ERC FUNDED PROJECTS

Cancer care will be revolutionized over the next decade by the introduction of novel therapeutics that target the underlying molecular mechanisms of the disease. With the advent of human genetics, a plethora of genes have been correlated with human diseases such as cancer the SNP maps. Since the sequences are now available, the next big challenge is to determine the function of these genes in the context of the entire organism. Genetic animal models have proven to be extremely valuable to elucidate the essential functions of genes in normal physiology and the pathogenesis of disease. Using gene-targeted mice we have previously identified RANKL as a master gene of bone loss in arthritis, osteoporosis, and cancer cell migration and metastases and genes that control heart and kidney function; wound healing; diabetes; or lung injury Our primary goal is to use functional genomics in Drosophila and mice to understand cell transformation, invasion, and cancer metastases of epithelial tumors. The following projects are proposed: 1. Role of the key osteoclast differentiation factors RANKL-RANK and its downstream signalling cascade in the development of breast and prostate cancer. 2. Requirement of osteoclasts for bone metastases and stem cell niches using a new RANKfloxed allele; function of RANKL-RANK in local tumor cell invasion. 3. Role of RANKL-RANK in the central fever response to understand potential implications of future RANKL-RANK directed therapies. 4. Integration of gene targeting in mice with state-of-the art technologies in fly genetics; use of whole genome tissue-specific in vivo RNAi Drosophila libraries to identify essential and novel pathways for cancer pathogenesis using whole genome screens. 5. Role of TSPAN6, as a candidate lung metastasis gene. Identification of new cancer disease genes will allow us to design novel strategies for cancer treatment and will have ultimately impact on the basic understanding of cancer, metastases, and human health.

2 499 465 €

Start date: 2009-01-01, End date: 2013-12-31

The main goal of the proposed research is to investigate the possibility of allowing below-ground support systems to respond to strong seismic shaking by going beyond a number of thresholds that would conventionally imply failure and are today forbidden by codes. Such thresholds include : (a) sliding at the soil-foundation interface ; (b) separation and uplifting of a shallow foundation from the soils ; (c) mobilization of bearing capacity failure mechanism for shallow foundations ; (d) structural yielding of pile foundations ; (e) combination of some of the above. Whereas under static loading conditions a slight exceedance of such thresholds leads to failure, the oscillatory nature of seismic shaking will allow such exceedances for a short period of time, with perhaps no detrimental or irreparable consequences. The latter take the form of permanent foundation displacements, rotations, or injuries , which the designer will aspire to confine within rational limits. The motivation and the need for this research has come from : (i) observations of actual behaviour in a variety of earthquakes ; conspicuous examples : the permanent tilting , overturning, and often survival of numerous buildings on extremely soft soil in Adapazari during the Kocaeli 1999 earthquake ; (ii) the foundation design of a number of critical structures (e.g., major bridge pier, air control tower, tall monuments, elevated water tanks,) against large seismic actions ; the disproportionately large overturning moment and/or base shear force of such slender structures can hardly be faced with today s conventional foundation methods, (iii) the need to seismically retrofit and rehabilitate older structures and historical monuments; (iv) structural yielding of pile foundations is now detectable (thanks to technological advances), thus eliminating one of the reasons for avoiding it.

2 399 992 €

Start date: 2008-12-01, End date: 2013-10-31

The project is multi-disciplinary by character. It focuses upon socio-historical processes of the transformation and 'circulation' of educated and ruling elites in several uniquely composite (both multi-ethnic and multi-confessional) East European regional or national societies, having experienced a number of radical changes of social and political regime as well as state souvereignty in the first half of the 20th century. The historical scope of the study extends from post-feudalism to communism. Societies involved comprise Hungary, Slovakia, Transylvania, Voivodina in the Carpathian Basin, Latvia and Estonia in the Baltics. The study draws upon sociological survey methods applied to historically successive elite brackets in form of exhaustive or quasi-exhaustive computerized prosopographical data banks, based on standardized individual biographies of elite members (as permitted by mostly archival sources to be exploited). The main targets would include secondary school graduates, students and graduates of higher education, the main intellectual professions (like doctors and lawyers.), the political power elites as well as 'reputational elites' - those cited in biographical dictionaries. The information fed into our data banks help to clarify thanks to various procedures of multi-variate statistical schemes the contrasting socio-cultural selection and recruitment of elite members, their educational path from primary to higher education, their professional career, intellectual creativity as well as socio-political standing and orientation. This is the first time that large region- or country-wide elite clusters are submitted to systematic socio-historical analyses, covering simultaneously all or most markets of activity and self-assertion of educated clusters in a vast international and comparative perspective related to culturally composite societal formations.

771 628 €

Start date: 2009-01-01, End date: 2012-03-31

Granular materials are of interest to different fields of the physical sciences and engineering. To model their behaviour, either a solid- or fluid mechanics approach is used. Rather than deforming uniformly, granular fluids develop thin shear-bands, which mark areas of flow, material failure and energy dissipation. The MEDIGRA project proposes a thorough experimental, theoretical and numerical study of the Mechanics of Energy DIssipation in dense GRAnular materials. The fundamental challenge faced by the project is to quantify the various energy dissipation mechanisms in dense granular materials using innovative thermo-poromechanical experiments. The measured characteristics are expected to lead to the formulation of appropriate analytical and numerical tools aimed to describe the mechanical behaviour of granular materials from the rigorous angle of energetics. In particular, the project proposes to: 1) Design, develop, install and exploit a novel Thermographic High Speed Cylinder Shear Apparatus (THSCSA) to study the properties of the mechanical and thermal boundary layer that is forming at the inner rotating-drum material interface, as well as determining the required thermographic properties of granular materials. 2) Convincingly quantify the way the total energy dissipation is split into heat production, grain breakage and other mechanisms, using the project-developed THSCSA apparatus and other advanced experimental apparatuses. 3) Develop physical models and robust numerical tools capable of incorporating the experimentally obtained dissipation characteristics. 4) Test the knowledge acquired within the project in two applications (shear segregation and landslide modelling). The project aims to advance our knowledge on the basic physics behind long-standing open problems such as the “heat-flow paradox” in earthquake mechanics, the lifetime prediction of imminent catastrophic landslides and the applicability of continuum approximations to segregation phenomena.

981 600 €

Start date: 2008-11-01, End date: 2011-10-31