ERC FUNDED PROJECTS

More than a century after Wernicke and Broca established that speech perception and production rely on temporal and prefrontal cortices of the left brain hemisphere, the biological determinants for this organization are still unknown. While functional neuroanatomy has been described in great detail, the neuroscience of language still lacks a physiologically plausible model of the neuro-computational mechanisms for coding and decoding of speech acoustic signal. We propose to fill this gap by testing the biological validity and exploring the computational implications of one promising proposal, the Asymmetric Sampling in Time theory. AST assumes that speech signals are analysed in parallel at multiple timescales and that these timescales differ between left and right cerebral hemispheres. This theory is original and provocative as it implies that a single computational difference, distinct integration windows in right and left auditory cortices could be sufficient to explain why speech is preferentially processed by the left brain, and possible even why the human brain has evolved toward such an asymmetric functional organization. Our proposal has four goals: 1/ to validate, invalidate or amend AST on the basis of physiological experiments in healthy human subjects including functional magnetic resonance imaging (fMRI), combined electroencephalography (EEG) and fMRI, magnetoencephalography (MEG) and subdural electrocorticography (EcoG), 2/ to use computational modeling to probe those aspects of the theory that currently remain inaccessible to empirical testing (evaluation, assessment), 3/ to apply AST to binaural artificial hearing with cochlear implants, 4/ to test for disorders of auditory sampling in autism and dyslexia, two language neurodevelopmental pathologies in which a genetic basis implicates the physiological underpinnings of AST, and 5/ to assess potential generalisation of AST to linguistic action in the context of speech production.

1 500 000 €

Start date: 2011-02-01, End date: 2016-01-31

Bulky DNA adducts formed from chemical carcinogens dictate structure, reactivity, and mechanism of chemical-biological reactions; therefore, their identification is central to evaluating and mitigating cancer risk. Natural food components, or others associated with certain food preparations or metabolic conversions, initiate potentially damaging genetic mutations after forming DNA adducts, which contribute critically to carcinogenesis, despite the fact that they are typically repaired biochemically and they are formed at extremely low levels. This situation places significant limitations on our ability to understand the role of formation, repair, and mutagenesis on the basis of the complex DNA reactivity profiles of food components. The long-term goals of this research are to contribute basic knowledge and advanced experimental tools required to understand, on the basis of chemical structure, the contributions of chronic, potentially adverse, dietary chemical carcinogen exposure to cancer development. It is proposed that a new class of synthetic nucleosides, devised on the basis of preliminary discoveries made in the independent laboratory of the applicant, will serve as molecular probes for bulky DNA adducts and can be effectively used to study and AMPlify, i.e. as a sensitive diagnostic tool, low levels of chemically-specific modes of DNA damage. The proposed research is a chemical biology-based approach to the study of carcinogenesis. Experiments involve chemical synthesis, thermodynamic and kinetic characterization DNA-DNA and enzyme-DNA interactions, and nanoparticle-based molecular probes. The proposal describes a potentially ground-breaking approach for profiling the biological reactivities of chemical carcinogens, and we expect to gain fundamental knowledge and chemical tools that can contribute to the prevention of diseases influenced by gene-environment interactions.

1 500 000 €

Start date: 2010-09-01, End date: 2015-08-31

Cell cycle progression is monitored by checkpoints that ensure the fidelity of cell division and prevent unrestricted cell proliferation. Checkpoints also serve to couple cell size with division – a mechanism important to adapt to changing environmental conditions. While most studies on cell size homeostasis have focused on the links between size and biosynthetic activity, we have recently discovered a novel geometry-sensing mechanism by which fission yeast cells couple cell length with entry into mitosis. Conceptually, the system is remarkably simple: it is composed of a signal – the protein kinase Pom1 – forming concentration gradients from the ends of the cells, which inhibits a sensor – the protein kinase Cdr2, itself an activator of mitotic entry – placed at the cell equator. Since Pom1 concentration at the cell middle is higher in short cells than in long cells, this suggests a model where Pom1 inhibits Cdr2 until the cell has reached a sufficient length. These findings open a conceptually new way of thinking about cell size homeostasis and suggest that cell polarity and cell shape have important effect on cell cycle progression. The proposed project investigates the mechanisms and functional importance of this geometry-sensing system through four specific aims: Aim 1. Defining and modeling the molecular mechanisms of Pom1 gradient formation Aim 2. Dissecting the mechanisms of Pom1 action Aim 3. Investigating the influence of altered cell shape on cell proliferation Aim 4. Exploring the effect of environmental stresses to the Pom1-Cdr2 system By combining genetic, biochemical, physical, live-imaging and modeling approaches, this project will provide an integrated understanding of how cell geometry can be perceived at the molecular level and how this information is transduced to control cell proliferation. This work will have wide-ranging implication for our understanding of gradient formation, cell size homeostasis, and the role of cell polarity in proliferation. It will thus be of interest to cell, developmental and cancer biologists alike.

1 500 000 €

Start date: 2010-09-01, End date: 2016-08-31

This research grant has two major aspects. The first seeks to understand the molecular and cellular basis of the evolution of clear cell renal cell carcinoma(ccRCC), the most frequent form of kidney cancer. We will utilise an integrated approach based on mouse genetics, the use of primary kidney epithelial cell culture systems, genetic screening approaches using RNA interference libraries and analysis of the genetic and molecular changes that arise in human kidney tumours. The rationale behind these studies is that by better understanding the molecular causes of ccRCC it will be possible to identify new molecules or signaling pathways that could serve as appropriate therapeutic targets. The second aspect of this grant relates to the development of a flexible experimental platform that will allow the rapid and simultaneous up- and down-regulation of gene expression in the mouse kidney in a manner in which the affected cells are marked by a luminescent marker. This system will be based on the injection of modified lentiviral gene overexpression and gene knockdown vectors, allowing us to exploit recently-developed genome-wide cDNA libraries and RNA interference libraries. This experimental system should be equally applicable to other organ systems and will allow for the first time a systematic approach to the manipulation of gene expression in living mice, additionally bypassing the time limitations associated with conventional mouse genetic approaches. We aim to develop this system within the biological context of this grant and will combine it with live-animal imaging approaches to generate a series of mouse models of ccRCC. These will ultimately serve as invaluable tools for testing novel therapeutic approaches against this currently untreatable disease.

1 500 000 €

Start date: 2010-12-01, End date: 2015-11-30

Primary cancers can induce lymphatic vessel growth (lymphangiogenesis), enhancing metastasis to draining lymph nodes (LNs). We found that tumors also induce lymphangiogenesis in draining LNs, leading to increased cancer spread to distal LNs and beyond. Very recently, we found that lymphatic vessel activation in peripheral tissues and draining LNs also plays a previously unanticipated role in the control of chronic inflammatory diseases. This proposal aims at a comprehensive characterization of the function of lymphatic vessels in inflammation, using a variety of genetic mouse models for enhanced or reduced lymphatic function, novel quantitative techniques for the in vivo imaging of lymphatic function, and a miniaturized 3-dimensional in vitro platform for the high-throughput phenotypic screening of libraries of small, drug-like molecules for modulators of lymphatic function. A genome-wide analysis of the gene expression profile shall be made from lymphatic vessels isolated by high-speed cell sorting and by immuno-laser capture microdissection from tumors and their lymph node metastases, inflamed tissue and its draining lymph nodes, and normal tissues, followed by functional characterization of potential therapeutic targets and diagnostic markers. Finally, we will establish novel genetically fluorescent mouse models for the in vivo real-time imaging of lymphatic activation, and we will develop an innovative approach for the in vivo detection of early micrometastases, using antibody-based PET and near-infrared imaging of tumor-induced stromal changes. These studies will improve our understanding of lymphatic involvement in inflammation and cancer metastasis, and will provide the basis for completely novel approaches to treat and detect inflammation and cancer metastasis.

2 493 300 €

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

If we are ever to unravel the mysteries of learning, we need a strong theoretical framework that will enable us to trace behavioural properties of memory formation and action learning back to rules for changes of synaptic connections. Experiments on the cell and microcircuit level need hypothesis from theory in order to drive the experimental search for plasticity rules and organize the vast amount of data collected in different labs across Europe and the world. Potential links between synaptic plasticity rules and behavioural outcomes need to be established by mathematical analysis and computer simulation on the systems level, and could ultimately also lead to novel therapeutical approaches. Both theoretical and experimental approaches to synaptic plasticity have been dominated, in the past 30 years, by Hebb¿s rule but the Hebbian framework is a limitation, because it focuses only on two factors: the activity of the presynaptic (sending) neuron and that of the postsynaptic (receiving) one. Hence it neglects additional factors, such as non-specific neuromodulators or global activity states of brain areas. Only very recently a few experiments have appeared that study STDP in the presence of neuromodulators. In this project, I want to break with the preoccupation of Hebbian rules, and formulate and study rules of synaptic plasticity that combine the two Hebbian activity factors with one or multiple global factors. With the new theoretical framework for multi-factor learning rules, to be developed in this project, I will be able to guide the design of novel experiments so that experimental paradigms probe parameters that are relevant for learning. I will be able to make predictions for functional outcomes of learning on the behavioural level, and possibly provide novel strategies for learning of new memories, or unlearning of unpleasant ones.

2 449 218 €

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

This proposal aims to harness a novel type of senescence that we have identified in response to acute Pten inactivation, and which we believe offers a radical therapeutic approach to target the quiescent cancer stem cell in vivo. In characterizing Pten loss Induced Cellular Senescence, which we have named PICS for short, we have discovered that PICS is distinct from other forms of cellular senescence including oncogene-induced senescence (OIS) and replicative senescence. These distinct differences are characterized by a lack of DNA damage and hyper-replication, breaking the current dogma for senescence induction. The ability to induce senescence, an irreversible growth arrest, in cells by targeting Pten signaling, without a requirement for hyper-replication and DNA damage opens up the possibility to target quiescent cells, including stem cells, that have a low proliferative index. This approach has tremendous therapeutic potential and represents one of the most exciting developments for the advancement of prostate cancer therapy in recent years. Through the manipulation of senescence induction pathways we will identify PICS enhancing drugs and redefine the paradigm for cancer therapy. By developing novel mouse models that target prostate stem cells we will evaluate these PICS pro-senescence drugs in a pre-clinical setting. Finally, these results will be cross referenced with data from human prostate stem cells and we will lay the ground work to translate this to the clinical setting, further developing the clinical potential of these findings to eradicate prostate cancer.

1 500 000 €

Start date: 2011-04-01, End date: 2016-03-31

The study of parasitism is important for human welfare but also addresses basic scientific questions cutting across biological disciplines. Traditionally, studies of host-parasite interactions have used various scenarios of how genotypes of the two parties interact based on well-developed theory. Yet, one of the most striking observations is the huge variation in resistance systems across organisms. We lack an appreciation of the diversity of these resistance systems and how they affect, in turn, the parasites. Here, it is proposed to investigate the hypothesis that variation in gene expression is a key element that defines an alternative, flexible and highly adaptable resistance system. The project attempts to unify genomic studies of defence mechanisms with questions of evolutionary ecology of host-parasite interactions. Therefore, the study focuses on an ecologically well-studied system of hosts (Bombus spp.) and their prevalent trypanosome infections (Crithidia). In this system, a highly genetically polymorphic parasite is kept in check by a host with seemingly conserved immune effectors (e.g. anti-microbial peptides, AMPs). Their expression varies depending on the host-parasite pairing, suggesting that variation of the synergistic mixture of expressed defence elements might be crucial and could affect parasite population structure in turn. In the project, experiments and cutting-edge molecular methods will be applied to a natural host-parasite system.

2 100 000 €

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

Song learning in oscine birds shares several characteristics with human language learning: it relies on social interaction, active participation, and error feedback, and must take place within a critical period. Songbirds learn their songs from a tutor: they memorize a template of tutor song and compare their own song to that template until a good match is achieved. The existence of a song template in the songbird brain has been clearly demonstrated in deafening, isolation, and lesion experiments, and therefore the songbird is one of the best animal models for unravelling neural principles of template-based vocal learning. Currently we know very little about neural mechanisms in the brain that support template-based learning. In songbirds, our knowledge about the template is limited to behavioural aspects that favour or hinder faithful imitation and to evidence about the brain areas in which the template is stored. Elusive about the template remains its neural representation, as well as the manner in which it is used for evaluating the plastic juvenile songs. Here we propose for the first time a set of experiments aimed at identifying neural mechanisms of template computations including template storage, template recall, and template-based evaluation of auditory feedback. We test the hypothesis that during singing, juvenile birds recall a memory of tutor song and use that memory to analyze and evaluate their own songs. In the zebra finch, our goal is to find a neural correlate of this memory trace in higher auditory association areas. We believe that our studies will provide fundamental insights into how the brain monitors its behavioral output and compares it to some desired output, for which a sensory template has been memorized.

2 011 440 €

Start date: 2011-06-01, End date: 2016-11-30