Research Areas

Mechanisms of viral replication

Our general research concept is based on the combined use of innovative biochemical and classical genetic/virological methods, predominantly in the area of virus and host proteomics. Projects focus on genetic, molecular and biochemical analyses of four adenovirus (Ad) regulatory proteins, the identification of cellular interaction partners, and the evaluation of their lytic and oncogenic properties in tissue culture as well as animal models. In particular, the possibility to analyze viral protein functions in the context of cell transformation and/or transformed cells is extremely useful to uncover novel principles of viral oncogenesis, and, importantly, has given new insights into molecular strategies used by Ad for viral replication in permissive cells. In fact, much of our current understanding of the molecular mechanisms controlling Ad replication has derived from the study of the viral regulatory proteins involved in cell transformation. Moreover, work in our group increasingly involves translational aspects, aiming at the therapeutic exploitation of our research results.

Over the past years our group has made important contributions to the understanding of the role of E1B-55K, E4orf6 and VI proteins in productive viral replication and their function in malignant cell transformation. Much of our current understanding on the molecular basis involved in viral and cellular mRNA transport in Ad-infected cells has derived from our analyses of the viral proteins and has led to the identification of novel, most likely, general mechanisms of viral oncogenesis.

In the upcoming years our department will concentrate on the analysis of intrinsic cellular defense mechanisms and host cell restriction factors (e.g. Daxx, PML, ATRX and SPOC1) that counteract Ad infection/cell transformation as well as the mechanisms by which E1B-55K and the viral late (capsid) components (V, VI and VII) antagonize the antiviral functions of these host cell factors. Additionally, we will continue to uncover the molecular basis underlying the selective shut-off of host cell mRNA-transport in productively Ad-infected cells.

Viral oncogenesis

A major project within our department will aim for an understanding of the molecular basis underlying the oncogenic capacity of hMSCs focusing particular attention on the identification of cellular factors involved in mesenchymal to epithelial transition (MET). These analyses comprise comparative studies of oncogenically transformed hMS cells by high-throughput transcriptome and proteome approaches as well as functional studies to substantiate the role of the identified factors in the transformation process. These studies should reveal new strategies of cell transformation, and thus, provide a platform for the design of anti-cancer therapeutics.

Antiviral targets

Another important development will involve translational aspects aiming at therapeutic exploitation of our research results. In this context emphasis will be given to potential therapeutic targets (cellular and viral) identified in our department including nuclear export receptors, E3-ubiquitin ligases and, most importantly ubiquitin specific proteases (USPs). Part of this project is integrated into and funded by the German Center for Infection Research (DZIF) in the Thematic Translational Unit (TTU) “Infections of the Immunocompromised Host“ (IICH). Work in this area will be supported by the establishment of differentiated cell culture and tissue culture systems as well as a humanized mouse model, which, in the long term, also should allow us to study mechanism of Ad persistence and pathogenicity in vivo in combination with clinical Ad isolates.