About UbiRegulators
The Ubiquitin-Proteasome System (UPS) represents an attractive target for drug development. Dynamic and reversible modification by ubiquitin and Ubiquitin-Like (UbL) molecules adds a level of complexity to the regulation of cellular processes that can best be compared to that of phosphorylation. Given the preliminary observations linking them to cancer, neurodegenerative diseases, cystic fibrosis, and to diabetes, the pathways are obvious candidates for therapeutic intervention. Identification of suitable targets for the development of future therapeutics requires a detailed knowledge of the molecules involved in ubiquitin and UbL modifications and the molecular dissection of their interactions. An approach combining state-of-the-art genomics and proteomics with clinically relevant systems and cell biological models is vital for that task. UbiRegulators is be the ideal instrument to structure the research activities into a multidisciplinary Network that takes on this task and, at the same time, will provide the platform for educating young scientists from academia to biomedicine and the pharmaceutical industry. The aim is to understand the mechanisms of post-translational protein modification by ubiquitin and UbL molecules, elucidating their role in the regulation of basic cellular processes and establishing their link to diseases, such as infectious and inflammatory conditions, cystic fibrosis, cancer, and neurodegenerative diseases like Alzheimer’s and Parkinson’s.
The emphasis of this project is on the understanding of fundamental, ubiquitin-driven molecular mechanisms within eukaryotic cells. The basic materials and technologies are available or relatively easy to expand, but the integrated application for specific aims is innovative. The major research activities towards the project objectives and goal are summarized below.
The RTN connects 12 teams of scientists with unique, complementary and multidisciplinary expertise. The integration of their research efforts within the present network will result in an unprecedented scientific and technological synergy at the crossroads of ubiquitination, signal transduction, and related to cellular location. In the past, scientific advances in the analysis of the complexity of these fields have been hampered by the paucity of proper analytical and imaging methods for their study in living cells or by the lack of integration between different approaches. This network provides a solution to this problem, merging excellence in instrumentation with specific expertise of highly interactive colleagues in top institutions in different European countries.
This proposal combines experts in crystallography, protein structure and function, and biophysical methods (Amsterdam), high-resolution light and electron microscopy and cell imaging (Utrecht, Paris), and protein (bio)chemistry (Haifa, Stuttgart, Göttingen, SyMo-Chem). On the other hand, it combines experts in immunology and virology (Stockholm), high throughput screening and drug discovery (Milan, Recharge), original technology to characterize the mono-ubiquitin proteome, combining specific antibodies and SILAC (stable isotope labelling with amino acids in cell culture) (Milan), membrane biology and lipid biochemistry (Paris, Warsaw, Milan, Utrecht), nucleo-cytoplasmic transport (Göttingen, Haifa), conditional mouse gene knock-out and knock-in technology (Utrecht), and yeast genetics (Munich, Stuttgart, Paris, Warsaw). In addition, most partners are involved in studying diseases which are all related to signal transduction and membrane dynamics: cystic fibrosis and other diseases connected to folding and membrane trafficking, (Stuttgart, Milan), ubiquitin and cancer analysing the role of the different classes of E3, and the DUBs on tissue micro-arrays by in situ hybridization in high-throughput mode (Haifa, Munich, Amsterdam, Milan), and infectious diseases (Stockholm). Several groups possess unique expertise and state-of-the-art equipment that will be used to train the young researchers: mass spectrometry including SILAC protocols, proteomics, new specialised high-resolution optical and electronic microscopy equipment, novel live-cell imaging techniques and functional morphology, proprietary microarray chips and readers.
-- Group Utrecht
