ERC FUNDED PROJECTS

"Translational research aims at applying mechanistic understanding in the development of "precision medicine", which depends on precise diagnostic tools and therapeutic approaches. Cancer therapy is experiencing a switch from non-specific, cytotoxic agents towards molecularly targeted and rationally designed compounds with the promise of greater efficacy and fewer side effects. The two cell-cycle kinases CDK4 and CDK6 normally facilitate cell-cycle progression but are abnormally activated in certain cancers. CDK6 is up-regulated in hematopoietic malignancies, where it is the predominant cell-cycle kinase. The importance of CDK4/6 for tumor development is underscored by the fact that the US FDA selected inhibitors of the kinase activity of CDK4/6 as "breakthrough of the year 2013". Our recent findings suggest that the effects of the inhibitors may be limited as CDK6 is not only involved in cell-cycle progression: ground-breaking research in my group and others has shown that CDK6 is involved in regulation of transcription in a kinase-independent manner thereby driving the proliferation of leukemic stem cells and tumor formation. We have now identified mutations in CDK6 that convert it from a tumor promoter into a tumor suppressor. This unexpected outcome is accompanied by a distinct transcriptional profile. Separating the tumor-promoting from the tumor suppressive functions may open a novel therapeutic avenue for drug development. We aim at understanding which domains and residues of CDK6 are involved in rewiring the transcriptional landscape to pave the way for sophisticated inhibitors. The idea of turning a cancer cell's own most potent weapon against itself is novel and would represent a new paradigm for drug design. Finally, the understanding of CDK6 functions in tumor promotion and maintenance will also result in better patient stratification and improved treatment decisions for a broad spectrum of cancer types."

2 497 520 €

Start date: 2016-09-01, End date: 2021-08-31

Household, family and fertility changes are key drivers of population dynamics. Discovering and explaining the velocity of these changes is essential to understand the current situation and to provide scientific evidence on our demographic future. DisCont will provide seminal contributions by studying the impact of macro-level discontinuities on household and family formation (including fertility) in post-industrial contemporary societies. In the past decade, two macro-level discontinuities have radically transformed lives: the Great Recession and the digitalization of life and of the life course. Although their short-term and long-term impacts are likely to be fundamental, they have not yet been systematically analysed. Through a coordinated series of theoretically-founded empirical studies based on linked macro- and micro-level data, and using a comparative perspective, DisCont will argue that macro-level discontinuities are crucial in explaining broad changes in household and family formation, and that their effects can be persistent either for the population as a whole, or for specific cohorts. DisCont will contribute to five areas: 1) it will make theoretical advances by showing the importance of macro-level discontinuities in the explanation of changes in household and family formation in particular, and in population dynamics in general; 2) it will substantially advance our knowledge of household and family formation in post-industrial contemporary societies; 3) it will contribute in a systematic and path-breaking way to research on the broader societal impact of digitalization and of the Great Recession; 4) it will bring a paradigm shift in Age-Period-Cohort modelling; 5) it will make ground-breaking contributions on the demographic use of “big data” and on the use of agent-based models for the population-level implications of household and family change.

2 400 555 €

Start date: 2017-02-01, End date: 2022-07-31

Epigenetic alterations can be detected in all cancers and in essentially every patient. Despite their prevalence, the concrete functional roles of these alterations are not well understood, for two reasons: First, cancer samples tend to carry many correlated epigenetic alterations, making it difficult to statistically distinguish relevant driver events from those that co-occur for other reasons. Second, we lack tools for targeted epigenome editing that could be used to validate biological function in perturbation and rescue experiments. The proposed project strives to overcome these limitations through experimental and bioinformatic methods development, with the ambition of making and breaking cancer cells in vitro by introducing defined sets of epigenetic alterations. We will focus on leukemia as our “model cancer” (given its low mutation rate, frequent defects in epigenetic regulators, and availability of excellent functional assays), but the concepts and methods are general. In Aim 1, we will generate epigenome profiles for a human knockout cell collection comprising 100 epigenetic regulators and use the data to functionally annotate thousands of epigenetic alterations observed in large cancer datasets. In Aim 2, we will develop an experimental toolbox for epigenome programming using epigenetic drugs, CRISPR-assisted recruitment of epigenetic modifiers for locus-specific editing, and cell-derived guide RNA libraries for epigenome copying. Finally, in Aim 3 we will explore epigenome programming (methods from Aim 2) of candidate driver events (predictions from Aim 1) with the ultimate goal of converting cancer cells into non-cancer cells and vice versa. In summary, this project will establish a broadly applicable methodology and toolbox for dissecting the functional roles of epigenetic alterations in cancer. Moreover, successful creation of a cancer that is driven purely by epigenetic alterations could challenge our understanding of cancer as a genetic disease.

1 281 205 €

Start date: 2016-12-01, End date: 2021-11-30

In Europe estimated 300.000 people are suffering from a spinal cord injury (SCI) with 11.000 new injuries per year. The consequences of spinal cord injury are tremendous for these individuals. The loss of motor functions especially of the arm and grasping function – 40% are tetraplegics – leads to a life-long dependency on care givers and therefore to a dramatic decrease in quality of life in these often young individuals. With the help of neuroprostheses, grasp and elbow function can be substantially improved. However, remaining body movements often do not provide enough degrees of freedom to control the neuroprosthesis. The ideal solution for voluntary control of an upper extremity neuroprosthesis would be to directly record motor commands from the corresponding cortical areas and convert them into control signals. This would realize a technical bypass around the interrupted nerve fiber tracts in the spinal cord. A Brain-Computer Interface (BCI) transform mentally induced changes of brain signals into control signals and serve as an alternative human-machine interface. We showed first results in EEG-based control of a neuroprosthesis in several persons with SCI in the last decade, however, the control is still unnatural and cumbersome. The objective of FEEL YOUR REACH is to develop a novel control framework that incorporates goal directed movement intention, movement decoding, error processing, processing of sensory feedback to allow a more natural control of a neuroprosthesis. To achieve this aim a goal directed movement decoder will be realized, and continuous error potential decoding will be included. Both will be finally joined together with an artificial kinesthetic sensory feedback display attached to the user. We hypothesize that with these mechanisms a user will be able to naturally control an neuroprosthesis with his/ her mind only.

1 994 161 €

Start date: 2016-05-01, End date: 2021-07-31