ERC FUNDED PROJECTS

The aim of the proposed project is to shed light on early childhood gender-differentiated socialization and gender-specific susceptibility to parenting within families in relation to disruptive behaviour in boys and girls in the first four years of life. The popular saying boys will be boys refers to the observation that boys show more disruptive behaviours (e.g., noncompliance or aggression) than girls, a pattern that has been confirmed frequently in scientific research. There is also evidence that parents treat boys differently from girls in ways that are likely to foster boys disruptive behaviour, and that boys are more susceptible to problematic family functioning than girls. The crucial question is whether gender differences in socialization, susceptibility to socialization, and children s behavioural outcomes are also salient when the same parents are doing the parenting of both a boy and a girl. Within-family comparisons are necessary to account for structural differences between families. To this end, families with two children born 22-26 months apart will be recruited from the general population. To account for birth order and gender-combination effects, the sample includes four groups of 150 families each, with the following sibling combinations: girl-boy, boy-girl, girl-girl, and boy-boy. The study has a four-wave longitudinal design, based on the youngest sibling with assessments at ages 12, 24, 36, and 48 months, because gender differences in disruptive behaviour develop during the toddler years. Each assessment consists of two home visits: one with mother and one with father, including observations of both children and of the children separately. Parenting behaviours will be studied in reaction to specific child behaviours, including aggression, noncompliance, and prosocial behaviours.

1 611 970 €

Start date: 2010-02-01, End date: 2015-03-31

CONTEXT - Nanoporous structures are used for application in catalysis, molecular separation, fuel cells, dye sensitized solar cells etc. Given the near molecular size of the porous network, it is extremely challenging to modify the interior surface of the pores after the nanoporous material has been synthesized. THIS PROPOSAL - Atomic Layer Deposition (ALD) is envisioned as a novel technique for creating catalytically active sites and for controlling the pore size distribution in nanoporous materials. ALD is a self-limited growth method that is characterized by alternating exposure of the growing film to precursor vapours, resulting in the sequential deposition of (sub)monolayers. It provides atomic level control of thickness and composition, and is currently used in micro-electronics to grow films into structures with aspect ratios of up to 100 / 1. We aim to make the fundamental breakthroughs necessary to enable atomic layer deposition to engineer the composition, size and shape of the interior surface of nanoporous materials with aspect ratios in excess of 10,000 / 1. POTENTIAL IMPACT Achieving these objectives will enable atomic level engineering of the interior surface of any porous material. We plan to focus on three specific applications where our results will have both medium and long term impacts: - Engineering the composition of pore walls using ALD, e.g. to create catalytic sites (e.g. Al for acid sites, Ti for redox sites, or Pt, Pd or Ni) - chemical functionalization of the pore walls with atomic level control can result in breakthrough applications in the fields of catalysis and sensors. - Atomic level control of the size of nanopores through ALD controlling the pore size distribution of molecular sieves can potentially lead to breakthrough applications in molecular separation and filtration. - Nanocasting replication of a mesoporous template by means of ALD can result in the mass-scale production of nanotubes.

1 432 800 €

Start date: 2010-01-01, End date: 2014-12-31

Human rights are under pressure, in Europe as elsewhere, due to several developments, namely [1] War on terror: the pressures generated by competing discourses [2] Coping with the dangers of rights inflation [3] Conflicting rights: how to handle rights as contested claims [4] The challenges of dealing with universality under fire In this context, the human rights leadership of the European Court of Human Rights is of crucial importance. Yet the Court is not fit for purpose. Inconsistencies and sloppy legal reasoning undermine both its credibility and the impact of its decisions. The research programme that I propose will strengthen the consistency and persuasiveness of Court s legal reasoning so as to improve its accountability and transparency. My aim is to identify new technical solutions for important human rights problems, by the development and application of creative methodologies. The substantive innovations within the field of European human rights law that I propose to make are: [a] the development of new legal tools, which will consistently integrate the accommodation of the particularities of non-dominant groups into the reasoning of the European Court of Human Rights [b] the development of a new theoretical framework combining minimum and maximum approaches to human rights protection, followed by its translation into clear legal criteria for use by the European Court of Human Rights [c] the development of a script that will enable the adoption of a consistent approach by the European Court of Human Rights to conflicts between human rights My methodological approach is characterized by the combination of empirical and normative dimensions, a 360° comparison, and the integration of qualitative research methods (interviews and focus groups with key stakeholders).

1 370 000 €

Start date: 2009-11-01, End date: 2014-10-31

Prostate cancer is the most frequently diagnosed malignancy in the western male population and the associated socio-economic impact on healthcare is more than worrying. There is one key feature of confined (stage T2) prostate cancer that needs to be addressed with immediate urgency: its true aggressiveness. Not all cancers are life threatening and early diagnosis, although needed to improve outcome, will lead to overtreatment of patients with indolent prostate cancer resulting in unnecessary treatment-related morbidity. Therefore, methods to identify clinically significant forms of prostate cancer have to be developed. To pursue this, the initial assessment of the extent of the disease process (clinical staging) needs to be adequate. Obtaining pre-treatment representative tumor tissue (biopsies) is a major clinical challenge, as the disease is often multi-focal and heterogeneous. Accurate functional in vivo imaging modalities could guide these biopsies. Modern genomics technologies have identified numerous cancer cell-associated genetic markers being expressed in prostate cancer tissue or body fluids. Closing the gap between genomics and a non-invasive metabolic assessment of the in vivo prostate, we propose to identify new in vivo targets/biomarkers indicating confined prostate cancer aggressiveness with the underlying central hypothesis: early functional metabolic differences in different tumor foci determine whether it will grow into life-threatening prostate cancer or not. To track these early metabolic differences, the very latest magnetic resonance methodologies, including 13C MR of hyperpolarized metabolites and 1H- and 31P-MRSI of the in vivo human prostate at a field strength of 7 Tesla, will be further developed and implemented. In the well-established translational research environment at the host institution, potential new biomarkers translate into molecular diagnostics or imaging tools for an accurate individual assessment of cancer aggressiveness.

1 800 209 €

Start date: 2010-03-01, End date: 2015-02-28

While significant progress has been made in the diagnosis and treatment of cancer, several major issues remain unresolved. First, only a minority of patients respond to most forms of (chemo)therapy. It is generally believed that this poor responsiveness to drugs has its origin, at least in part, in the molecular heterogeneity of cancer. This heterogeneity requires the use of biomarkers to stratify patients having seemingly similar tumors according to their likely responses to specific cancer therapies. To identify such biomarkers, we will use large-scale genetic screens to identify genes that are causally involved in controlling responses to cancer drugs. Such genes are likely biomarkers of drug responsiveness in the clinic. Availability of such drug response biomarkers will facilitate a more personalized therapy choice for each individual patient. A second major deficit in effective cancer therapy is the lack of sufficient highly selective drug targets. The large-scale cancer genome re-sequencing efforts already indicate that there is a paucity of druggable genes that are consistently mutated in cancer and the same holds true for genes that are consistently over-expressed in cancer. Hence, there is an urgent need for innovative drug targets that have a similar cancer-selectivity as the genes that are specifically mutated or over-expressed in cancer. In this project, we will use large-scale loss of function genetic screens, exploiting the concept of synthetic lethality , to identify genes whose inactivation is selectively toxic to cells having a defined cancer-specific genetic alteration. Drugs against these targets will be highly cancer-selective, as their activity hinges on the presence of a specific genetic defect, which is only present in the cancer cell.

2 176 000 €

Start date: 2010-06-01, End date: 2015-05-31

Equal segregation of chromosomes during cell division is vital to all life. Using a unique combination of cell biological and biochemical techniques, I will show how an essential set of enzymes promotes error-free chromosome segregation. During each cell division, genetically identical daughter cells are generated by accurate partitioning of the duplicated chromosomes. This relies on proper spatio-temporal execution of various highly dynamic processes. The activity of a small group of enzymes is crucial for at least two of these processes: correct chromosome positioning on the cell's equator prior to cell division and the ability to prevent cell division until every chromosome is thus positioned. The molecular fundamentals of signalling to and from these enzymes will be uncovered by chemical genetics, quantitative (phospho)proteomics, rapid affinity purifications and live-cell deconvolution microscopy. The resulting insights will open research avenues that will ultimately contribute to comprehensive models of how biochemical networks manage to prevent chromosome mis-segregation.

1 572 000 €

Start date: 2009-11-01, End date: 2014-10-31

Wnt proteins dictate critical cell growth and lineage decisions during development and in adult tissue homeostasis. Inappropriate activation of Wnt signalling is a frequent cause of cancer. The earliest events that occur after Wnts bind their receptors at the cell surface, such as receptor endocytosis and recruitment of cytoplasmic effectors, are decisive for downstream gene activation but the underlying mechanisms by which these events process and tune the Wnt signal remain poorly understood. The key objective of this proposal is to resolve critical molecular events that drive initiation of the Wnt cascade by focusing on two central questions: How does protein trafficking control Wnt signalling initiation? What molecular mechanisms underlie Wnt-induced formation and activation of multiprotein complexes? I will take a unique approach combining advanced live cell imaging and high resolution immuno-electron microscopy with sophisticated peptide chemistry, gene silencing and biochemistry to dissect early Wnt signalling events at the level of isolated molecules, in cultured cells and in complex tissues of living animals. With the proposed interdisciplinary work I expect to uncover where key Wnt signalling steps occur, which proteins are involved, how they direct protein complex assembly, trafficking and turnover and how these events control transmission of the Wnt signal. Mechanistic insight in how Wnt signals are transmitted is vital to understand how pathway specificity and sensitivity is controlled. Basic insight in these processes will be of utmost importance for the design of strategies to interfere with Wnt signalling in cancer.

1 513 800 €

Start date: 2009-12-01, End date: 2014-11-30

Our intestinal tract is colonized by a myriad of microbes that exceed our body cells in number and coding capacity and have important metabolic and signaling functions. Analysis of the diversity of these microbes inside revealed more than 1000 species, some of which have developed intimate interactions that are operating at the mucus interface separating the intestinal and microbial cells. Notably, we sustain and stimulate these interactions by feeding our microbes inside by the production of large amounts of mucus that equal the undigested components of our diet in caloric value. The understanding of the mucosal interactions is of great importance as they affect our immune system, signal to the brain-gut axis and provide a protective barrier against pathogens. Hence, this project aims to obtain fundamental understanding in the diversity and function of our microbes inside with a focus on mucus-binding bacteria that are either indigenous in the human intestine or ingested as part of our diet. The project will capitalize on (i) the recently developed high-throughput functional (meta)genomics approaches for human subjects, (ii) the genomic characterization of the mucus-degrading species Akkermansia muciniphila, an emerging biomarker for a healthy intestine, and (iii) the genome-driven discovery that the paradigm probiotic, Lactobacillus rhamnosus GG (LGG), contains cell-wall extended pili that strongly bind mucus and signal to human cells. A novel screening system will allow isolation of LGG derivatives with altered mucus-binding that will be instrumental in cause effect and other mechanistic studies. Moreover, the results will contribute to detailed insight in how our microbes inside develop mutualistic interactions, allowing for the design of new food-based approaches.

2 499 000 €

Start date: 2010-06-01, End date: 2015-05-31

Stem cells at the base of the intestinal crypts are in a dynamic equilibrium with their differentiated derivatives. Homeostatic equilibria depend on the presence of negative feedback loops. The role of the Wnt signaling pathway as a driver of epithelial stem cell self renewal and proliferation in the intestine has been relatively well characterized. Much less is known about the negative feedback signals that must exist to control stem cell behavior and the way these may be deregulated in disease. We found that Indian hedgehog is secreted by differentiated intestinal epithelial cells and acts as a negative feedback signal. Hedgehog signaling acts as a break on Wnt signaling in intestinal precursor cells via a secondary signal in the mesenchyme. We will use conditional mutant mice, our large biobank of patient materials and in vitro experiments to further characterize the signals involved in this feedback loop. Our objective is to study the role of this epithelial mesenchymal signaling circuit in the normal intestine and examine the way it is deregulated in intestinal cancer development and inflammation.

1 524 462 €

Start date: 2009-10-01, End date: 2014-09-30

Proline and related secondary amines were found to be efficient organocatalysts of aldol, alkylation, Michael addition, and other challenging bond-forming reactions. The design of even more efficient systems that would allow extending this remarkable catalytic strategy to a useful and environmentally benign synthetic methodology would be highly desirable. This proposal aims to develop a new class of biocatalysts that use the powerful proline-based enamine mechanism of organocatalysts but that take advantage of the water solubility and stereochemical control available with enzymes. As a scaffold for engineering, we will exploit the active-site template of the tautomerase superfamily proteins, the only known group of enzymes that has the unique feature of using a N-terminal proline in catalysis. By systematically screening tautomerases for promiscuous carbonyl transformation activities, we aim to demonstrate that Pro-1 residues within these tautomerases can react with carbonyl compounds to give enamine intermediates, and thus may facilitate various bond-forming reactions. The most promising enzymes will be used in directed evolution experiments to enhance the desired activities to a practical level. For this, new screening and selection methods will be developed that allow the efficient passage through protein sequence space. Furthermore, unnatural secondary amines will be introduced by total chemical synthesis. In this way, we envision to generate superior biocatalysts for carbon-carbon bond-forming reactions. The idea of using a protein scaffold in which a catalytic proline is present as nucleophile and that has a unique reactivity to form enamines would be a completely new approach to making carbon-carbon bonds. It does not copy something in Nature, but is based on the synthetic requirements of the desired bond-forming reactions. I believe that this type of approach is the future of enzyme engineering and is the key to more application of biocatalysis in industry.

2 000 000 €

Start date: 2010-05-01, End date: 2015-04-30

I will analyze the changes in the genome of the pig during speciation, domestication and selection at the molecular level. Domestication and selection have resulted in a large number of distinct breeds worldwide with very distinct characteristics. Unique are also the availability of 12 closely related pig species that have diverged over a time span of 1 to 10 million years. Furthermore, the availability of a high quality genome sequence of the pig by the end of 2009 and the recent advances in next generation sequencing technology makes the SelSweep proposal extremely timely. Within the SelSweep project I will explore the genes and genomic regions that are and have been under strong selection during speciation, early domestication and during subsequent development of specific breeds in the pig. The results of the project will substantially advance our knowledge of evolutionary biology at the molecular level. Moreover, knowledge about the genes affected by selection opens up new directions for further improvement of this important livestock species. The direct sequencing of individuals from a variety of populations using next generation sequencing enables an unbiased capture of the full breadth of genetic variation in the porcine genome addressing both single nucleotide polymorphisms (SNPs) as well as copy number variants (CNVs). The analysis will be done using a previously established porcine HapMap population consisting of domestic breeds from China, Europe and the US, wild boar populations from across the world as well as museum samples representing ancient pig populations. Also included in the panel are other Suidae enabling the identification of the ancestral alleles further strengthening the identification of selective sweeps in the porcine genome.

2 496 381 €

Start date: 2010-03-01, End date: 2015-02-28

Supersymmetry provides an invaluable tool for quantitatively exploring a large variety of non-perturbative phenomena arising in gauge theories and gravitation. This proposal intends to exploit this fact to make significant progress on three important topics in theoretical physics, namely, black holes, strongly-coupled gauge fields, and instantons and supersymmetry breaking. Besides supersymmetry, there is a variety of cross-links between these topics, as well as joint applications. The specific objectives of the proposal are as follows. The first objective concerns the determination of supersymmetric black hole entropy for finite electric and magnetic charges, improving our understanding of critical aspects of the field-theoretic description of the entropy, in direct confrontation with the results based on the counting of microscopic states. The second objective is a construction of the exact spectrum of quantum strings moving in an anti-de Sitter space-time, which, according to the gauge-string correspondence, yields the spectrum of a corresponding dual supersymmetric gauge theory. Deforming the anti-de Sitter space will then lead to stringy descriptions of non-perturbative phenomena in a generic gauge theory with a confining phase. The third objective pertains to instantons and their implications for phenomenologically viable string compactifications on spaces with generalized geometries, which include background electric and magnetic fields. An instanton calculus will be developed to improve the understanding of non-perturbative string theory and its implication for moduli stabilization and supersymmetry breaking.

1 910 093 €

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

Cancer lethality is most often associated to occurrence of distant metastases. To grow and become aggressive, cancers may undergo 2 critical adaptations: the glycolytic switch, corresponding to uncoupling glycolysis from the tricarboxylic acid (TCA) cycle, and the angiogenic switch, promoting neovascularization. In this high risk/high gain research program, we propose that the glycolytic switch precedes and promotes angiogenesis and metastatic dissemination in most types of cancer. We further envision that lactate, the end product of glycolysis, interfaces glycolysis and the latter processes through activation of hypoxia-inducible factor HIF-1. A thorough characterization of the molecular pathway(s) initiated by lactate (using transcriptomic, gene silencing, enzymatic and pharmacological interventions) has the potential to unravel new therapeutic targets that would simultaneously inhibit the consequences of the glycolytic switch on cancer aggressiveness. We anticipate the plasma membrane lactate transporters of the (sodium) monocarboxylate transporter (S)MCT family to be key determinants of autocrine and paracrine lactate signaling in cancer. Modulation of their activity or expression (notably by the generation of (S)MCT knock out mice) could thus profoundly affect tumor angiogenesis and metastasis. Since hypoxia is a hallmark of cancer and glycolysis its direct consequence in cancer cells surviving to hypoxia, the findings could have important consequences for the treatment of virtually all types of cancers. It could also impact our understanding of other pathologies, such as wound healing and heart infarction, in which the interplay between glycolysis, HIF-1 activation and angiogenesis could play a critical role.

1 493 320 €

Start date: 2009-12-01, End date: 2014-11-30