ERC FUNDED PROJECTS

My vision is to establish, within the framework of an ERC CoG, a multidisciplinary group which will work in concert towards pioneering the integration of novel 2-Dimensional nanomaterials with novel additive fabrication techniques to develop a unique class of energy storage devices. Batteries and supercapacitors are two very complementary types of energy storage devices. Batteries store much higher energy densities; supercapacitors, on the other hand, hold one tenth of the electricity per unit of volume or weight as compared to batteries but can achieve much higher power densities. Technology is currently striving to improve the power density of batteries and the energy density of supercapacitors. To do so it is imperative to develop new materials, chemistries and manufacturing strategies. 3D2DPrint aims to develop micro-energy devices (both supercapacitors and batteries), technologies particularly relevant in the context of the emergent industry of micro-electro-mechanical systems and constantly downsized electronics. We plan to use novel two-dimensional (2D) nanomaterials obtained by liquid-phase exfoliation. This method offers a new, economic and easy way to prepare ink of a variety of 2D systems, allowing to produce wide device performance window through elegant and simple constituent control at the point of fabrication. 3D2DPrint will use our expertise and know-how to allow development of advanced AM methods to integrate dissimilar nanomaterial blends and/or “hybrids” into fully embedded 3D printed energy storage devices, with the ultimate objective to realise a range of products that contain the above described nanomaterials subcomponent devices, electrical connections and traditional micro-fabricated subcomponents (if needed) ideally using a single tool.

2 499 942 €

Start date: 2016-10-01, End date: 2021-09-30

In todays advanced technological world, we can track the exact movement of individuals, analyse their genetic makeup and predict predisposition to certain diseases. However, we are unable to accurately assess an individual’s dietary intake. This is without a doubt one of the main stumbling blocks in assessing the link between diet and disease/health. The present proposal (A-DIET) will address this issue with the overarching objective to develop novel strategies for assessment of dietary intake. Using approaches to (1) identify biomarkers of specific foods (2) classify people into dietary patterns (nutritypes) and (3) develop a tool for integration of dietary and biomarker data, A-DIET has the potential to dramatically enhance our ability to accurately assess dietary intake. The ultimate output from A-DIET will be a dietary assessment tool which can be used to obtain an accurate assessment of dietary intake by combining dietary and biomarker data which in turn will allow investigations into relationships between diet, health and disease. New biomarkers of specific foods will be identified and validated using intervention studies and metabolomic analyses. Methods will be developed to classify individuals into dietary patterns based on biomarker/metabolomic profiles thus demonstrating the novel concept of nutritypes. Strategies for integration of dietary and biomarker data will be developed and translated into a tool that will be made available to the wider scientific community. Advances made in A-DIET will enable nutrition epidemiologist’s to properly examine the relationship between diet and disease and develop clear public health messages with regard to diet and health. Additionally results from A-DIET will allow researchers to accurately assess people’s diet and implement health promotion strategies and enable dieticians in a clinical environment to assess compliance to therapeutic diets such as adherence to a high fibre diet or a gluten free diet.

1 995 548 €

Start date: 2015-08-01, End date: 2020-07-31

The proposed work concerns the theoretical and numerical development of robust and adaptive methodologies for broadband imaging in clutter. The word clutter expresses our uncertainty on the wave speed of the propagation medium. Our results are expected to have a strong impact in a wide range of applications, including underwater acoustics, exploration geophysics and ultrasound non-destructive testing. Our machinery is coherent interferometry (CINT), a state-of-the-art statistically stable imaging methodology, highly suitable for the development of imaging methods in clutter. We aim to extend CINT along two complementary directions: novel types of applications, and further mathematical and numerical development so as to assess and extend its range of applicability. CINT is designed for imaging with partially coherent array data recorded in richly scattering media. It uses statistical smoothing techniques to obtain results that are independent of the clutter realization. Quantifying the amount of smoothing needed is difficult, especially when there is no a priori knowledge about the propagation medium. We intend to address this question by coupling the imaging process with the estimation of the medium's large scale features. Our algorithms rely on the residual coherence in the data. When the coherent signal is too weak, the CINT results are unsatisfactory. We propose two ways for enhancing the resolution of CINT: filter the data prior to imaging (noise reduction) and waveform design (optimize the source distribution). Finally, we propose to extend the applicability of our imaging-in-clutter methodologies by investigating the possibility of utilizing ambient noise sources to perform passive sensor imaging, as well as by studying the imaging problem in random waveguides.

690 000 €

Start date: 2010-06-01, End date: 2015-11-30

"Ageing is the gradual and irreversible breakdown of living systems associated with the advancement of time, which leads to an increase in vulnerability and eventual mortality. Despite recent advances in ageing research, the intrinsic complexity of the ageing process has prevented a full understanding of this process, therefore, ageing remains a grand challenge in contemporary biology. In AGELESS, we will tackle this challenge by uncovering the molecular mechanisms of halted ageing in a unique model system, the bats. Bats are the longest-lived mammals relative to their body size, and defy the ‘rate-of-living’ theories as they use twice as much the energy as other species of considerable size, but live far longer. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity. In AGELESS, we will identify the molecular mechanisms that enable mammals to achieve extraordinary longevity, using state-of-the-art comparative genomic methodologies focused on bats. We will identify, using population transcriptomics and telomere/mtDNA genomics, the molecular changes that occur in an ageing wild population of bats to uncover how bats ‘age’ so slowly compared with other mammals. In silico whole genome analyses, field based ageing transcriptomic data, mtDNA and telomeric studies will be integrated and analysed using a networks approach, to ascertain how these systems interact to halt ageing. For the first time, we will be able to utilize the diversity seen within nature to identify key molecular targets and regions that regulate and control ageing in mammals. AGELESS will provide a deeper understanding of the causal mechanisms of ageing, potentially uncovering the crucial molecular pathways that can be modified to halt, alleviate and perhaps even reverse this process in man."

1 499 768 €

Start date: 2013-01-01, End date: 2017-12-31

What does the fossil record tell us about the evolution of colour in animals through deep time? Evidence of colour in fossils can inform on the visual signalling strategies used by ancient animals. Research to date often has a narrow focus, lacks a broad phylogenetic and temporal context, and rarely incorporates information on taphonomy. This proposal represents a bold new holistic approach to the study of fossil colour: it will couple powerful imaging- and chemical analytical techniques with a rigorous programme of fossilisation experiments simulating decay, burial, and transport, and analysis of fossils and their sedimentary context, to construct the first robust models for the evolution of colour in animals through deep time. The research will resolve the original integumentary colours of fossil higher vertebrates, and the original colours of fossil hair; the fossil record of non-melanin pigments in feathers and insects; the biological significance of monotonal patterning in fossil insects; and the evolutionary history of scales and 3D photonic crystals in insects. Critically, the research will test, for the first time, whether evidence of fossil colour can solve broader evolutionary questions, e.g. the true affinities of enigmatic Cambrian chordate-like metazoans, and feather-like integumentary filaments in dinosaurs. The proposal entails construction of a dedicated experimental maturation laboratory for simulating the impact of burial on tissues. This laboratory will form the core of the world’s first integrated ‘experimental fossilisation facility’, consolidating the PI’s team as the global hub for fossil colour research. The research team comprises the PI, three postdoctoral researchers, and three PhD students, and will form an extensive research network via collaborations with 13 researchers from Europe and beyond. The project will reach out to diverse scientists and will inspire a positive attitude to science among the general public and policymakers alike.

1 562 000 €

Start date: 2016-01-01, End date: 2020-12-31

Green Mobility requires an integrated approach to the chain fuel/engine/emissions. The present project aims at ground breaking advances in the area of Green Mobility by (a) enabling the production of affordable, carbon-neutral, clean, solar fuels using exclusively renewable/recyclable raw materials, namely solar energy, water and captured Carbon Dioxide from combustion power plants (b) developing a highly compact, multifunctional reactor, able to eliminate gaseous and particulate emissions from the exhaust of engines operated on such clean fuels. The overall research approach will be based on material science, engineering and simulation technology developed by the PI over the past 20 years in the area of Diesel Emission Control Reactors, which will be further extended and cross-fertilized in the area of Solar Thermochemical Reactors, an emerging discipline of high importance for sustainable development, where the PI’s research group has already made significant contributions, and received the 2006 European Commission’s Descartes Prize for the development of the first ever solar reactor, holding the potential to produce on a large scale, pure renewable Hydrogen from the thermochemical splitting of water, also known as the HYDROSOL technology.

1 750 000 €

Start date: 2011-02-01, End date: 2017-01-31

ASTROFLOW aims to make ground-breaking progress in our physical understanding of exoplanetary mass loss, by quantifying the influence of stellar outflows on atmospheric escape of close-in exoplanets. Escape plays a key role in planetary evolution, population, and potential to develop life. Stellar irradiation and outflows affect planetary mass loss: irradiation heats planetary atmospheres, which inflate and more likely escape; outflows cause pressure confinement around otherwise freely escaping atmospheres. This external pressure can increase, reduce or even suppress escape rates; its effects on exoplanetary mass loss remain largely unexplored due to the complexity of such interactions. I will fill this knowledge gap by developing a novel modelling framework of atmospheric escape that will, for the first time, consider the effects of realistic stellar outflows on exoplanetary mass loss. My expertise in stellar wind theory and 3D magnetohydrodynamic simulations is crucial for producing the next-generation models of planetary escape. My framework will consist of state-of-the-art, time-dependent, 3D simulations of stellar outflows (Method 1), which will be coupled to novel 3D simulations of atmospheric escape (Method 2). My models will account for the major underlying physical processes of mass loss. With this, I will determine the response of planetary mass loss to realistic stellar particle, magnetic and radiation environments and will characterise the physical conditions of the escaping material. I will compute how its extinction varies during transit and compare synthetic line profiles to atmospheric escape observations from, eg, Hubble and our NASA cubesat CUTE. Strong synergy with upcoming observations (JWST, TESS, SPIRou, CARMENES) also exists. Determining the lifetime of planetary atmospheres is essential to understanding populations of exoplanets. ASTROFLOW’s work will be the foundation for future research of how exoplanets evolve under mass-loss processes.

1 999 956 €

Start date: 2019-09-01, End date: 2024-08-31

The dielectric properties of biological tissues are of fundamental importance to the understanding of the interaction of electromagnetic fields with the human body. These properties are used to determine the safety of electronic devices, and in the design, development and refinement of electromagnetic medical imaging and therapeutic devices. Many historical studies have aimed to establish the dielectric properties of a broad range of tissues. A growing number of recent studies have sought to more accurately estimate these dielectric properties by standardising measurement procedures, and in some cases, measuring the dielectric properties in-vivo. However, these studies have often produced results in direct conflict with historical studies, casting doubt on the accuracy of the currently utilised dielectric properties. At best, this uncertainty could significantly delay the development of electromagnetic imaging or therapeutic medical devices. At worst, the health dangers of electromagnetic radiation could be under-estimated. The applicant will embark upon frontier research to develop improved methods and standards for the measurement of the dielectric properties of biological tissue. The research programme will accelerate the design and development of electromagnetic imaging and therapeutic devices, at a time when the technology is gaining significant momentum. The primary objective of the research is to develop a deep understanding of the fundamental factors which contribute to errors in dielectric property measurement. These factors will include in-vivo/ex-vivo measurements and dielectric measurement method used, amongst many others. Secondly, a new open-access repository of dielectric measurements will be created based on a greatly enhanced understanding of the mechanisms underlying dielectric property measurement. Finally, new electromagnetic-based imaging and therapeutic medical devices will be investigated, based on the solid foundation of dielectric data.

1 499 329 €

Start date: 2015-10-01, End date: 2020-09-30

This program’s goal is to develop a scaffold using a new biomaterial source that is functionalised with on-demand delivery of genes for coordinated healing of diabetic foot ulcers (DFUs). DFUs are chronic wounds that are often recalcitrant to treatment, which devastatingly results in lower leg amputation. This project builds on the PI’s experience growing matrix from induced-pluripotent stem cell derived (iPS)-fibroblasts and in developing on-demand drug delivery technologies. The aim of this project is to first develop a SiPS: a scaffold from iPS-fibroblast grown matrix, which has never been tested as a source material for scaffolds. iPS-fibroblasts grow a more pro-repair and angiogenic matrix than (non-iPS) adult fibroblasts. The SiPS structure will be bilayered to mimic native skin: dermis made mostly by fibroblasts and epidermis made by keratinocytes. The dermal layer will consist of a porous scaffold with optimised pore size and mechanical properties and the epidermal layer will be film-like, optimised for keratinisation. Second, the SiPS will be functionalised with delivery of plasmid-DNA (platelet derived growth factor gene, pPDGF) to direct angiogenesis on-demand. As DFUs undergo uncoordinated healing, timed pPDGF delivery will guide them through angiogenesis and healing. To achieve this, alginate microparticles, designed to respond to ultrasound by releasing pPDGF, will be interspersed throughout the SiPS. This BONDS will be tested in an in vivo pre-clinical DFU model to confirm its ability to heal wounds by providing cells with the appropriate biomimetic scaffold environment and timed directions for healing. With >100 million current diabetics expected to get a DFU, the BONDS would have a powerful clinical impact. This research program combines a disruptive technology, the SiPS, with a new platform for on-demand delivery of pDNA to heal DFUs. The PI will build his lab around these innovative platforms, adapting them for treatment of diverse complex wounds.

1 372 135 €

Start date: 2017-10-01, End date: 2022-09-30

Precision medicine is an emerging paradigm that aims at maximizing the benefits and minimizing the harm of drugs. Realistic mechanistic models are needed to understand and limit heterogeneity in drug responses. Consequently, novel approaches are required that explicitly account for individual variations in response to environmental influences, in addition to genetic variation. The human gut microbiota metabolizes drugs and is modulated by diet, and it exhibits significant variation among individuals. However, the influence of the gut microbiota on drug failure or drug side effects is under-researched. In this study, I will combine whole-body, genome-scale molecular resolution modeling of human metabolism and human gut microbial metabolism, which represents a network of genes, proteins, and biochemical reactions, with physiological, clinically relevant modeling of drug responses. I will perform two pilot studies on human subjects to illustrate that this innovative, versatile computational modeling framework can be used to stratify patients prior to drug prescription and to optimize drug bioavailability through personalized dietary intervention. With these studies, BugTheDrug will advance mechanistic understanding of drug-microbiota-diet interactions and their contribution to individual drug responses. I will perform the first integration of cutting-edge approaches and novel insights from four distinct research areas: systems biology, quantitative systems pharmacology, microbiology, and nutrition. BugTheDrug conceptually and technologically addresses the demand for novel approaches to the study of individual variability, thereby providing breakthrough support for progress in precision medicine.

1 687 458 €

Start date: 2018-04-01, End date: 2023-03-31

Discovering the causal mechanisms of a complex system of interacting components is necessary in order to control it. Computational Causal Discovery (CD) is a field that offers the potential to discover causal relations under certain conditions from observational data alone or with a limited number of interventions/manipulations. An important, challenging biological problem that may take decades of experimental work is the induction of biological cellular pathways; pathways are informal causal models indispensable in biological research and drug design. Recent exciting advances in flow/mass cytometry biotechnology allow the generation of large-sample datasets containing measurements on single cells, thus setting the problem of pathway learning suitable for CD methods. CAUSALPATH builds upon and further advances recent breakthrough developments in CD methods to enable the induction of biological pathways from cytometry and other omics data. As a testbed problem we focus on the differentiation of human T-cells; these are involved in autoimmune and inflammatory diseases, as well as cancer and thus, are targets of new drug development for a range of chronic diseases. The biological problem acts as our campus for general novel formalisms, practical algorithms, and useful tools development, pointing to fundamental CD problems: presence of feedback cycles, presence of latent confounding variables, CD from time-course data, Integrative Causal Analysis (INCA) of heterogeneous datasets and others. Three features complement CAUSALPATH’s approach: (A) methods development will co-evolve with biological wet-lab experiments periodically testing the algorithmic postulates, (B) Open-source tools will be developed for the non-expert, and (C) Commercial exploitation of the results will be sought out. CAUSALPATH brings together an interdisciplinary team, committed to this vision. It builds upon the PI’s group recent important results on INCA algorithms.

1 724 000 €

Start date: 2015-01-01, End date: 2019-12-31

Every 30 seconds a person suffers an osteoporosis-related bone fracture in the EU, resulting in significant morbidity, mortality, and health-care costs estimated at €36billion annually. Current therapeutics target bone resorbing osteoclasts, but these are associated with severe side effects. Osteoporosis arises when mesenchymal stem cells (MSC) fail to produce sufficient numbers of bone forming osteoblasts. A key regulator of MSC behaviour is physical loading, yet the mechanisms by which MSCs sense and respond to changes in their mechanical environment are virtually unknown. Primary cilia are nearly ubiquitous ‘antennae-like’ cellular organelles that have very recently emerged as extracellular mechano/chemo-sensors and thus, are strong candidates to play a role in regulating MSC responses in bone. Therefore, the objective of this research program is to determine the role of the primary cilium and associated molecular components in the osteogenic differentiation and recruitment of human MSCs in loading-induced bone adaptation. This will be achieved through ground-breaking in vitro and in vivo techniques developed by the applicant. The knowledge generated in this proposal will represent a profound advance in our understanding of stem cell mechanobiology. In particular, the identification of the cilium and associated molecules as central to stem cell behaviour will lead to the direct manipulation of MSCs via novel cilia-targeted therapeutics that mimic the regenerative influence of loading at a molecular level. These novel therapeutics would therefore target bone formation, providing an alternative path to treatment, resulting in an improved supply of bone forming cells, preventing osteoporosis. Furthermore, these novel therapeutics will be incorporated into biomaterials, generating bioactive osteoinductive scaffolds. These advances will not only improve quality of life for the patient but will significantly reduce the financial burden of bone loss diseases in the EU.

1 455 068 €

Start date: 2013-11-01, End date: 2018-10-31

The genetic code was established at a very early stage during the evolution of life on Earth and is nearly universal. In eukaryotic nuclear genes, the only known examples of a sense codon that underwent an evolutionary change of meaning, from one amino acid to another, occur in yeast species. The codon CUG is translated as Leu in the universal genetic code, but it has long been known to be translated as Ser in some Candida species. In recent work, we discovered that this switch is one of three parallel reassignments of CUG that occurred in three closely related clades of yeasts. CUG was reassigned once from Leu to Ala, and twice from Leu to Ser, in three separate events. The meaning of sense codons in the nuclear genetic code has otherwise remained completely stable during all of eukaryotic evolution, so why was CUG so unstable in yeasts? CODEKILLER will test a radical new hypothesis that the genetic code changes were caused by a killer toxin that specifically attacked the tRNA that translated CUG as Leu. The hypothesis implies that the reassignments of CUG were not driven by selection in favor of their effects on the proteome, as commonly assumed, but by selection against the existence of a particular tRNA. As well as searching for this killer toxin, we will study the detailed mechanism of genetic code change by engineering a reversal of a CUG-Ser species back to CUG-Leu translation, and investigate translation in some species that naturally contain both tRNA-Leu and tRNA-Ser molecules capable of decoding CUG.

2 368 356 €

Start date: 2018-10-01, End date: 2023-09-30

Hypertension is a leading risk factor for cardiovascular disease (CVD) globally, accounting for 25-35% of the population-attributable fraction. Sodium (salt) intake is a key determinant of blood pressure, and reducing sodium intake has emerged as an important target for population-based interventions to prevent CVD. However, there is considerable uncertainty about the optimal level of sodium (salt) intake that is associated with lowest CVD risk, and whether optimal levels differ for different populations and individuals. In this proposal, we will answer key fundamental research questions about the association of sodium intake with blood pressure and CVD risk. Our research challenges current guideline recommendations of low-sodium intake for all populations. Specifically, we will: a) determine whether sustained (long-term) low sodium intake is associated with beneficial (or adverse) effects on established and novel CV biomarkers. b) explore whether inter-daily ‘pattern’ of sodium intake is an important determinant of 24-hour blood pressure pattern; c) determine whether the association between sodium intake and CVD varies by ethnicity, sex, age, other dietary factors (e.g. potassium intake), or other factors in 2 large international epidemiologic studies (PURE and INTERSTROKE; n>125,000 individuals). d) quantify the population-attributable fraction of excess sodium intake on global burden of CVD (stroke, myocardial infarction, heart failure and CV death), and model the potential impact of various population-based approaches to reducing sodium intake; e) determine whether sodium intake is associated with other vascular-related clinical conditions, namely including atrial fibrillation, cognitive impairment and falls (providing novel information); f) determine whether genetic variants associated with ‘salt sensitivity’ and hypertension are association with blood pressure and stroke, and whether these associations are modified by sodium intake.

1 499 431 €

Start date: 2015-05-01, End date: 2020-04-30

The traditional formulation of relativistic quantum theory is ill-equipped to handle the range of difficult computations needed to describe particle collisions at the Large Hadron Collider (LHC) within a suitable time frame. Yet, recent work shows that probability amplitudes in quantum gauge field theories, such as those describing the Standard Model and its extensions, take surprisingly simple forms. The simplicity indicates deep structure in gauge theory that has already led to dramatic computational improvements, but remains to be fully understood. For precision calculations and investigations of the deep structure of gauge theory, a comprehensive method for computing multi-loop amplitudes systematically and efficiently must be found. The goal of this proposal is to construct a new and complete approach to computing amplitudes from a detailed understanding of their singularities, based on prior successes of so-called on-shell methods combined with the latest developments in the mathematics of Feynman integrals. Scattering processes relevant to the LHC and to formal investigations of quantum field theory will be computed within the new framework.

1 954 065 €

Start date: 2015-10-01, End date: 2020-09-30

A key challenge for the 21st century is, therefore to provide billions of people with the means to access, move and manipulate, what has become, huge volumes of information. The environmental and economic implications becoming serious, making energy efficient data communications key to the operation of today’s society. In this project, the Principal Investigator will develop a new framework for optical interconnects and provide a common platform that spans Fibre-to-the-home to chip-to-chip links, even as far as global on-chip interconnects. The project is based on the efficient coupling of the Photonic Crystal resonators with the outside world. These provide the ultimate confinement of light in both space and time allowing orders of magnitude improvements in performance relative to the state of the art, yet in a simpler simple system- the innovator’s dream. New versions of the key components of optical links- light sources, modulators and photo-detectors- will be realised in this new framework providing a new paradigm for energy efficient communication.

1 495 450 €

Start date: 2013-12-01, End date: 2019-05-31

Deep brain stimulation (DBS) is an effective therapy for treating the symptoms of Parkinson’s disease (PD). Despite its success, the mechanisms of DBS are not understood and there is a need to improve DBS to improve long-term stimulation in a wider patient population, limit side-effects, and extend battery life. Currently DBS operates in ‘open-loop’, with stimulus parameters empirically set. Closed-loop DBS, which adjusts parameters based on the state of the system, has the potential to overcome current limitations to increase therapeutic efficacy while reducing side-effects, costs and energy. Several key questions need to be addressed before closed loop DBS can be implemented clinically. This research will develop a new multiscale model of the neuromuscular system for closed-loop DBS. The model will simulate neural sensing and stimulation on a scale not previously considered, encompassing the electric field around the electrode, the effect on individual neurons and neural networks, and generation of muscle force. This will involve integration across multiple temporal and spatial scales, in a complex system with incomplete knowledge of system variables. Experiments will be conducted to validate the model, and identify new biomarkers of neural activity that can used with signals from the brain to enable continuous symptom monitoring. The model will be used to design a new control strategy for closed-loop DBS that can accommodate the nonlinear nature of the system, and short- and long-term changes in system behavior. Though challenging, this research will provide new insights into the changes that take place in PD and the mechanisms by which DBS exerts its therapeutic influence. This knowledge will be used to design a new strategy for closed-loop DBS, ready for testing in patients, with the potential to significantly improve patient outcomes in PD and fundamentally change the way in which implanted devices utilise electrical stimulation to modulate neural activity.

1 999 474 €

Start date: 2015-08-01, End date: 2020-07-31

Genome maintenance, chromatin remodelling and transcription are tightly linked biological processes that are currently poorly understood and vastly unexplored. Nucleotide excision repair (NER) is a major DNA repair pathway that mammalian cells employ to maintain their genome intact and faithfully transmit it into their progeny. Besides cancer and aging, however, defects in NER give rise to developmental disorders whose clinical heterogeneity and varying severity can only insufficiently be explained by the DNA repair defect. Recent work reveals that NER factors play a role, in addition to DNA repair, in transcription and the three-dimensional organization of our genome. Indeed, NER factors are now known to function in the regulation of gene expression, the transcriptional reprogramming of pluripotent stem cells and the fine-tuning of growth hormones during mammalian development. In this regard, the non-random organization of our genome, chromatin and the process of transcription itself are expected to play paramount roles in how NER factors coordinate, prioritize and execute their distinct tasks during development and disease progression. At present, however, no solid evidence exists as to how NER is functionally involved in such complex processes, what are the NER-associated protein complexes and underlying gene networks or how NER factors operate within the complex chromatin architecture. This is primarily due to our difficulties in dissecting the diverse functional contributions of NER proteins in an intact organism. Here, we propose to use a unique series of knock-in, transgenic and NER progeroid mice to decode the functional role of NER in mammals, thus paving the way for understanding how genome maintenance pathways are connected to developmental defects and disease mechanisms in vivo.

1 995 000 €

Start date: 2016-01-01, End date: 2020-12-31

Evolutionary change of gene copy number through gene duplication is a relatively pervasive phenomenon in eukaryotic genomes. However, for a subset of genes such changes are deleterious because they result in imbalances in the cell. Such dosage-sensitive genes have been increasingly implicated in disease, particularly through the association of copy number variants (CNVs) with pathogenicity. In my lab we have previously discovered that many genes in the human genome which were retained after whole genome duplication (WGD) are refractory to gene duplication both over evolutionary timescales and within populations. These are expected characteristics of dosage-balanced genes. Many of these genes are implicated in human disease. I now propose to take a computational (dry-lab) approach to examine the evolution of dosage-balanced genes further and to develop a sophisticated model of evolutionary constraint of copy number. These models will enable the identification of dosage-balanced genes and their consideration as novel candidate disease loci. Recognising and interpreting patterns of constraint is the cornerstone of molecular evolution. Through careful analysis of genome sequences with respect to gene duplication over evolutionary times and within populations, we will develop a formal and generalised model of copy-number evolution and constraint. We will use these models to identify candidate disease loci within pathogenic CNVs. We will also study the characteristics of known disease genes in order to identify novel candidate loci for dosage-dependent disease. This is an ambitious and high impact project that has the potential to yield major insights into gene copy-number constraint and its relationship to complex disease.

1 358 534 €

Start date: 2013-01-01, End date: 2018-12-31

Accurate genome duplication is controlled by multi-subunit protein complexes which associate with chromatin and dictate when and where replication should take place. Dynamic changes in these complexes lie at the heart of their ability to ensure the maintenance of genomic integrity. Defects in origin bound complexes lead to re-replication of the genome across evolution, have been linked to DNA-replication stress and may predispose for gene amplification events. Such genomic aberrations are central to malignant transformation. We wish to understand how once per cell cycle replication is normally controlled within the context of the living cell and how defects in this control may result in loss of genome integrity and provide genome plasticity. To this end, live cell imaging in human cells in culture will be combined with genetic studies in fission yeast and modelling and in silico analysis. The proposed research aims to: 1. Decipher the regulatory mechanisms which act in time and space to ensure once per cell cycle replication within living cells and how they may be affected by system aberrations, using functional live cell imaging. 2. Test whether aberrations in the licensing system may provide a selective advantage, through amplification of multiple genomic loci. To this end, a natural selection experiment will be set up in fission yeast . 3. Investigate how rereplication takes place along the genome in single cells. Is there heterogeneity amongst a population, leading to a plethora of different genotypes? In silico analysis of full genome DNA rereplication will be combined to single cell analysis in fission yeast. 4. Assess the relevance of our findings for gene amplification events in cancer. Does ectopic expression of human Cdt1/Cdc6 in cancer cells enhance drug resistance through gene amplification? Our findings are expected to offer novel insight into mechanisms underlying cancer development and progression.

1 531 000 €

Start date: 2012-02-01, End date: 2017-01-31

"Why do individuals vary in their cognitive abilities? This proposal takes the disciplines of cognition and evolutionary biology into a natural setting to answer this question by investigating a variety of proximate causes and population-level consequences of individual variation in cognitive ability. It represents the first large-scale integrative study of cognitive ability on any wild population. State of the art observational (remote sensing and automated self-administration trials of learning in the wild), chemical (stable isotope analysis of diet), physiological (stress, energetics, immunocompetence), molecular (DNA fingerprinting and metabarcoding) and analytical (reaction norm, quantitative genetic) techniques will be used. The chosen study system, the great tit Parus major, is one of the most widely used in Europe, but uniquely here will consist of 12 subpopulations across deciduous and conifer woodland fragments. The proposal’s broad scope is captured in three objectives: 1) To characterise proximate causes of variation in cognitive (associative/reversal learning; problem solving; brain size) and other traits (the reactive-proactive personality axis; bill morphology), all of which can influence similar ecologically important behaviour. Quantitative genetic, social, parasite-mediated, and physiological causes will be explored. 2) To examine links between these traits, and key behaviours and trade-offs, e.g., space use, niche specialization, predation, parental care and promiscuity; and 3) To examine the consequences of this variation for life histories and fitness. The research team consists of the PI, five early career biologists, and three PhD students, and will collaborate with eight researchers from Europe and further afield. The project will reveal ground-breaking insight into why individuals vary in their cognitive ability. It aims to impact a wide scientific community, to raise public interest in science, and to inform EU biodiversity policy."

1 993 189 €

Start date: 2015-03-01, End date: 2020-12-31

Dietary intake has an enormous impact on aspects of human health, yet scientific consensus about how what we eat affects our biology remains elusive. To address the complex biological impact of diet, I propose to apply an unconventional, ‘humans-as-model-organisms’ approach to compare the molecular and functional effects of a highly structured dietary regime, specified by the Eastern Orthodox Christian Church (EOCC), to the unstructured diet followed by the general population. Individuals who follow the EOCC regime abstain from meat, dairy products and eggs for 180-200 days annually, in a temporally-structured manner initiated in childhood. I aim to explore the biological signatures of structured vs. unstructured diet by addressing three objectives. First I will investigate the effects of the two regimes, and of genetic variation, on higher-level phenotypes including anthropometric, physiological and biomarker traits. Second, I will carry out a comprehensive set of omics assays (metabolomics, transcriptomics, epigenomics and investigation of the gut microbiome), will associate omics phenotypes with genetic variation, and will integrate data across biological levels to uncover complex molecular signatures. Third, I will interrogate the functional consequences of dietary regimes at the cellular level through primary cell culture. Acute and long-term effects of dietary intake will be explored for all objectives through a two timepoint sampling strategy. This proposal therefore comprises a unique opportunity to study a specific perturbation (EOCC structured diet) introduced to a steady-state system (unstructured diet followed by the general population) in a ground-breaking human systems biology type of study. This approach brings together expertise from genomics, computational biology, statistics, medicine and epidemiology. It will lead to novel insights regarding the potent signalling nature of nutrients and is likely to yield results of high translational value.

1 500 000 €

Start date: 2017-06-01, End date: 2022-05-31

Each year cardiovascular diseases such as atherosclerosis and aneurysms cause 48% of all deaths in Europe. Arteries may be regarded as fibre-reinforced materials, with the stiffer collagen fibres present in the arterial wall bearing most of the load during pressurisation. Degenerative vascular diseases such as atherosclerosis and aneurysms alter the macroscopic mechanical properties of arterial tissue and therefore change the arterial wall composition and the quality and orientation of the underlying fibrous architecture. Information on the complex fibre architecture of arterial tissues is therefore at the core of understanding the aetiology of vascular diseases. The current proposal aims to use a combination of in vivo Diffusion Tensor Magnetic Resonance Imaging, with parallel in silico modelling, to non-invasively identify differences in the fibre architecture of human carotid arteries which can be directly linked with carotid artery disease and hence used to diagnose vulnerable plaque rupture risk. Knowledge of arterial fibre patterns, and how these fibres alter in response to their mechanical environment, also provides a means of understanding remodelling of tissue engineered vessels. Therefore, in the second phase of this project, this novel imaging framework will be used to determine fibre patterns of decellularised arterial constructs in vitro with a view to directing mesenchymal stem cell growth and differentiation and creating a biologically and mechanically compatible tissue engineered vessel. In silico mechanobiological models will also be used to help identify the optimum loading environment for the vessels to encourage cell repopulation but prevent excessive intimal hyperplasia. This combination of novel in vivo, in vitro and in silico work has the potential to revolutionise approaches to early diagnosis of vascular diseases and vascular tissue engineering strategies.

1 521 875 €

Start date: 2015-09-01, End date: 2020-08-31

HIGHWAVE is an interdisciplinary project at the frontiers of coastal/ocean engineering, earth system science, statistics and fluid mechanics that will explore fundamental open questions in wave breaking. Why do waves break, how do they dissipate energy and why is this important? A central element of the work builds on recent international developments in the field of wave breaking and wave run-up led by the PI that have provided the first universal criterion for predicting the onset of breaking of water waves in uniform water depths from deep to intermediate. This work has also shown that the run-up of nonlinear waves impinging on a vertical wall can exceed up to 12 times the far-field amplitude of the incoming waves. These results have now opened up the possibility for more accurate operational wave models. They have practical and economic benefits in determining structural loads on ships and coastal/offshore infrastructure, evaluating seabed response to extreme waves, and optimizing operational strategies for maritime and marine renewable energy enterprises. This is a tremendous advance comparable to the introduction of wave prediction during World War II, and the PI aims to be at the forefront of this research effort to take research in wave breaking into fundamentally new directions. The objectives of the project are: (i) to develop an innovative approach to include accurate wave breaking physics into coupled sea state and ocean weather forecasting models; (ii) to obtain improved criteria for the design of ships and coastal/offshore infrastructure; (iii) to quantify erosion by powerful breaking waves, and (iv) to develop new concepts in wave measurement with improved characterization of wave breaking using real-time instrumentation. This highly interdisciplinary project will involve an ambitious and unconventional combination of computational simulation/theory, laboratory experiments, and field measurements of sea waves, closely informed by application needs.

2 499 946 €

Start date: 2019-09-01, End date: 2024-08-31