ERC FUNDED PROJECTS

The biomembrane is a prerequisite of life. It enables the cell to maintain a controlled environment and to establish electrochemical gradients as rapidly accessible energy stores. Biomembranes also provide scaffold for organisation and spatial definition of signal transmission in the cell. Crystal structures of membrane proteins are determined with an increasing pace. Along with functional studies integral studies of individual membrane proteins are now widely implemented. The BIOMEMOS proposal goes a step further and approaches the function of the biomembrane at the higher level of membrane protein complexes. Through a combination of X-ray crystallography, electrophysiology, general biochemistry, biophysics and bioinformatics and including also the application of single-particle cryo-EM and small-angle X-ray scattering, the structure and function of membrane protein complexes of key importance in life will be investigated. The specific targets for investigation in this proposal include: 1) higher-order complexes of P-type ATPase pumps such as signalling complexes of Na+,K+-ATPase, and 2) development of methods for structural studies of membrane protein complexes Based on my unique track record in structural studies of large, difficult structures (ribosomes and membrane proteins) in the setting of a thriving research community in structural biology and biomembrane research in Aarhus provides a critical momentum for a long-term activity. The activity will take advantage of the new possibilities offered by synchrotron sources in Europe. Furthermore, a single-particle cryo-EM research group formed on my initiative in Aarhus, and a well-established small-angle X-ray scattering community provides for an optimal setting through multiple cues in structural biology and functional studies

2 444 180 €

Start date: 2010-04-01, End date: 2015-03-31

Mechanisms governing interaction between multicellular organisms and microbes are central for understanding pathogenesis, symbiosis and the function of ecosystems. We propose to address these mechanisms by pioneering an interdisciplinary approach for understanding cellular signalling, response processes and organ development. The challenge is to determine factors synchronising three processes, organogenesis, infection thread formation and bacterial infection, running in parallel to build a root nodule hosting symbiotic bacteria. We aim to exploit the unique possibilities for analysing endocytosis of bacteria in model legumes and to develop genomic, genetic and biological chemistry tools to break new ground in our understanding of carbohydrates in plant development and plant-microbe interaction. Surface exposed rhizobial polysaccharides play a crucial but poorly understood role in infection thread formation and rhizobial invasion resulting in endocytosis. We will undertake an integrated functional characterisation of receptor-ligand mechanisms mediating recognition of secreted polysaccharides and subsequent signal amplification. So far progress in this field has been limited by the complex nature of carbohydrate polymers, lack of a suitable experimental model system where both partners in an interaction could be manipulated and lack of corresponding methods for carbohydrate synthesis, analysis and interaction studies. In this context our legume model system and the discovery that the legume Nod-factor receptors recognise bacterial lipochitin-oligosaccharide signals at their LysM domains provides a new opportunity. Combined with advanced bioorganic chemistry and nanobioscience approaches this proposal will engage the above mentioned limitations.

2 399 127 €

Start date: 2011-05-01, End date: 2016-04-30

"DNA methylation patterns are frequently perturbed in human diseases such as imprinting disorders and cancer. In cancer increased aberrant DNA methylation is believed to work as a silencing mechanism for tumor suppressor genes such as INK4A, RB1 and MLH1. The high frequency of abnormal DNA methylation found in cancer might be due to the inactivation of a proofreading and/or fidelity system regulating the correct patterns of DNA methylation. Currently we have very limited knowledge about such mechanisms. In this research proposal, we will focus on elucidating the biological function of a novel protein family, which catalyzes the conversion of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl cytosine (5-hmC). By catalyzing this reaction the TET proteins most likely work as DNA demethylases, and they might therefore have a role in regulating DNA methylation fidelity. Interestingly, accumulated data has in the last 2 years shown that TET2 is one of the most frequently mutated genes in various hematological cancers. We propose to investigate the molecular mechanisms by which TET2 regulates normal hematopoiesis, how its inactivation leads to hematopoietic malignancies and how the protein contributes to the regulation of DNA methylation patterns and transcription. Furthermore, we propose several experimental approaches for identifying proteins required for the recruitment of TET proteins to target genes and to analyze their role in the regulation of DNA methylation patterns and in cancer. Finally, we will investigate the potential functional role of 5-hmC and explore the potential mechanisms by which this modification could be erased. We expect to provide new insights into the biology of DNA methylation, hydroxymethylation and contribute to unravel the roles of TET proteins in normal physiology and cancer."

2 298 000 €

Start date: 2012-07-01, End date: 2017-06-30

The project’s overall target is to arrive at a fundamental understanding of electrolyte thermodynamics and thus enable the engineering of a new generation of useful, physically sound models for electrolyte solutions. These models should be general and applicable to a very wide range of conditions so that they can be potentially used for a wide range of applications. Electrolyte solutions are present almost anywhere and find numerous applications in physical sciences including chemistry, geology, material science, medicine, biochemistry and physiology as well as in many engineering fields especially chemical & biochemical, electrical and petroleum engineering. In all these applications the thermodynamics plays a crucial role over wide ranges of temperature, pressure and composition. As the subject is important, a relatively large body of knowledge has been accumulated with lots of data and models. However, disappointingly the state-of-the art thermodynamic models used today in engineering practice are semi-empirical and require numerous experimental data. They lack generality and have not enhanced our understanding of electrolyte thermodynamics. Going beyond the current state of the art, we will create the scientific foundation for studying, at their extremes, both “primitive” and “non-primitive” approaches for electrolyte solutions and identify strengths and limitations. The project is based on the PI’s many years of experience in thermodynamics. The ambition is to make new advances to clarify major questions and misunderstandings in electrolyte thermodynamics, some remaining for over 100 years, which currently prevent real progress from being made, and create a new paradigm which will ultimately pave the way for the development of new engineering models for electrolyte solutions. This is a risky, ambitious and crucial task, but a successful completion will have significant benefits in many industrial sectors as well as in environmental studies and biotechnology.

2 500 000 €

Start date: 2019-09-01, End date: 2024-08-31