstetter J, Dudvarski Stankovic N, Endres T, Bhandare P, Vos SM, Adhikari B Schwarz JD, Narain A, Vogt M, Wang SJ, Düster R, Jung LA, Vanselow JT, Wiegering A, Geyer M, Maric HM, Gallant P, Walz S, Schlosser A, Cramer P, Eilers M, Wolf E. MYC recruits SPT5 to RNA polymerase II to promote processive transcription elongation. Molecular Cell (2019) doi.org/10.1016/j.molcel.2019.02.031


Kasaragod, V., Hausrat, T.J., Schaefer, N., Kuhn, M., Christensen, N.R., Tessmer, I., Maric, H.M., Lindegaard Madsen, K., Sotriffer, C., Villmann, C., Kneussel, M., Schindelin, H. Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins. Neuron 2019 Jan 28  doi:doi.org/10.1016/j.neuron.2019.01.001


Hines, R., Maric, H.M., Hines, D., Modgil, A., Panzanelli, P., Nakamura, Y., Nathanson, A., Cross, A., Deeb, T., Brandon, N., Davies, P., Fritschy, J.M., Schindelin, H., Moss, S. (2018) Developmental seizures and mortality result from reducing GABAA Receptor α2 subunit interaction with collybistin. Nature Communications, 9, 3130 (2018) doi: 10.1038/s41467-018-05481-1


Bleem, A., Christiansen, G., Madsen, D.J., Maric, H.M., Strømgaard, K., Bryers, J.D., Daggett, V., Meyer, R.L., Otzen, D.E., (2018) Protein Engineering Reveals Mechanisms of Functional Amyloid Formation in Pseudomonas aeruginosa Biofilms, Journal of Molecular Biology (2018) doi.org/10.1016/j.jmb.2018.06.043


Büchel G., Carstensen A., Mak K.Y., Roeschert I., Leen E., Sumara O., Hofstetter J., Herold S., Kalb J., Baluapuri A., Poon W, Kwok C, Chesler L, Maric H.M., Rickman D.S., Wolf E., Bayliss R., Walz S., Eilers M. Association with Aurora-A Controls N-MYC-Dependent Promoter Escape and Pause Release of RNA Polymerase II during the Cell Cycle. Cell Reports, Volume 21 , Issue 12 , 3483 – 3497 (2018) doi  10.1016/j.celrep.2017.11.090


Maric, H. M.*, Hausrat, T. J., Neubert, F., Dalby, N.O., Doose S., Sauer M., Kneussel M., Strømgaard K. (2017), Gephyrin-Binding Peptides Visualize Post-Synaptic Sites and Modulate Neurotransmission, Nature Chemical Biology, 13, 153–160 (2017) doi: 10.1038/nchembio.2246

(*First authorship and shared corresponding authorship)


Cheng J., Sahani S., Hausrat T. J., Yang J. W., Ji H., Schmarowski N., Endle H., Liu X., Li Y., Bottche R., Radyushkin K., Maric H. M., Hoerder-Suabedissen A., Molnar Z., Prouvot P. H., Trimbuch T., Ninnemann O., Huai J., Fan W., Visentin B., Sabbadini R., Strømgaard K., Stroh A., Luhmann H. J., Kneussel M., Nitsch R. Vogt J.  (2016). Precise Somatotopic Thalamocortical Axon Guidance Depends on LPA-Mediated PRG-2/Radixin Signaling. Neuron 92(1): 126-142. doi: 10.1016/j.neuron.2016.08.035


Maric H. M., Kasaragod V. B., Haugaard-Kedström L., Hausrat T. J., Kneussel, M., Schindelin, H. and Strømgaard, K. (2015), Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors. Angewandte Chemie International Edition 2015, 54, p. 490–494. doi: 10.1002/anie.201409043

Selected as Hot Paper – Outstanding importance in a rapidly evolving field of high current interest


Maric, H. M.*, Kasaragod, V. B.*, Schindelin, H. (2014), Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin. Nature Communications 2014, 5(5767). doi: 10.1038/ncomms6767

(*shared first authorship)


Maric, H. M., Kasaragod, V. B., Schindelin, H. (2014), Modulation of the Gephyrin-Glycine Receptor Affinity by Multivalency. ACS Chemical Biology 2014, 9(11), p. 2554–2562. doi: 10.1021/cb500303a


Maric, H. M., Mukherjee J., Tretter, V., Moss, S. J., & Schindelin, H. (2011), Gephyrin-mediated γ-Aminobutyric Acid Type A and Glycine Receptor Clustering Relies on a Common Binding Site.The Journal of Biological Chemistry 2011, 286(49), p. 42105-42114. doi:10.1074/jbc.M111.303412


Mukherjee J., Kretschmannova K.*, Gouzer G.*, Maric H. M.*, Ramsden S., Tretter V., Harvey K., Davies P.A., Triller A., Schindelin H., Moss S.J. (2011), The residence time of GABAARs at inhibitory synapses is determined by direct binding of the receptor α1 subunit to gephyrin. The Journal of Neuroscience 2011, 31(41), p. 14677-87. doi:  10.1523/JNEUROSCI.2001-11.2011

(*shared second authorship.)


Tretter V., Kerschner B., Milenkovic I., Ramsden S. L., Ramerstorfer J., Saiepour L., Maric H.M., Moss S. J., Schindelin H., Harvey R. J., Sieghart W., Harvey K. (2011), Molecular basis of the GABAA α3 subunit interaction with the clustering protein gephyrin. The Journal of Biological Chemistry 2011, 286(43): p. 37702-11. doi: 10.1074/jbc.M111.291336.


Tretter V., Mukherjee J., Maric H. M., Schindelin H., Sieghart W., Moss S. J. (2012), Gephyrin, the enigmatic organizer at GABAergic synapses. Frontiers in Cellular Neuroscience 2012. 6: p. 23. doi: 10.3389/fncel.2012.00023.

Sonja Kachler

Technische/r Assistent/in
Rudolf-Virchow-Zentrum - Center for Integrative and Translational Bioimaging
Universität Würzburg
Josef-Schneider-Str. 2
97080 Würzburg
Deutschland
Building: Haus D15
Room: 01.011

Vladimir Khayenko

Doktorand/in
Rudolf-Virchow-Zentrum - Center for Integrative and Translational Bioimaging
Universität Würzburg
Josef-Schneider-Str. 2
97080 Würzburg
Deutschland
Building: Haus D15
Room: 01.012

Vladimir has graduated magna cum laude from The Hebrew University of Jerusalem with B.Sc. in Pharmacy and M.Sc. in Medicinal Chemistry. Having a highly versatile background he fitted perfectly into our team and in June 2018 began working on microarray-based development of novel peptide probes and their integration in super resolution fluorescent microscopy. He currently focuses on the probes targeting Gephyrin – the universal hallmark and the major scaffolding protein of the inhibitory neuronal synapse.

Publications:
Khayenko V, Maric HM. Targeting GABAAR-Associated Proteins: New Modulators, Labels and Concepts. Front Mol Neurosci. 2019;12:162. Published 2019 Jun 26. doi:10.3389/fnmol.2019.00162

Dr. Hans Maric

Gruppenleiter
Rudolf-Virchow-Zentrum - Center for Integrative and Translational Bioimaging
Universität Würzburg
Josef-Schneider-Str.2
97080 Würzburg
Deutschland
Building: Haus D15
Room: 001.010

Clemens Schulte

Doktorand/in
Rudolf-Virchow-Zentrum für Experimentelle Biomedizin
Universität Würzburg
Josef-Schneider-Str. 2

97080 Würzburg
Deutschland
Building: Haus D15
Room: 01.012

Clemens graduated from the University of Wuerzburg with an M.Sc. in Biochemistry in 2019, including a research stay at the Oregon Health and Science University in 2018. Since the start of his doctoral studies, he focuses on the profiling of native protein-protein interactions using complementary high-throughput technologies.

Current position

Junior Group Leader at the Rudolf Virchow Center of the University of Würzburg (since January 2018)

Research Experience

04/2015-07/2017   Assistant Professor, Center for Biopharmaceuticals, University of Copenhagen, Denmark
07/2013-03/2015 Postdoctoral Fellow, Lundbeck Trust, Copenhagen, Denmark  
12/2012-06/2013 Postdoctoral Fellow, Career Development Fellowship, GSLS Würzburg  
   

Education

2008 - 2012   Ph.D. Student, Rudolf Virchow Center, Würzburg, Germany
2002 - 2008 MSc (Diplom) in Chemistry, University of Würzburg, Germany                                      
 

Patents
Co-inventor of a novel biopharmaceutical substance PA 2015 70783 and PCT DK2016 050369 and co-author of 14 peer-reviewed publications with an accumulated impact of +123, so far yielding over 400 citations.

Fellowships, Awards and External Funding
Association with the CRC/Transregio 166 - Receptor Light (2019)
Material Costs Allowance of the Fonds of the chemical industry (FCI) (2018)
Excellent Ideas Program, Fellowship fo the University of Würzburg (2018 - 2022)
Fonds der chemischen Industrie „Exzellente Ideen“ Programm (2018)
Hoerslev Fonden (2018)
Torben og Alice Frimodts Fond (2017)
Brødrene Hartmanns Fond (2016)
Lundbeck Fellowship (2013 - 2015)
GSLS Career Development Fellowship (2012 - 2013)

Position

Supervisor – Biomedicine
Member of the Chair for Biophysics and Biotechnology

Courses

SS 2018/2019
Biophysics and Molecular Biotechnology
Lecture – Thermodynamics