ERC FUNDED PROJECTS

Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.

1 000 000 €

Start date: 2008-07-01, End date: 2013-06-30

Long-term studies of free-living vertebrate populations have proved a rich resource for understanding evolutionary and ecological processes, because individuals’ life histories can be measured by tracking them from birth/hatching through to death. In recent years the ‘animal model’ has been applied to pedigreed long-term study populations with great success, dramatically advancing our understanding of quantitative genetic parameters such as heritabilities, genetic correlations and plasticities of traits that are relevant to microevolutionary responses to environmental change. Unfortunately, quantitative genetic approaches have one major drawback – they cannot identify the actual genes responsible for genetic variation. Therefore, it is impossible to link evolutionary responses to a changing environment to molecular genetic variation, making our picture of the process incomplete. Many of the best long-term studies have been conducted in passerine birds. Unfortunately genomics resources are only available for two model avian species, and are absent for bird species that are studied in the wild. I will fill this gap by exploiting recent advances in genomics technology to sequence the entire transcriptome of the longest running study of wild birds – the great tit population in Wytham Woods, Oxford. Having identified most of the sequence variation in the great tit transcriptome, I will then genotype all birds for whom phenotype records and blood samples are available This will be, by far, the largest phenotype-genotype dataset of any free-living vertebrate population. I will then use gene mapping techniques to identify genes and genomic regions responsible for variation in a number of key traits such as lifetime recruitment, clutch size and breeding/laying date. This will result in a greater understanding, at the molecular level, how microevolutionary change can arise (or be constrained).

1 560 770 €

Start date: 2008-10-01, End date: 2014-06-30

An important question of modern neurobiology is how neurons regulate synaptic function in response to excitation. In particular, the roles of alternative pre-mRNA splicing and mRNA translation regulation in this response are poorly understood. We will study the RNA-binding proteins (RBPs) that control these post-transcriptional changes using a UV crosslinking-based purification method (CLIP) and ultra-high throughput sequencing. Computational analysis of the resulting data will define the sequence and structural features of RNA motifs recognized by each RBP. Splicing microarrays and translation reporter assays will then allow us to examine the regulatory functions of RBPs and RNA motifs. By integrating the biochemical and functional datasets, we will relate the position of RNA motifs to the activity of bound RBPs, and predict the interactions that act as central nodes in the regulatory network. The physiological role of these core RBP-RNA interactions will then be tested using antisense RNAs. Together, these projects will provide insights to the regulatory mechanisms underlying neuronal activity-dependent changes, and provide new opportunities for future treatments of neurodegenerative disorders.

900 000 €

Start date: 2008-09-01, End date: 2013-08-31

Bacterial dehalorespiration is a microbial respiratory process in which halogenated hydrocarbons, from natural or anthropogenic origin, act as terminal electron acceptors. This leads to effective dehalogenation of these compounds, and as such their degradation and detoxification. The bacterial species, their enzymes and other components responsible for this unusual metabolism have only recently been identified. Unlocking the full potential of this process for bioremediation of persistent organohalides, such as polychlorinated biphenyls (PCBs) and tetrachloroethene, requires detailed understanding of the underpinning biochemistry. However, the regulation, mechanism and structure of the reductive dehalogenase (the enzyme responsible for delivering electrons to the halogenated substrates) are poorly understood. This ambitious proposal seeks to study representatives of the distinct reductive dehalogenase classes as well as key elements of the associated regulatory systems. Our group has been at the forefront of studying the biochemistry underpinning transcriptional regulation of dehalorespiration, providing detailed insights in the protein CprK at the atomic level. However, it is now apparent that only a subset of dehalogenases are regulated by CprK homologues with little known about the other regulators. In addition, studies on the reductive dehalogenases have been hampered by the inability to purify sufficient quantities. Using an interdisciplinary, biophysical approach focused around X-ray crystallography, enzymology and molecular biology, combined with novel reductive dehalogenase production methods, we aim to provide a detailed understanding and identification of the structural elements crucial to reductive dehalogenase mechanism and regulation. At the same time, we aim to apply the knowledge gathered and study the feasibility of generating improved dehalorespiratory components for biosensing or bioremediation applications through laboratory assisted evolution.

1 148 522 €

Start date: 2008-09-01, End date: 2013-08-31

We are building a parallel and independent (orthogonal) translational machinery for the encoded biosynthesis of unnatural polymers in living cells. The orthogonal translation system has many potential applications beyond those possible with the natural translation system: I propose to use it: 1) To expand the chemical scope of monomers that can be polymerized by the ribosome in living cells, allowing the incorporation of monomers with unnatural backbones into proteins; 2) To increase the efficiency of in vivo unnatural amino acid mutagenesis via amber suppression, so that no truncated protein is produced and multi-site incorporation of unnatural amino acids is possible; 3) To create probes of protein function for use in vivo; 4) To free numerous codons for simultaneous encoding of multiple distinct unnatural monomers, and to experimentally explore alternate genetic codes; 5) To explore the evolution of encoded unnatural polymers toward new cellular functions.

1 782 918 €

Start date: 2009-01-01, End date: 2014-12-31

This project examines the governance of financial services in the European Union (EU). This research is both academically interesting and policy relevant. Academic research has not kept pace with new developments in this field, and interdisciplinary research is very much needed, as financial services governance is at the cross road between politics, economics and law. At the practical level, the financial sector is a core part of national economies and one of the most active areas of EU policy making. Moreover, this research will contribute to informing the public discussion in a policy area that is often perceived as 'technical', which tends to limit the public scrutiny of it. For the purposes of this research, the governance of financial services in the EU includes: i) the institutional framework through which policies are made; ii) regulation, which is comprised of market-making and market-framing measures; and iii) supervision, that is: the monitoring and enforcement of regulation as well as the practical cooperation between supervisory authorities. First, the project will map the complex institutional framework underpinning financial services governance in the EU, explaining how such framework interplays with regulatory and supervisory arrangements in international arenas and in selected countries. Second, through competitive hypotheses testing, the project will analyse the EU policy-making processes in the financial sector: the main policy-makers and stakeholders involved; their resources, relationships and influence on the policy process; and the outcome. Besides contributing to the policy-oriented debate on financial services regulation and supervision in the EU, the ultimate theoretical goal of the research is to devise an integrated analytical framework that by combining various theoretical approaches and identifying their scope conditions could account for financial services governance in the EU, advancing theories of EU policy making.

377 464 €

Start date: 2008-10-01, End date: 2012-03-31

Growth and development of plants are regulated by signalling substances such as hormones. In plants, interactions between hormonal pathways represent crucial factors that govern their action. As the molecular basis for such hormonal cross-talk remains largely unknown, we will investigate the underlying mechanisms with a special focus on regulation of postembryonic organogenesis. We consider lateral root formation in Arabidopsis as an ideally suited model system, because it encompasses fundamental aspects of plant growth and development, such as dedifferentiation, re-entry into the cell cycle, coordinated cell divisions and differentiation. Furthermore, in lateral root formation, these processes are controlled by multiple hormonal pathways. In our proposal, we will focus on four main research directions. 1. Convergence of hormonal pathways on transport-dependent auxin distribution upstream of lateral root formation. Here, we want to identify key points in which auxin and other signalling pathways converge during lateral root formation and the molecular components involved in the process. 2. Role of auxin-cytokinin interaction in lateral root formation. Molecular events involved in auxin-cytokinin regulated lateral root formation will be studied by transcriptome analysis. 3. Identification of components of hormonal cross-talk by genetic approaches. Using lateral root formation as a model, we will perform mutant screens that will specifically target interactions between selected hormonal pathways. The spectrum of identified molecular components will be further expanded by a chemical genomics approach. 4. Formulation of general models for hormonal regulation of organogenesis. The acquired knowledge on molecular networks and their mutual interactions will be used to mathematically model lateral root development and to extrapolate them also on other developmental situations.

1 300 000 €

Start date: 2008-07-01, End date: 2014-03-31

This project develops new theories and constructs new datasets to understand the determinants of net and gross foreign assets, the trade balance and the exchange rate. It also quantifies their respective roles in the dynamics of countries’ external deficits. In previous work, I constructed a database of US foreign assets and liabilities to analyse the sustainability of US current account deficits. I propose to build on this work along four related lines. First, I will generalize the analysis to other countries, contrasting the external balance sheets of large financially developed economies (US, UK) with those of small open economies (Canada, Australia). I will compare the historical role of the UK as a world banker to the current position of the US in the international monetary system. I will construct disaggregated databases of foreign assets at market value for these countries. Second, I will develop new theories of portfolio investment where international wealth transfers and predictable excess returns play a key role. These elements are rarely incorporated in open economy models but are essential for realism. I will develop and calibrate a new class of portfolio balance models compatible with the macroeconomic stylized facts on capital flows to study how countries’ capacity to accumulate foreign debt depends on changes in portfolio preferences (e.g. erosion of home bias). Third, I will use a disaggregated database of international investment positions of institutional investors to test for portfolio rebalancing at the microeconomic level. This exceptional database should also provide insights on the international propagation of financial crises. I will link the magnitude of price drops of given equities in crisis times to the institutional and geographical characteristics of their holders. Fourth, I will extend the methodology developed to analyze external adjustment to the issue of fiscal adjustment and twin deficits.

1 340 000 €

Start date: 2008-07-01, End date: 2013-06-30

The ability of spindle microtubules of to interact dynamically with centromeric chromatin is a critical feature of chromosome segregation and ensures the faithful distribution of genetic material. Errors in this process lead to abnormal chromosome numbers and are a hallmark of cancer and birth defects. The kinetochore is the key cell division organelle that enables high fidelity transmission of genetic information by coupling chromosomes to the plus-ends of spindle microtubules during mitosis and meiosis. Despite its cytological description more than a century ago, little information is available on kinetochore function at a molecular level. Here, I propose to dissect the molecular mechanisms of kinetochore function using the budding yeast Saccharomyces cerevisiae as a model system. My previous work has demonstrated that fundamental aspects of kinetochore organization are conserved throughout evolution. I will use a combination of biochemistry, electron microscopy, in-vitro assays with static and dynamic microtubule substrates as well as yeast cell biology to address fundamental questions of kinetochore function. Specifically, my experiments aim to elucidate 1) the mechanism of phospho-regulation at the kinetochore-microtubule interface 2) the roles of plus-end tracking proteins in chromosome segregation 3) the roles of kinetochore subcomplexes in connecting microtubules and centromeres. Successful completion of the project will help to move the kinetochore field towards a detailed understanding of the molecular mechanisms of chromosome segregation and can open up new perspectives for analyzing the functions of this complex macromolecular machine.

900 000 €

Start date: 2008-10-01, End date: 2013-09-30

Transcription, the copying of DNA into RNA, is the first step in the realisation of genetic information. RNA is either directly used by the cell or decoded into proteins during translation. The accuracy of transcription is thus essential for proper functioning of the cell. In all living organisms transcription is performed by multisubunit RNA polymerases, enzymes that are highly conserved in evolution from bacteria to humans. Surprisingly, the mechanisms that ensure accuracy of transcription remain largely unknown. Recently I discovered a novel mechanism of transcriptional proofreading used by bacterial RNA polymerase. I showed that the RNA transcript itself assists RNA polymerase in identifying and correcting mistakes. This discovery led to the hypothesis that this transcript-assisted proofreading is the universal mechanism of transcriptional error correction in all three domains of life. In this proposal we will investigate this hypothesis and search for other mechanisms of transcriptional proofreading used by bacterial, archaeal, and three eukaryotic RNA polymerases. For the first time experimental systems will be built for the simultaneous investigation of transcription elongation complexes formed by bacterial, archaeal and eukaryotic RNA polymerases I, II and III, which will be used to elucidate the mechanisms of error correction used by these RNA polymerases. Using molecular modelling, directed mutagenesis and in vivo screenings we will investigate the impact of these proofreading mechanisms on the total fidelity of transcription in vitro and in vivo. Experimental systems built in this research may be of use for screening of potential antibacterial and antifungal drugs taking advantage of the simultaneous investigation of RNA polymerases from all domains of Life. This research may also have potential applications in drug design by providing new targets for antibiotics.

1 149 831 €

Start date: 2008-11-01, End date: 2013-10-31

Democracy promotion has been a key political project in the post-Cold War era and many studies have documented the successes and failures of democratisation. Yet, the current practice of, and academic literature on, democratisation have been characterised by two key limitations. First, engagement with the essentially contested meaning of the concept of democracy has been weak. Second, the contextualisation of models of democracy promoted within wider social, cultural, political and economic discourses has received relatively little attention. It is the general objective of this research to address these limitations. The research seeks to meet this objective by specifically focusing on conducting an innovative analysis of the complex conjunction between the conceptions of democracy advanced by current democracy promoters and the economic discourses and theories adhered to by them. The specific objectives of this project relate to the study of ‘political economy models of democracy’, in theory and in practice. The research is guided by three sets of questions: 1. What is the nature of the link between models of democracy and economic discourses/theories? How do economic discourses condition conceptions of democracy? Do particular economic theories entail particular models of democracy and, if so, what kind of politico-economic models of democracy can we delineate? 2. What assumptions do democracy promoters make about political economies of democracy? What are the consequences, and the strengths and weaknesses, of the politico-economic models of democracy adhered to? 3. What policy-making implications can be drawn from the theoretical and empirical analysis of politico-economic models of democracy? This unique research highlights the complex but often-ignored link between economic theories/discourses and models of democracy, and encourages democracy promoters and academics in the field to remain open to multiple politico-economic models of democracy.

817 922 €

Start date: 2008-07-01, End date: 2012-12-31

This project will help to meet the vital need for empirical research into the theory and practice of Payments for Environmental Services (PES). PES approaches to conservation have become rapidly more popular in the last few years, driven by compelling evidence of their effectiveness compared with indirect approaches to financing conservation. This research will exploit a current opportunity to build robust research protocols into the initial design of a PES scheme, thus allowing credible research into its outcomes. This will be undertaken through work with selected communities around the Nyungwe National Park in Rwanda. Communities will be offered cash transfers, contingent on their performance in relation to a set of conservation indicators. One of the great advantages of this project location is the availability of high quality ranger monitoring that, for example, provides regular geo-referenced data on the location of snares, tree-felling and other illicit activities. The outcomes of this experiment will be investigated through interdisciplinary research based on four main types of data. Firstly, data on forest user behaviour, based on the ranger data and additional transect studies; secondly, livelihood surveys that build an understanding of relationships between communities and park resources; thirdly, qualitative data, based on interviews and focus groups, to build an understanding of the social dynamics arising from introduction of the PES scheme; fourthly, public goods games to elicit data on attitudes towards the Park. The research findings will be of use to a wide range of African and international agencies with an interest in better understanding ways of reconciling biodiversity conservation and poverty alleviation. The results will provide a timely input to our understanding of the theory and practice of PES schemes.

1 027 633 €

Start date: 2008-07-01, End date: 2012-09-30

The role of the sea in drawing together peoples and cultures from distant places and continents in the historical period is readily apparent from textual sources and archaeological remains. In particular, and in contrast to the Atlantic, for example, which has served as a formidable natural barrier to east-west movement and migration, both the Indian Ocean and the Mediterranean have served as important zones of interaction and trade, across which populations have migrated and mixed for at least several thousand years. Recent research findings, including those from the applicant’s archaeological field project in south India, suggest that long-distance maritime activities in this region actually have quite precocious beginnings, and that important species and population transfers across the Indian Ocean probably began to occur well before the historical period. Such findings are perhaps not surprising in light of the evidence for human maritime activity dating back to the colonisation of Australia around 45,000 years ago, but they do suggest that the much more apparent historical evidence for maritime activity has biased maritime research in favour of later periods. This project will accordingly focus on the study of prehistoric maritime activity, and exploration of the specific developments that resulted in the transition from occasional seagoing to regular seafaring and then planned, long-distance voyaging. To do so, it will draw not only upon the traditional disciplines of archaeology and historical linguistics, but also the powerful new methods of molecular genetics, cladistics, and palaeoenvironmental studies. Such research is important not only for its value to researchers trying to reconstruct the histories of human populations, domesticated plants and animals, technologies and societies, but also for its potentially important role in highlighting for the wider public the cultural exchanges and ethnic mixing that have long characterised human societies.

1 200 000 €

Start date: 2008-11-01, End date: 2014-10-31

Antagonistic coevolution between hosts and parasites, the reciprocal evolution of host defence and parasite counter-defence, has far-reaching consequences for evolutionary ecology, agriculture and medicine. It can drive patterns of biodiversity, population dynamics, the evolution of evolvability and parasite virulence. However, the impact of coevolution on these processes is crucially dependent on the specificity of the interaction between host and parasite. That is, do parasite genotypes specialize on host genotypes, or can host and parasites evolve more generalized patterns of resistance and infectivity, respectively? If hosts and parasites specialize on each other, coevolution will be characterized by cycling of genotypes, favouring ongoing coevolution and the maintenance of diversity. By contrast, if generalists evolve, coevolution will be characterised by a directional arms race, resulting in ‘super-parasites’ and the purging of diversity. Host-parasite specificity will be determined by both the genetic bases of the interaction, and the environment. The environment is likely to affect specificity because there are often fitness costs associated with being a generalist, and costs vary under different environmental conditions. The aim of this proposal is to identify the genetic and ecological drivers of host-parasite specificity, and the consequences of this specificity to diversity, virulence, population dynamics and evolvability. The primary approach will be experimental evolution of a well-studied bacteria and phage system; these organisms undergo persistent coevolution in real time under laboratory conditions. Early stages of coevolution are directional; and there are fitness costs associated with the evolution of generalists which vary between environments. We will complement the work by studies of the specificity between bacteria and phage in natural environments and mathematical modeling.

988 860 €

Start date: 2008-11-01, End date: 2012-04-30

When humans process language, they rarely do so in isolation. Linguistic input often occurs synchronously with visual input, e.g., in everyday activities such as attending a lecture or following directions on a map. The visual context constrains the interpretation of the linguistic input, and vice versa, making processing more efficient and less ambiguous. Given the ubiquity of synchronous linguistic and visual processing, it is surprising that there is only a sparse experimental literature that deals with this topic, while virtually no computational models exist that capture the synchronous interpretation process. We propose an experimental research program that will investigate key features of synchronous processing by tracking participants' eye movements when they view a naturalistic scene and listen to a speech stimulus at the same time. The aim is to understand synchronous processing better by studying the interaction of saliency and ambiguity, and the role of incrementality, object context, and task factors. These experimental results will feed into a series of computational models that predict the eye-movement patterns that humans exhibit when they view a scene and listen to speech at the same time. The key modeling idea is to treat synchronous processing as an alignment problem, for which a rich literature exists in computational linguistics. Building on this literature, we will develop models that incrementally construct aligned linguistic and visual representations, and that can be evaluated against eye-tracking data.

1 126 000 €

Start date: 2008-09-01, End date: 2014-08-31

Tetrahymena eliminates micronuclear-limited sequences from the developing macronucleus during sexual reproduction (DNA elimination). It is believed that the DNA to be eliminated is identified by their homology with ~28 nt small RNAs (scnRNAs) which are made by a RNAi-related mechanism. Detailed mechanisms as well as exact biological functions of the RNA-directed DNA elimination remain obscure. The goal of this specific project is to understand: (i) How a RNAi-related mechanism directs DNA elimination. (ii) How the mating types are determined as a consequence of DNA elimination. We recently revealed that scnRNAs are processed by Dicer protein Dcl1p and form complex with Argonaute protein Twi1p. The RNA helicase Ema1p facilitates interaction of scnRNA and chromatin and this interaction induces H3K9 and K27 methylations that are catalyzed by the histone methyltransferase Ezl1p. To understand how these proteins are connected to each other, their detailed functions and novel proteins interacting with them will be analyzed. One of the possible biological functions of the DNA elimination is mating type determination. Tetrahymena possesses seven mating types and the different mating types are thought to be determined by alternative DNA elimination of a single locus. But how mating types are determined is totally unknown. We aim to identify mating type determinants using microarray screening, proteomics and mating type transformation with a cDNA library. Then, we will analyze how expression of those molecules is controlled by DNA elimination. In diverse eukaryotes, RNA silencing mechanisms mediate heterochromatin formation and regulate many chromatin functions. Through our study, we could gain deeper insights not only into DNA elimination in a curious microbe, but also into how chromatin functions are epigenetically controlled by small RNAs in most of the eukaryotes. We are confident that this work will provide a big impact on RNA silencing and chromatin studies.

900 000 €

Start date: 2008-09-01, End date: 2013-12-31