ERC FUNDED PROJECTS

Most hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.

1 100 000 €

Start date: 2008-09-01, End date: 2014-04-30

Climate change and the decreasing availability of fossil fuels require society to move towards sustainable and renewable resources. 2DNanoCaps will focus on electrochemical energy storage, specifically supercapacitors. In terms of performance supercapacitors fill up the gap between batteries and the classical capacitors. Whereas batteries possess a high energy density but low power density, supercapacitors possess high power density but low energy density. Efforts are currently dedicated to move supercapacitors towards high energy density and high power density performance. Improvements have been achieved in the last few years due to the use of new electrode nanomaterials and the design of new hybrid faradic/capacitive systems. We recognize, however, that we are reaching a newer limit beyond which we will only see small incremental improvements. The main reason for this being the intrinsic difficulty in handling and processing materials at the nano-scale and the lack of communication across different scientific disciplines. I plan to use a multidisciplinary approach, where novel nanomaterials, existing knowledge on nano-scale processing and established expertise in device fabrication and testing will be brought together to focus on creating more efficient supercapacitor technologies. 2DNanoCaps will exploit liquid phase exfoliated two-dimensional nanomaterials such as transition metal oxides, layered metal chalcogenides and graphene as electrode materials. Electrodes will be ultra-thin (capacitance and thickness of the electrodes are inversely proportional), conductive, with high dielectric constants. Intercalation of ions between the assembled 2D flakes will be also achievable, providing pseudo-capacitance. The research here proposed will be initially based on fundamental laboratory studies, recognising that this holds the key to achieving step-change in supercapacitors, but also includes scaling-up and hybridisation as final objectives.

1 501 296 €

Start date: 2011-10-01, End date: 2016-09-30

"This proposal develops a unified, underpinning technology to create novel, complex and biomimetic 3D environments for the control of tissue growth. As director of Cambridge Centre for Medical Materials, I have recently been approached by medical colleagues to help to solve important problems in the separate therapeutic areas of breast cancer, cardiac disease and blood disorders. In each case, the solution lies in complex 3D engineered environments for cell culture. These colleagues make it clear that existing 3D scaffolds fail to provide the required complex orientational and spatial anisotropy, and are limited in their ability to impart appropriate biochemical and mechanical cues. I have a strong track record in this area. A particular success has been the use of a freeze drying technology to make collagen based porous implants for the cartilage-bone interface in the knee, which has now been commercialised. The novelty of this proposal lies in the broadening of the established scientific base of this technology to enable biomacromolecular structures with: (A) controlled and complex pore orientation to mimic many normal multi-oriented tissue structures (B) compositional and positional control to match varying local biochemical environments, (C) the attachment of novel peptides designed to control cell behaviour, and (D) mechanical control at both a local and macroscopic level to provide mechanical cues for cells. These will be complemented by the development of (E) robust characterisation methodologies for the structures created. These advances will then be employed in each of the medical areas above. This approach is highly interdisciplinary. Existing working relationships with experts in each medical field will guarantee expertise and licensed facilities in the required biological disciplines. Funds for this proposal would therefore establish a rich hub of mutually beneficial research and opportunities for cross-disciplinary sharing of expertise."

2 486 267 €

Start date: 2013-04-01, End date: 2018-03-31

Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown. Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps. This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer

1 999 750 €

Start date: 2017-03-01, End date: 2022-02-28

The realization of “the internet of things” is inevitably constrained at the level of miniaturization that can be achieved in the electronic devices. A variety of technologies are now going through a process of miniaturization from micro-electromechanical systems (MEMS) to biomedical sensors, and actuators. The ultimate goal is to combine several components in an individual multifunctional platform, realizing on-chip technology. Devices have to be constrained to small footprints and exhibit high performance. Thus, the miniaturization process requires the introduction of new manufacturing processes to fabricate devices in the 3D space over small areas. 3D printing via robocasting is emerging as a new manufacturing technique, which allows shaping virtually any materials from polymers to ceramic and metals into complex architectures. The goal of this research is to establish a 3D printing paradigm to produce miniaturized complex shape devices with diversified functions for on-chip technologies adaptable to “smart environment” such as flexible substrates, smart textiles and biomedical sensors. The elementary building blocks of the devices will be two-dimensional nanomaterials, which present unique optical, electrical, chemical and mechanical properties. The synergistic combination of the intrinsic characteristics of the 2D nanomaterials and the specific 3D architecture will enable advanced performance of the 3D printed objects. This research programme will demonstrate 3D miniaturized energy storage and energy conversion units fabricated with inks produced using a pilot plant. These units are essential components of any on-chip platform as they ensure energy autonomy via self-powering. Ultimately, this research will initiate new technologies based on miniaturized 3D devices.

1 999 968 €

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

The architecture of DNA in the cell nucleus is an emerging epigenetic key contributor to genome function. We recently developed 4C technology, a high-throughput technique that combines state-of-the-art 3C technology with tailored micro-arrays to uniquely allow for an unbiased genome-wide search for DNA loci that interact in the nuclear space. Based on 4C technology, we were the first to provide a comprehensive overview of long-range DNA contacts of selected loci. The data showed that active and inactive chromatin domains contact many distinct regions within and between chromosomes and genes switch long-range DNA contacts in relation to their expression status. 4C technology not only allows investigating the three-dimensional structure of DNA in the nucleus, it also accurately reconstructs at least 10 megabases of the one-dimensional chromosome sequence map around the target sequence. Changes in this physical map as a result of genomic rearrangements are therefore identified by 4C technology. We recently demonstrated that 4C detects deletions, balanced inversions and translocations in patient samples at a resolution (~7kb) that allowed immediate sequencing of the breakpoints. Excitingly, 4C technology therefore offers the first high-resolution genomic approach that can identify both balanced and unbalanced genomic rearrangements. 4C is expected to become an important tool in clinical diagnosis and prognosis. Key objectives of this proposal are: 1. Explore the functional significance of DNA folding in the nucleus by systematically applying 4C technology to differentially expressed gene loci. 2. Adapt 4C technology such that it allows for massive parallel analysis of DNA interactions between regulatory elements and gene promoters. This method would greatly facilitate the identification of functionally relevant DNA elements in the genome. 3. Develop 4C technology into a clinical diagnostic tool for the accurate detection of balanced and unbalanced rearrangements.

1 225 000 €

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

The rupture of an Aortic Aneurysm (AA), which is often lethal, is a mechanical phenomenon that occurs when the wall stress state exceeds the local strength of the tissue. Our current understanding of arterial rupture mechanisms is poor, and the physics taking place at the microscopic scale in these collagenous structures remains an open area of research. Understanding, modelling, and quantifying the micro-mechanisms which drive the mechanical response of such tissue and locally trigger rupture represents the most challenging and promising pathway towards predictive diagnosis and personalized care of AA. The PI's group was recently able to detect, in advance, at the macro-scale, rupture-prone areas in bulging arterial tissues. The next step is to get into the details of the arterial microstructure to elucidate the underlying mechanisms. Through the achievements of AArteMIS, the local mechanical state of the fibrous microstructure of the tissue, especially close to its rupture state, will be quantitatively analyzed from multi-photon confocal microscopy and numerically reconstructed to establish quantitative micro-scale rupture criteria. AArteMIS will also address developing micro-macro models which are based on the collected quantitative data. The entire project will be completed through collaboration with medical doctors and engineers, experts in all required fields for the success of AArteMIS. AArteMIS is expected to open longed-for pathways for research in soft tissue mechanobiology which focuses on cell environment and to enable essential clinical applications for the quantitative assessment of AA rupture risk. It will significantly contribute to understanding fatal vascular events and improving cardiovascular treatments. It will provide a tremendous source of data and inspiration for subsequent applications and research by answering the most fundamental questions on AA rupture behaviour enabling ground-breaking clinical changes to take place.

1 499 783 €

Start date: 2015-04-01, End date: 2020-03-31

"Combustion is essential to the world’s energy generation and transport needs, and will remain so for the foreseeable future. Mitigating its impact on the climate and human health, by reducing its associated emissions, is thus a priority. One significant challenge for gas-turbine combustion is combustion instability, which is currently inhibiting reductions in NOx emissions (these damage human health via a deterioration in air quality). Combustion instability is caused by a two-way coupling between unsteady combustion and acoustic waves - the large pressure oscillations that result can cause substantial mechanical damage. Currently, the lack of fast, accurate modelling tools for combustion instability, and the lack of reliable ways of suppressing it are severely hindering reductions in NOx emissions. This proposal aims to make step improvements in both fast, accurate modelling of combustion instability, and in developing reliable active control strategies for its suppression. It will achieve this by coupling low order combustor models (these are fast, simplified models for simulating combustion instability) with advances in analytical modelling, CFD simulation, reduced order modelling and control theory tools. In particular: * important advances in accurately incorporating the effect of entropy waves (temperature variations resulting from unsteady combustion) and non-linear flame models will be made; * new active control strategies for achieving reliable suppression of combustion instability, including from within limit cycle oscillations, will be developed; * an open-source low order combustor modelling tool will be developed and widely disseminated, opening access to researchers worldwide and improving communications between the fields of thermoacoustics and control theory. Thus the proposal aims to use analytical and computational methods to contribute to achieving low NOx gas-turbine combustion, without the penalty of damaging combustion instability."

1 489 309 €

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

With the recognition that wind energy will become an important contributor to the world’s energy portfolio, several wind farms with a capacity of over 1 gigawatt are in planning phase. In the past, engineering of wind farms focused on a bottom-up approach, in which atmospheric wind availability was considered to be fixed by climate and weather. However, farms of gigawatt size slow down the Atmospheric Boundary Layer (ABL) as a whole, reducing the availability of wind at turbine hub height. In Denmark’s large off-shore farms, this leads to underperformance of turbines which can reach levels of 40%–50% compared to the same turbine in a lone-standing case. For large wind farms, the vertical structure and turbulence physics of the flow in the ABL become crucial ingredients in their design and operation. This introduces a new set of scientific challenges related to the design and control of large wind farms. The major ambition of the present research proposal is to employ optimal control techniques to control the interaction between large wind farms and the ABL, and optimize overall farm-power extraction. Individual turbines are used as flow actuators by dynamically pitching their blades using time scales ranging between 10 to 500 seconds. The application of such control efforts on the atmospheric boundary layer has never been attempted before, and introduces flow control on a physical scale which is currently unprecedented. The PI possesses a unique combination of expertise and tools enabling these developments: efficient parallel large-eddy simulations of wind farms, multi-scale turbine modeling, and gradient-based optimization in large optimization-parameter spaces using adjoint formulations. To ensure a maximum impact on the wind-engineering field, the project aims at optimal control, experimental wind-tunnel validation, and at including multi-disciplinary aspects, related to structural mechanics, power quality, and controller design.

1 499 241 €

Start date: 2012-10-01, End date: 2017-09-30

Space exploration is one of boldest and most exciting endeavors that humanity has undertaken, and it holds enormous promise for the future. Our next challenges for the spatial conquest include bringing back samples to Earth by means of robotic missions and continuing the manned exploration program, which aims at sending human beings to Mars and bring them home safely. Inaccurate prediction of the heat-flux to the surface of the spacecraft heat shield can be fatal for the crew or the success of a robotic mission. This quantity is estimated during the design phase. An accurate prediction is a particularly complex task, regarding modelling of the following phenomena that are potential “mission killers:” 1) Radiation of the plasma in the shock layer, 2) Complex surface chemistry on the thermal protection material, 3) Flow transition from laminar to turbulent. Our poor understanding of the coupled mechanisms of radiation, ablation, and transition leads to the difficulties in flux prediction. To avoid failure and ensure safety of the astronauts and payload, engineers resort to “safety factors” to determine the thickness of the heat shield, at the expense of the mass of embarked payload. Thinking out of the box and basic research are thus necessary for advancements of the models that will better define the environment and requirements for the design and safe operation of tomorrow’s space vehicles and planetary probes for the manned space exploration. The three basic ingredients for predictive science are: 1) Physico-chemical models, 2) Computational methods, 3) Experimental data. We propose to follow a complementary approach for prediction. The proposed research aims at: “Integrating new advanced physico-chemical models and computational methods, based on a multidisciplinary approach developed together with physicists, chemists, and applied mathematicians, to create a top-notch multiphysics and multiscale numerical platform for simulations of planetary atmosphere entries, crucial to the new challenges of the manned space exploration program. Experimental data will also be used for validation, following state-of-the-art uncertainty quantification methods.”

1 494 892 €

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

1.2 billion people worldwide lack access to safe drinking water. Drinking water quality is threatened by newly emerging organic micro-pollutants (pesticides, pharmaceuticals, industrial chemicals) in source waters. Nanofiltration is a technology that is expected to play a key role in future water treatment processes due to its effectiveness in removal of micropollutants. However, the loss of membrane flux due to fouling is one of the main impediments in the development of membrane processes for use in drinking water treatment. Currently there is a wholly inadequate mechanistic understanding of the role of biofilm on the fouling of nanofiltration membranes. Applying techniques including confocal microscopy, force spectroscopy, and infrared spectroscopy using an experimental programme informed by a technique known as scale-down together with mathematical modelling, it is confidently expected that significant advances will be gained in the mechanistic understanding of nanofiltration biofouling. The specific objectives are 1. How is the rate of formation and extent of such biofilms influenced by the biological response to the local microenvironment? 2 Elucidate the effect of extracellular polysaccharide substances on physical properties, composition and structure of these biofilms. 3: Investigate mechanisms to enhance biofilm removal by a physical detachment process complemented by techniques that alter biofilm material properties. A more fundamental insight into the mechanisms of nanofiltration operation will help in further development of this treatment method in future water treatment processes.

1 468 987 €

Start date: 2011-10-01, End date: 2016-09-30

A hot topic in today's debate on global warming is drag reduction in aeronautics. The most beneficial concept for drag reduction is to maintain the major portion of the airfoil laminar. Estimations show that the potential drag reduction can be as much as 15%, which would give a significant reduction of NOx and CO emissions in the atmosphere considering that the number of aircraft take offs, only in the EU, is over 19 million per year. An important element for successful flow control, which can lead to a reduced aerodynamic drag, is enhanced physical understanding of the transition to turbulence process. In previous wind tunnel measurements we have shown that roughness elements can be used to sensibly delay transition to turbulence. The result is revolutionary, since the common belief has been that surface roughness causes earlier transition and in turn increases the drag, and is a proof of concept of the passive control method per se. The beauty with a passive control technique is that no external energy has to be added to the flow system in order to perform the control, instead one uses the existing energy in the flow. In this project proposal, AFRODITE, we will take this passive control method to the next level by making it twofold, more persistent and more robust. Transition prevention is the goal rather than transition delay and the method will be extended to simultaneously control separation, which is another unwanted flow phenomenon especially during airplane take offs. AFRODITE will be a catalyst for innovative research, which will lead to a cleaner sky.

1 418 399 €

Start date: 2010-11-01, End date: 2015-10-31

Understanding how proteins respond to mutations is of paramount importance to biology and disease. While protein stability and misfolding have been instrumental in rationalizing the impact of mutations, we recently discovered that an alternative route is also frequent, where mutations at the surface of symmetric proteins trigger novel self-interactions that lead to infinite self-assembly. This mechanism can be involved in disease, as in sickle-cell anemia, but may also serve in adaptation. Importantly, it differs fundamentally from aggregation, because misfolding does not drive it. Thus, we term it “agglomeration”. The ease with which agglomeration can occur, even by single point mutations, shifts the paradigm of how quickly new protein assemblies can emerge, both in health and disease. This prompts us to determine the basic principles of protein agglomeration and explore its implications in cell physiology and human disease. We propose an interdisciplinary research program bridging atomic and cellular scales to explore agglomeration in three aims: (i) Map the landscape of protein agglomeration in response to mutation in endogenous yeast proteins; (ii) Characterize how yeast physiology impacts agglomeration by changes in gene expression or cell state, and, conversely, how protein agglomerates impact yeast fitness. (iii) Analyze agglomeration in relation to human disease via two approaches. First, by predicting single nucleotide polymorphisms that trigger agglomeration, prioritizing them using knowledge from Aims 1 & 2, and characterizing them experimentally. Second, by providing a proof-of-concept that agglomeration can be exploited in drug design, whereby drugs induce its formation, like mutations can do. Overall, through this research, we aim to establish agglomeration as a paradigm for protein assembly, with implications for our understanding of evolution, physiology, and disease.

2 574 819 €

Start date: 2019-04-01, End date: 2024-03-31

As diploid organisms inherit one gene copy from each parent, a gene can be expressed from both alleles (biallelic) or from only one allele (monoallelic). Although transcription from both alleles is detected for most genes in cell population experiments, little is known about allele-specific expression in single cells and its phenotypic consequences. To answer fundamental questions about allelic transcription heterogeneity in single cells, this research program will focus on single-cell transcriptome analyses with allelic-origin resolution. To this end, we will investigate both clonally stable and dynamic random monoallelic expression across a large number of cell types, including cells from embryonic and adult stages. This research program will be accomplished with the novel single-cell RNA-seq method developed within my lab to obtain quantitative, genome-wide gene expression measurement. To distinguish between mitotically stable and dynamic patterns of allelic expression, we will analyze large numbers a clonally related cells per cell type, from both primary cultures (in vitro) and using transgenic models to obtain clonally related cells in vivo. The biological significance of the research program is first an understanding of allelic transcription, including the nature and extent of random monoallelic expression across in vivo tissues and cell types. These novel insights into allelic transcription will be important for an improved understanding of how variable phenotypes (e.g. incomplete penetrance and variable expressivity) can arise in genetically identical individuals. Additionally, the single-cell transcriptome analyses of clonally related cells in vivo will provide unique insights into the clonality of gene expression per se.

1 923 060 €

Start date: 2015-07-01, End date: 2020-06-30

ALUFIX proposes an original strategy for the development of aluminium-based materials involving damage mitigation and extrinsic self-healing concepts exploiting the new opportunities of the solid-state friction stir process. Friction stir processing locally extrudes and drags material from the front to the back and around the tool pin. It involves short duration at moderate temperatures (typically 80% of the melting temperature), fast cooling rates and large plastic deformations leading to far out-of-equilibrium microstructures. The idea is that commercial aluminium alloys can be locally improved and healed in regions of stress concentration where damage is likely to occur. Self-healing in metal-based materials is still in its infancy and existing strategies can hardly be extended to applications. Friction stir processing can enhance the damage and fatigue resistance of aluminium alloys by microstructure homogenisation and refinement. In parallel, friction stir processing can be used to integrate secondary phases in an aluminium matrix. In the ALUFIX project, healing phases will thus be integrated in aluminium in addition to refining and homogenising the microstructure. The “local stress management strategy” favours crack closure and crack deviation at the sub-millimetre scale thanks to a controlled residual stress field. The “transient liquid healing agent” strategy involves the in-situ generation of an out-of-equilibrium compositionally graded microstructure at the aluminium/healing agent interface capable of liquid-phase healing after a thermal treatment. Along the road, a variety of new scientific questions concerning the damage mechanisms will have to be addressed.

1 497 447 €

Start date: 2017-01-01, End date: 2021-12-31

One already available method to expand the range of material properties is to adjust the composition of materials at the molecular level using chemistry. We would like to develop the alternative approach of homogenization which broadens the definition of a material to include artificially structured media (fluids and solids) in which the effective electromagnetic, hydrodynamic or elastic responses result from a macroscopic patterning or arrangement of two or more distinct materials. This project will explore the latter avenue in order to markedly enhance control of surface water waves and elastodynamic waves propagating within artificially structured fluids and solid materials, thereafter called acoustic metamaterials. Pendry's perfect lens, the paradigm of electromagnetic metamaterials, is a slab of negative refractive index material that takes rays of light and causes them to converge with unprecedented resolution. This flat lens is a combination of periodically arranged resonant electric and magnetic elements. We will draw systematic analogies with resonant mechanical systems in order to achieve similar control of hydrodynamic and elastic waves. This will allow us to extend the design of metamaterials to acoustics to go beyond the scope of Snell-Descartes' laws of optics and Newton's laws of mechanics. Acoustic metamaterials allow the construction of invisibility cloaks for non-linear surface water waves (e.g. tsunamis) propagating in structured fluids, as well as seismic waves propagating in thin structured elastic plates. Maritime and civil engineering applications are in the protection of harbours, off-shore platforms and anti-earthquake passive systems. Acoustic cloaks for an enhanced control of pressure waves in fluids will be also designed for underwater camouflaging. Light and sound interplay will be finally analysed in order to design controllable metamaterials with a special emphasis on undetectable microstructured fibres (acoustic wormholes).

1 280 391 €

Start date: 2011-10-01, End date: 2016-09-30

Malaria parasite infection in humans has been called “the strongest known force for evolutionary selection in the recent history of the human genome”, and I hypothesize that a similar statement may apply to the mosquito vector, which is the definitive host of the malaria parasite. We previously discovered efficient malaria-resistance mechanisms in natural populations of the African malaria vector, Anopheles gambiae. Aim 1 of the proposed project will implement a novel genetic mapping design to systematically survey the mosquito population for common and rare genetic variants of strong effect against the human malaria parasite, Plasmodium falciparum. A product of the mapping design will be living mosquito families carrying the resistance loci. Aim 2 will use the segregating families to functionally dissect the underlying molecular mechanisms controlled by the loci, including determination of the pathogen specificity spectra of the host-defense traits. Aim 3 targets arbovirus transmission, where Anopheles mosquitoes transmit human malaria but not arboviruses such as Dengue and Chikungunya, even though the two mosquitoes bite the same people and are exposed to the same pathogens, often in malaria-arbovirus co-infections. We will use deep-sequencing to detect processing of the arbovirus dsRNA intermediates of replication produced by the RNAi pathway of the mosquitoes. The results will reveal important new information about differences in the efficiency and quality of the RNAi response between mosquitoes, which is likely to underlie at least part of the host specificity of arbovirus transmission. The 3 Aims will make significant contributions to understanding malaria and arbovirus transmission, major global public health problems, will aid the development of a next generation of vector surveillance and control tools, and will produce a definitive description of the major genetic factors influencing host-pathogen interactions in mosquito immunity.

2 307 800 €

Start date: 2013-03-01, End date: 2018-02-28

Humans diverged from our closest living relatives, chimpanzees and other great apes, 6-10 million years ago. Since this divergence, our ancestors acquired genetic changes that enhanced cognition, altered metabolism, and endowed our species with an adaptive capacity to colonize the entire planet and reshape the biosphere. Through genome comparisons between modern humans, Neandertals, chimpanzees and other apes we have identified genetic changes that likely contribute to innovations in human metabolic and cognitive physiology. However, it has been difficult to assess the functional effects of these genetic changes due to the lack of cell culture systems that recapitulate great ape organ complexity. Human and chimpanzee pluripotent stem cells (PSCs) can self-organize into three-dimensional (3D) tissues that recapitulate the morphology, function, and genetic programs controlling organ development. Our vision is to use organoids to study the changes that set modern humans apart from our closest evolutionary relatives as well as all other organisms on the planet. In ANTHROPOID we will generate a great ape developmental cell atlas using cortex, liver, and small intestine organoids. We will use single-cell transcriptomics and chromatin accessibility to identify cell type-specific features of transcriptome divergence at cellular resolution. We will dissect enhancer evolution using single-cell genomic screens and ancestralize human cells to resurrect pre-human cellular phenotypes. ANTHROPOID utilizes quantitative and state-of-the-art methods to explore exciting high-risk questions at multiple branches of the modern human lineage. This project is a ground breaking starting point to replay evolution and tackle the ancient question of what makes us uniquely human?

1 500 000 €

Start date: 2019-06-01, End date: 2024-05-31

The idea of mechanical actuator based on intrinsic material properties of liquid-crystalline elastomers (rather than complex engineering of interacting components) has been understood for 20+ years. The remarkable characteristics of LCE actuation (fully reversible action; large-amplitude, with a stroke of 5%-300%; stress-strain-speed response almost exactly matching the human muscle) make it highly attractive in biomedical engineering, robotics, smart textiles, and other fields. Yet, there is a profound difficulty (bottleneck), which remains the reason why this concept has not found its way into any practical devices & applications. LCE actuation requires alignment (monodomain structure) of the local anisotropy in the permanently crosslinked polymer network - which has been impossible to achieve in any useful large-scale configuration except the flat film, due to the unavoidable restrictions of two competing processes: orientational alignment and network crosslinking. Recently, we made a breakthrough, developing LCE vitrimers (polymer networks covalently crosslinked by a bond-exchange reaction). Vitrimers are much more stable than other transient elastomer networks, allow easy thermal re-moulding (making the material fully renewable), and permit molding of complex shapes with intricate local alignment (which are impossible in traditional elastomers). This project will bridge from the concept to technology, tuning the material design for robust nematic LCE vitrimers, imparting photo-actuation capacity with a controlled wavelength, and finally utilising them in practical-engineering actuator applications where the reversible mechanical action is stimulated by light, solvent exposure, or more traditionally - heat. These applications include (but not limited to): continuous spinning light-driven motor, tactile dynamic Braille display, capillary pump and toggle flow switch for microfuidics, active textile fibre, and heliotracking filament that always points at the Sun.

2 012 136 €

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

The aim of this project is to develop and to demonstrate a novel theoretical framework devoted to rationalizing the formulation of composite electrodes containing next-generation material chemistries for high energy density secondary batteries. The framework will be established through the combination of discrete particle and continuum mathematical models within a multiscale computational workflow integrating the individual models and mimicking the different steps along the electrode fabrication process, including slurry preparation, drying and calendering. Strongly complemented by dedicated experimental characterizations which are devoted to its validation, the goal of this framework is to provide insights about the impacts of material properties and fabrication process parameters on the electrode mesostructures and their corresponding correlation to the resulting electrochemical performance. It targets self-organization mechanisms of material mixtures in slurries by considering the interactions between the active and conductive materials, solvent, binders and dispersants and the relationship between the materials properties such as surface chemistry and wettability. Optimal electrode formulation, fabrication process and the arising electrode mesostructure can then be achieved. Additionally, the framework will be integrated into an online and open access infrastructure, allowing predictive direct and reverse engineering for optimized electrode designs to attain high quality electrochemical performances. Through the demonstration of a multidisciplinary, flexible and transferable framework, this project has tremendous potential to provide insights leading to proposals of new and highly efficient industrial techniques for the fabrication of cheaper and reliable next-generation secondary battery electrodes for a wide spectrum of applications, including Electric Transportation.

1 976 445 €

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

New generations of devices for tissue engineering (TE) should rationalize better the physical and biochemical cues operating in tandem during native regeneration, in particular at the scale/organizational-level of the stem cell niche. The understanding and the deconstruction of these factors (e.g. multiple cell types exchanging both paracrine and direct signals, structural and chemical arrangement of the extra-cellular matrix, mechanical signals…) should be then incorporated into the design of truly biomimetic biomaterials. ATLAS proposes rather unique toolboxes combining smart biomaterials and cells for the ground-breaking advances of engineering fully time-self-regulated complex 2D and 3D devices, able to adjust the cascade of processes leading to faster high-quality new tissue formation with minimum pre-processing of cells. Versatile biomaterials based on marine-origin macromolecules will be used, namely in the supramolecular assembly of instructive multilayers as nanostratified building-blocks for engineer such structures. The backbone of these biopolymers will be equipped with a variety of (bio)chemical elements permitting: post-processing chemistry and micro-patterning, specific/non-specific cell attachment, and cell-controlled degradation. Aiming at being applied in bone TE, ATLAS will integrate cells from different units of tissue physiology, namely bone and hematopoietic basic elements and consider the interactions between the immune and skeletal systems. These ingredients will permit to architect innovative films with high-level dialogue control with cells, but in particular sophisticated quasi-closed 3D capsules able to compartmentalise such components in a “globe-like” organization, providing local and long-range order for in vitro microtissue development and function. Such hybrid devices could be used in more generalised front-edge applications, including as disease models for drug discovery or test new therapies in vitro.

2 498 988 €

Start date: 2015-12-01, End date: 2020-11-30

Regulation of gene expression plays a key role in the ability of bacteria to rapidly adapt to changing environments and to colonize extremely diverse habitats. The relatively recent discovery of a plethora of small regulatory RNAs and the beginning of their characterization has unravelled new aspects of bacterial gene expression. First, the expression of many bacterial genes responds to a complex network of both transcriptional and post-transcriptional regulators. However, the properties of the resulting regulatory circuits on the dynamics of gene expression and in the bacterial adaptive response have been poorly addressed so far. In a first part of this project, we will tackle this question by characterizing the circuits that are formed between two widespread classes of bacterial regulators, the sRNAs and the two-component systems, which act at the post-transcriptional and the transcriptional level, respectively. The study of sRNAs also led to major breakthroughs regarding the basic mechanisms of gene expression. In particular, we recently showed that repressor sRNAs can target activating stem-loop structures located within the coding region of mRNAs that promote translation initiation, in striking contrast with the previously recognized inhibitory role of mRNA structures in translation. The second objective of this project is thus to draw an unprecedented map of non-canonical translation initiation events and their regulation by sRNAs. Overall, this project will greatly improve our understanding of how bacteria can so rapidly and successfully adapt to many different environments, and in the long term, provide clues towards the development of anti-bacterial strategies.

1 999 754 €

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

Lithium ion batteries offer tremendous potential as an enabling technology for sustainable transportation and development. However, their widespread usage as the energy storage solution for electric mobility and grid-level integration of renewables is impeded by the fact that current state-of-the-art lithium ion batteries have energy densities that are too small, charge- and discharge rates that are too low, and costs that are too high. Highly publicized instances of catastrophic failure of lithium ion batteries raise questions of safety. Understanding the limitations to battery performance and origins of the degradation and failure is highly complex due to the difficulties in studying interrelated processes that take place at different length and time scales in a corrosive environment. In the project, we will (1) develop and implement quantitative methods to study the complex interrelations between structure and electrochemistry occurring at the nano-, micron-, and milli-scales in lithium ion battery active materials and electrodes, (2) conduct systematic experimental studies with our new techniques to understand the origins of performance limitations and to develop design guidelines for achieving high performance and safe batteries, and (3) investigate economically viable engineering solutions based on these guidelines to achieve high performance and safe lithium ion batteries.

1 500 000 €

Start date: 2016-05-01, End date: 2021-04-30

The key ideas motivating this project are that: 1) precise control of the properties of porous systems can be obtained by exploiting bacteria and their fantastic abilities; 2) conversely, porous media (large surface to volume ratios, complex structures) could be a major part of bacterial synthetic biology, as a scaffold for growing large quantities of microorganisms in controlled bioreactors. The main scientific obstacle to precise control of such processes is the lack of understanding of biophysical mechanisms in complex porous structures, even in the case of single-strain biofilms. The central hypothesis of this project is that a better fundamental understanding of biofilm biomechanics and physical ecology will yield a novel theoretical basis for engineering and control. The first scientific objective is thus to gain insight into how fluid flow, transport phenomena and biofilms interact within connected multiscale heterogeneous structures - a major scientific challenge with wide-ranging implications. To this end, we will combine microfluidic and 3D printed micro-bioreactor experiments; fluorescence and X-ray imaging; high performance computing blending CFD, individual-based models and pore network approaches. The second scientific objective is to create the primary building blocks toward a control theory of bacteria in porous media and innovative designs of microbial bioreactors. Building upon the previous objective, we first aim to extract from the complexity of biological responses the most universal engineering principles applying to such systems. We will then design a novel porous micro-bioreactor to demonstrate how the permeability and solute residence times can be controlled in a dynamic, reversible and stable way - an initial step toward controlling reaction rates. We envision that this will unlock a new generation of biotechnologies and novel bioreactor designs enabling translation from proof-of-concept synthetic microbiology to industrial processes.

1 649 861 €

Start date: 2019-01-01, End date: 2023-12-31

In the last decade, solar and photovoltaic (PV) technologies have emerged as a potentially major technology for power generation in the world. So far the PV field has been dominated by silicon devices, even though this technology is still expensive.Dye-sensitized solar cells (DSC) are an important type of thin-film photovoltaics due to their potential for low-cost fabrication and versatile applications, and because their aesthetic appearance, semi-transparency and different color possibilities.This advantageous characteristic makes DSC the first choice for building integrated photovoltaics.Despite their great potential, DSCs for building applications are still not available at commercial level. However, to bring DSCs to a marketable product several developments are still needed and the present project targets to give relevant answers to three key limitations: encapsulation, glass substrate enhanced electrical conductivity and more efficient and low-cost raw-materials. Recently, the proponent successfully addressed the hermetic devices sealing by developing a laser-assisted glass sealing procedure.Thus, BI-DSC proposal envisages the development of DSC modules 30x30cm2, containing four individual cells, and their incorporation in a 1m2 double glass sheet arrangement for BIPV with an energy efficiency of at least 9% and a lifetime of 20 years. Additionally, aiming at enhanced efficiency of the final device and decreased total costs of DSCs manufacturing, new materials will be also pursued. The following inner-components were identified as critical: carbon-based counter-electrode; carbon quantum-dots and hierarchically TiO2 photoelectrode. It is then clear that this project is divided into two research though parallel directions: a fundamental research line, contributing to the development of the new generation DSC technology; while a more applied research line targets the development of a DSC functional module that can be used to pave the way for its industrialization.

1 989 300 €

Start date: 2013-03-01, End date: 2018-08-31

Cavitation is the formation of vapor cavities inside a liquid due to low pressure. Cavitation is an ubiquitous and destructive phenomenon common to most engineering applications that deal with flowing water. At the same time, the extreme conditions realized in cavitation are increasingly exploited in medicine, chemistry, and biology. What makes cavitation unpredictable is its multiscale nature: nucleation of vapor bubbles heavily depends on micro- and nanoscale details; mesoscale phenomena, as bubble collapse, determine relevant macroscopic effects, e.g., cavitation damage. In addition, macroscopic flow conditions, such as turbulence, have a major impact on it. The objective of the BIC project is to develop the lacking multiscale description of cavitation, by proposing new integrated numerical methods capable to perform quantitative predictions. The detailed and physically sound understanding of the multifaceted phenomena involved in cavitation (nucleation, bubble growth, transport, and collapse in turbulent flows) fostered by BIC project will result in new methods for designing fluid machinery, but also therapies in ultrasound medicine and chemical reactors. The BIC project builds upon the exceptionally broad experience of the PI and of his research group in numerical simulations of flows at different scales that include advanced atomistic simulations of nanoscale wetting phenomena, mesoscale models for multiphase flows, and particle-laden turbulent flows. The envisaged numerical methodologies (free-energy atomistic simulations, phase-field models, and Direct Numerical Simulation of bubble-laden flows) will be supported by targeted experimental activities, designed to validate models and characterize realistic conditions.

2 491 200 €

Start date: 2014-02-01, End date: 2019-01-31

"Nanomaterials such as carbon nanotubes or graphene sheets represent the future of material science, due to their potentially exceptional mechanical properties. One great drawback of all artificial materials, however, is the decrease of strength with increasing toughness, and viceversa. This problem is not encountered in many biological nanomaterials (e.g. spider silk, bone, nacre). Other biological materials display exceptional adhesion or damping properties, and can be self-cleaning or self-healing. The “secret” of biomaterials seems to lie in “hierarchy”: several levels can often be identified (2 in nacre, up to 7 in bone and dentine), from nano- to micro-scale. The idea of this project is to combine Nature and Nanotechnology to design hierarchical composites with tailor made characteristics, optimized with respect to both strength and toughness, as well as materials with strong adhesion/easy detachment, smart damping, self-healing/-cleaning properties or controlled energy dissipation. For example, one possible objective is to design the “world’s toughest composite material”. The potential impact and importance of these goals on materials science, the high-tech industry and ultimately the quality of human life could be considerable. In order to tackle such a challenging design process, the PI proposes to adopt ultimate nanomechanics theoretical tools corroborated by continuum or atomistic simulations, multi-scale numerical parametric simulations and Finite Element optimization procedures, starting from characterization experiments on biological- or nano-materials, from the macroscale to the nanoscale. Results from theoretical, numerical and experimental work packages will be applied to a specific case study in an engineering field of particular interest to demonstrate importance and feasibility, e.g. an airplane wing with a considerably enhanced fatigue resistance and reduced ice-layer adhesion, leading to a 10 fold reduction in wasted fuel."

1 004 400 €

Start date: 2012-01-01, End date: 2016-12-31

Biomechanical interactions between cells and their environment are essential in almost any biological process, from embryonic development to organ function to diseases. Hence, biomechanical interactions are crucial for health and disease. Examples are hydrodynamic interactions through fluid flow, and forces acting directly on cells. Existing methods to analyze and understand these interactions are limited however, since they do not offer the required combination of precisely controlled flow and accurate applying and sensing of forces. Also, they often lack a physiological environment. A breakthrough in biomechanical analysis is therefore highly needed. We will realize a novel microfluidic platform for biomechanical analysis with unprecedented possibilities of controlling fluid flow and applying and sensing time-dependent forces at subcellular scales in controlled environments. The platform will be uniquely based on bio-inspired magnetic artificial cilia, rather than on conventional microfluidic valves and pumps. Cilia are microscopic hairs ubiquitously present in nature, acting both as actuators and sensors, essential for swimming of microorganisms, transport of dirt out of our airways, and sensing of sound, i.e. they exactly fulfill functions needed in biomechanical analysis. We will develop novel materials and fabrication methods to realize microscopic polymeric artificial cilia, and integrate these in microfluidic devices. Magnetic actuation and optical readout systems complete the platform. We will apply the novel platform to address three fundamental and unresolved biomechanical questions: 1. How do hydrodynamic interactions with actuated cilia steer cellular and particle transport? 2. How do local and dynamic mechanical forces on cells fundamentally influence their motility and differentiation? 3. How do hydrodynamic interactions between cilia steer embryonic development? This unique platform will enable to address many other future biomechanical questions.

3 083 625 €

Start date: 2019-10-01, End date: 2024-09-30

Imagine in the future, bionic devices that can merge device and biology which can perform molecular sensing, simulate the functions of grown-organs in the lab, or even replace or improve parts of the organ as smart implants? Such bionic devices is set to transform a number of emerging fields, including synthetic biotechnology, regenerative medicine, and human-machine interfaces. Merging biology and man-made devices also mean that materials of vastly different properties need to be seamlessly integrated. One of the promising strategies to manufacture these devices is through 3D printing, which can structure different materials into functional devices, and simultaneously intertwining with biological matters. However, the requirement for biocompatibility, miniaturisation, portability and high performance in bionic devices pushes the current limit for micro- nanoscale 3D printing. This proposal aims to develop a new multi-material, cross-length scale biofabrication platform, with specific focus in making future smart bionic devices. In particular, a new mechanism is proposed to smoothly interface diverse classes of materials, such that an active device component can be ‘shrunk’ into a single small fibre. This mechanism utilises the polymeric materials’ flow property under applied tensile forces, and their abilities to combine with other classes of materials, such as semi-conductors and metals to impart further functionalities. This smart device fibre can be custom-made to perform different tasks, such as light emission or energy harvesting, to bridge 3D bioprinting for the future creation of high performance, compact, and cell-friendly bionic and medical devices.

1 486 938 €

Start date: 2018-01-01, End date: 2022-12-31

Rupture of Aortic Aneurysms (AA), which kills more than 30 000 persons every year in Europe and the USA, is a complex phenomenon that occurs when the wall stress exceeds the local strength of the aorta due to degraded properties of the tissue. The state of the art in AA biomechanics and mechanobiology reveals that major scientific challenges still have to be addressed to permit patient-specific computational predictions of AA rupture and enable localized repair of the structure with targeted pharmacologic treatment. A first challenge relates to ensuring an objective prediction of localized mechanisms preceding rupture. A second challenge relates to modelling the patient-specific evolutions of material properties leading to the localized mechanisms preceding rupture. Addressing these challenges is the aim of the BIOLOCHANICS proposal. We will take into account internal length-scales controlling localization mechanisms preceding AA rupture by implementing an enriched, also named nonlocal, continuum damage theory in the computational models of AA biomechanics and mechanobiology. We will also develop very advanced experiments, based on full-field optical measurements, aimed at characterizing localization mechanisms occurring in aortic tissues and at identifying local distributions of material properties at different stages of AA progression. A first in vivo application will be performed on genetic and pharmacological models of mice and rat AA. Eventually, a retrospective clinical study involving more than 100 patients at the Saint-Etienne University hospital will permit calibrating estimations of AA rupture risk thanks to our novel approaches and infuse them into future clinical practice. Through the achievements of BIOLOCHANICS, nonlocal mechanics will be possibly extended to other soft tissues for applications in orthopaedics, oncology, sport biomechanics, interventional surgery, human safety, cell biology, etc.

1 999 396 €

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

In mammals, transcriptional control of many genes relies on cis-regulatory elements such as enhancers, which are often located tens to hundreds of kilobases away from their cognate promoters. Functional interactions between distal regulatory elements and target promoters require mutual physical proximity, which is linked to the three-dimensional structure of the chromatin fiber. Chromosome conformation capture studies revealed that chromosomes are partitioned into Topologically Associating Domains (TADs), sub-megabase domains of preferential physical interactions of the chromatin fiber. Genetic evidence showed that TAD boundaries restrict the genomic range of enhancer-promoter communication, and that interactions between regulatory sequences within TADs are further fine-tuned by smaller-scale structures. However, the mechanistic details of how physical interactions translate into transcriptional outputs are totally unknown. Here we propose to explore the biophysical mechanisms that link chromosome conformation and long-range transcriptional regulation using molecular biology, genetic engineering, single-cell experiments and physical modeling. We will measure chromosomal interactions in single cells and in time using a novel method that relies on an enzymatic process in vivo. Genetic engineering will be used to establish a cell system that allows quantitative measurement of how enhancer-promoter interactions relate to transcription at the population and single-cell levels, and to test the effects of perturbations without confounding effects. Finally, we will develop physical models of promoter operation in the presence of distal enhancers, which will be used to interpret the experimental data and formulate new testable predictions. With this integrated approach we aim at providing an entirely new layer of description of the general principles underlying transcriptional control, which could establish new paradigms for research in epigenetics and gene regulation.

1 500 000 €

Start date: 2018-01-01, End date: 2022-12-31

In BIORECAR I will develop a new breakthrough multifunctional biomaterial-based platform for myocardial regeneration after myocardial infarction, provided with biochemical cues able to enhance the direct reprogramming of human cardiac fibroblasts into functional cardiomyocytes. My expertise in bioartificial materials and biomimetic scaffolds and the versatile chemistry of polyurethanes will be the key elements to achieve a significant knowledge and technological advancement in cell reprogramming therapy, opening the way to the future translation of the therapy into the clinics. I will implement this advanced approach through the design of a novel 3D in vitro tissue-engineered model of human cardiac fibrotic tissue, as a tool for testing and validation, to maximise research efforts and reduce animal tests. I will adapt novel nanomedicine approaches I have recently developed for drug release to design innovative cell-friendly and efficient polyurethane nanoparticles for targeted reprogramming of cardiac fibroblasts. I will design an injectable bioartificial hydrogel based on a blend of a thermosensitive polyurethane and a natural component selected among a novel cell-secreted natural polymer mixture (“biomatrix”) recapitulating the complexity of cardiac extracellular matrix or one of its main protein constituents. Such multifunctional hydrogel will deliver in situ agents stimulating recruitment of cardiac fibroblasts together with the nanoparticles loaded with reprogramming therapeutics, and will provide biochemical signalling to stimulate efficient conversion of fibroblasts into mature cardiomyocytes. First-in-field biomaterials-based innovations introduced by BIORECAR will enable more effective regeneration of functional myocardial tissue respect to state-of-the art approaches. BIORECAR innovation is multidisciplinary in nature and will be accelerated towards future clinical translation through my clinical, scientific and industrial collaborations.

2 000 000 €

Start date: 2018-07-01, End date: 2023-06-30

Water is the first molecule to come into contact with biomaterials in biological systems and thus essential to the processes of biodegradation, biocompatibility and biofouling. Despite this fact, little is currently known about how biomaterials interact with water. This knowledge is crucial for the development and optimisation of novel functional biomaterials for human health (e.g. biosensing devices, erodible biomaterials, drug release carriers, wound dressings). BioWater will develop near and mid infrared chemical imaging (NIR-MIR-CI) techniques to investigate the fundamental interaction between biomaterials and water in order to understand the key processes of biodegradation, biocompatibility and biofouling. This ambitious yet achievable project will focus on two major categories of biomaterials relevant to human health: extracellular collagens and synthetic biopolymers. Initially, interactions between these biomaterials and water will be investigated; subsequently interactions with more complicated matrices (e.g. protein solutions and cellular systems) will be studied. CI data will be correlated with standard surface characterization, biocompatibility and biodegradation measurements. Molecular dynamic simulations will complement this work to identify the most probable molecular structures of water at different biomaterial interfaces. Advanced understanding of the role of water in biocompatibility, biofouling and biodegradation processes will facilitate the optimization of biomaterials tailored to specific cellular environments with a broad range of therapeutic applications (e.g. drug eluting stents, tissue engineering, wound healing). The new NIR-MIR-CI/chemometric methodologies developed in BioWater will allow for the rapid characterization and monitoring of novel biomaterials at pre-clinical stages, improving process control by overcoming the laborious and time consuming large-scale sampling methods currently required in biomaterials development.

1 487 682 €

Start date: 2014-02-01, End date: 2019-01-31

Implants are often employed in orthopaedic and dental surgeries. However, risks of failure, which are difficult to anticipate, are still experienced and may have dramatic consequences. Failures are due to degraded bone remodeling at the bone-implant interface, a multiscale phenomenon of an interdisciplinary nature which remains poorly understood. The objective of BoneImplant is to provide a better understanding of the multiscale and multitime mechanisms at work at the bone-implant interface. To do so, BoneImplant aims at studying the evolution of the biomechanical properties of bone tissue around an implant during the remodeling process. A methodology involving combined in vivo, in vitro and in silico approaches is proposed. New modeling approaches will be developed in close synergy with the experiments. Molecular dynamic computations will be used to understand fluid flow in nanoscopic cavities, a phenomenon determining bone healing process. Generalized continuum theories will be necessary to model bone tissue due to the important strain field around implants. Isogeometric mortar formulation will allow to simulate the bone-implant interface in a stable and efficient manner. In vivo experiments realized under standardized conditions will be realized on the basis of feasibility studies. A multimodality and multi-physical experimental approach will be carried out to assess the biomechanical properties of newly formed bone tissue as a function of the implant environment. The experimental approach aims at estimating the effective adhesion energy and the potentiality of quantitative ultrasound imaging to assess different biomechanical properties of the interface. Results will be used to design effective loading clinical procedures of implants and to optimize implant conception, leading to the development of therapeutic and diagnostic techniques. The development of quantitative ultrasonic techniques to monitor implant stability has a potential for industrial transfer.

1 992 154 €

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

One out of 5 people in their fifties will experience a bone fracture due to osteoporosis (OP)-induced fragility in their lifetime. The OP socio-economic burden is dramatic and involves tens of millions of people in the EU, with a steadily increasing number due to population ageing. Current treatments entail drug-therapy coupled with a healthy lifestyle but OP fractures need mechanical fixation to rapidly achieve union: the contribution of biomaterial scientists in this field is still far from taking its expected leading role in cutting-edge research. Bone remodelling is a well-coordinated process of bone resorption by osteoclasts followed by the production of new bone by osteoblasts. This process occurs continuously throughout life in a coupling with a positive balance during growth and negative with ageing, which can result in OP. We believe that an architecture driven stimulation of the osteoclast/osteoblast coupling, with an avant-garde focus on osteoclasts activity, is the key to success in treating unbalanced bone remodelling. We aim to manufacture a scaffold that mimics healthy bone features which will establish a new microenvironment favoring a properly stimulated and active population of osteoclasts and osteoblasts, i.e. a well-balanced bone cooperation. After 5 years we will be able to prove the efficacy of this approach. A benchmark will be set up for OP fracture treatment and for the realization of smart bone substitutes that will be able to locally “trick” aged bone cells stimulating them to act as healthy ones. BOOST results will have an unprecedented impact on the scientific research community, opening a new approach to set up smart, biomimetic strategies to treat aged, unbalanced bone tissues and to reduce OP-associated disabilities and financial burdens.

1 977 500 €

Start date: 2016-05-01, End date: 2021-12-31

Brain tumors represent an extremely heterogeneous group of more than 100 different molecularly distinct diseases, many of which are still almost uniformly lethal despite five decades of clinical trials. In contrast to hematologic malignancies and carcinomas, the cell-of-origin for the vast majority of these entities is unknown. This knowledge gap currently precludes a comprehensive understanding of tumor biology and also limits translational exploitation (e.g., utilizing lineage targets for novel therapies and circulating brain tumor cells for liquid biopsies). The BRAIN-MATCH project represents an ambitious program to address this challenge and unmet medical need by taking an approach that (i) extensively utilizes existing molecular profiles of more than 30,000 brain tumor samples covering more than 100 different entities, publicly available single-cell sequencing data of normal brain regions, and bulk normal tissue data at different times of development across different species; (ii) generates unprecedented maps of normal human CNS development by using state-of-the art novel technologies; (iii) matches these molecular portraits of normal cell types with tumor datasets in order to identify specific cell-of-origin populations for individual tumor entities; and (iv) validates the most promising cell-of-origin populations and tumor-specific lineage and/or surface markers in vivo. The expected outputs of BRAIN-MATCH are four-fold: (i) delivery of an unprecedented atlas of human normal CNS development, which will also be of great relevance for diverse fields other than cancer; (ii) functional validation of at least three lineage targets; (iii) isolation and molecular characterization of circulating brain tumor cells from patients´ blood for at least five tumor entities; and (iv) generation of at least three novel mouse models of brain tumor entities for which currently no faithful models exist.

1 999 875 €

Start date: 2019-05-01, End date: 2024-04-30

The cerebral microvascular system is essential to a large variety of physiological processes in the brain, including blood delivery and blood flow regulation as a function of neuronal activity (neuro-vascular coupling). It plays a major role in the associated mechanisms leading to disease (stroke, neurodegenerative diseases, …). In the last decade, cutting edge technologies, including two-photon scanning laser microscopy (TPSLM) and optical manipulation of blood flow, have produced huge amounts of anatomic and functional experimental data in normal and Alzheimer Disease (AD) mice. These require accurate, highly quantitative, physiologically informed modeling and analysis for any coherent understanding and for translating results between species. In this context, our first aim is to develop a general methodological framework for physiologically informed microvascular fluid dynamics modeling, understood in a broad meaning, i.e. blood flow, molecule transport and resulting functional imaging signals or signal surrogates. Our second aim is to validate this methodological framework by direct comparison of in vivo anatomical and functional TPSLM measurements with the simulation results based on the same anatomical data. The third objective is to exploit these methodologies in order to identify the logic of the structure/function relationships of brain microcirculation and neurovascular coupling, in human health and disease, with a focus on the role of vascular factors in AD. Specific hypotheses on how vascular changes in AD affect both vascular function and neurovascular coupling can be experimentally tested in animal models of AD. Crucially, similar anatomical (but not functional) data can be acquired in healthy and AD humans. This will enable us to model how AD-induced vascular alterations could affect human patients. Ultimately, it provides us with new avenues for design and/or evaluation of improved diagnosis/preventive/treatment strategies.

1 999 873 €

Start date: 2014-06-01, End date: 2019-05-31

"We aim to perform academic development of a novel biomedical opportunity: localized synthesis of drugs within biocatalytic therapeutic vascular implants (BVI) for site-specific drug delivery to target organs and tissues. Primary envisioned targets for therapeutic intervention using BVI are atherosclerosis, viral hepatitis, and hepatocellular carcinoma: three of the most prevalent and debilitating conditions which affect hundreds of millions worldwide and which continue to increase in their importance in the era of increasingly aging population. For hepatic applications, we aim to develop drug eluting beads which are equipped with tools of enzyme-prodrug therapy (EPT) and are administered to the liver via trans-arterial catheter embolization. Therein, the beads perform localized synthesis of drugs and imaging reagents for anticancer combination therapy and theranostics, antiviral and anti-inflammatory agents for the treatment of hepatitis. Further, we conceive vascular therapeutic inserts (VTI) as a novel type of implantable biomaterials for treatment of atherosclerosis and re-endothelialization of vascular stents and grafts. Using EPT, inserts will tame “the guardian of cardiovascular grafts”, nitric oxide, for which localized, site specific synthesis and delivery spell success of therapeutic intervention and/or aided tissue regeneration. This proposal is positioned on the forefront of biomedical engineering and its success requires excellence in polymer chemistry, materials design, medicinal chemistry, and translational medicine. Each part of this proposal - design of novel types of vascular implants, engineering novel biomaterials, developing innovative fabrication and characterization techniques – is of high value for fundamental biomedical sciences. The project is target-oriented and once successful, will be of highest practical value and contribute to increased quality of life of millions of people worldwide."

1 996 126 €

Start date: 2014-04-01, End date: 2019-09-30

Life is tough for planktonic copepods, constantly washed by turbulent flows. Yet, these millimetric crustaceans dominate the oceans in numbers. What have made them so successful? Copepod antennae are covered with hydrodynamic and chemical sensing hairs that allow copepods to detect preys, predators and mates, although they are blind. How do copepods process this sensing information? How do they extract a meaningful signal from turbulence noise? Today, we do not know. C0PEP0D hypothesises that reinforcement learning tools can decipher how copepod process hydrodynamic and chemical sensing. Copepods face a problem similar to speech recognition or object detection, two common applications of reinforcement learning. However, copepods only have 1000 neurons, much less than in most artificial neural networks. To approach the simple brain of copepods, we will use Darwinian evolution together with reinforcement learning, with the goal of finding minimal neural networks able to learn. If we are to build a learning virtual copepod, challenging problems are ahead: we need fast methods to simulate turbulence and animal-flow interactions, new models of hydrodynamic signalling at finite Reynolds number, innovative reinforcement learning algorithms that embrace evolution and experiments with real copepods in turbulence. With these theoretical, numerical and experimental tools, we will address three questions: Q1: Mating. How do male copepods follow the pheromone trail left by females? Q2: Finding. How do copepods use hydrodynamic signals to ‘see’? Q3: Feeding. What are the best feeding strategies in turbulent flow? C0PEP0D will decipher how copepods process sensing information, but not only that. Because evolution is explicitly considered, it will offer a new perspective on marine ecology and evolution that could inspire artificial sensors. The evolutionary approach of reinforcement learning also offers a promising tool to tackle complex problems in biology and engineering.

2 215 794 €

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

A sudden decrease in pressure triggers the formation of vapour and gas bubbles inside a liquid medium (also called cavitation). This leads to many (key) engineering problems: material loss, noise and vibration of hydraulic machinery. On the other hand, cavitation is a potentially a useful phenomenon: the extreme conditions are increasingly used for a wide variety of applications such as surface cleaning, enhanced chemistry, and waste water treatment (bacteria eradication and virus inactivation). Despite this significant progress a large gap persists between the understanding of the mechanisms that contribute to the effects of cavitation and its application. Although engineers are already commercializing devices that employ cavitation, we are still not able to answer the fundamental question: What precisely are the mechanisms how bubbles can clean, disinfect, kill bacteria and enhance chemical activity? The overall objective of the project is to understand and determine the fundamental physics of the interaction of cavitation bubbles with different contaminants. To address this issue, the CABUM project will investigate the physical background of cavitation from physical, biological and engineering perspective on three complexity scales: i) on single bubble level, ii) on organised and iii) on random bubble clusters, producing a progressive multidisciplinary synergetic effect. The proposed synergetic approach builds on the PI's preliminary research and employs novel experimental and numerical methodologies, some of which have been developed by the PI and his research group, to explore the physics of cavitation behaviour in interaction with bacteria and viruses. Understanding the fundamental physical background of cavitation in interaction with contaminants will have a ground-breaking implications in various scientific fields (engineering, chemistry and biology) and will, in the future, enable the exploitation of cavitation in water and soil treatment processes.

1 904 565 €

Start date: 2018-07-01, End date: 2023-06-30

Despite intense research efforts in almost every branch of the natural sciences, cancer continues to be one of the leading causes of death worldwide. It is thus remarkable that little or no therapeutic use has been made of a whole discipline, heterogeneous catalysis, which is noted for its specificity and for enabling chemical reactions in otherwise passive environments. At least in part, this could be attributed to practical difficulties: the selective delivery of a catalyst to a tumour and the remote activation of its catalytic function only after it has reached its target are highly challenging objectives. Only recently, the necessary tools to overcome these problems seem within reach. CADENCE aims for a breakthrough in cancer therapy by developing a new therapeutic concept. The central hypothesis is that a growing tumour can be treated as a special type of reactor in which reaction conditions can be tailored to achieve two objectives: i) molecules essential to tumour growth are locally depleted and ii) toxic, short-lived products are generated in situ. To implement this novel approach we will make use of core concepts of reactor engineering (kinetics, heat and mass transfer, catalyst design), as well as of ideas borrowed from other areas, mainly those of bio-orthogonal chemistry and controlled drug delivery. We will explore two different strategies (classical EPR effect and stem cells as Trojan Horses) to deliver optimized catalysts to the tumour. Once the catalysts have reached the tumour they will be remotely activated using near-infrared (NIR) light, that affords the highest penetration into body tissues. This is an ambitious project, addressing all the key steps from catalyst design to in vivo studies. Given the novel perspective provided by CADENCE, even partial success in any of the approaches to be tested would have a significant impact on the therapeutic toolbox available to treat cancer.

2 483 136 €

Start date: 2017-09-01, End date: 2022-08-31

Deep environmental sequencing (metagenomics) will be used to characterize microbial communities associated with 3 different cancer types: cervical cancer, oral squamous cell carcinoma and colorectal cancer. For all 3 types, non-invasive molecular diagnostics and prognostics are feasible via utilization of vaginal, oral and faecal samples, respectively. The project consequently aims to identify microbial markers in these ¿readouts¿ that correlate with cancer presence or progression. Microbial markers can be individual species or specific community compositions, but also particular genes or pathways. The microbial communities will be sampled locally at tumor surfaces and in healthy control tissues. After DNA extraction and sequencing, a complex bioinformatics pipeline will be developed to characterise the microbiomes and to identify the cancer-specific functional and phylogenetic markers therein. For colorectal cancer, the project intends to go into more details in that it tries i) to establish a correlation of microbiota with cancer progression and it ii) explores differences between distinct cancer subtypes. For each of the 3 cancer types, at least two samples from 40 individuals will be sequenced (as well as controls) at a depth of at least 5Gb each using Illumina technology. This is expected to be sufficient for the identification of microbial markers and also allows superficial genotyping of the individuals at ca 2-3x coverage as a by-product (the samples will contain considerable amounts of human DNA). Further analyses will be designed to study the potential of certain microbial species or community compositions to enhance or even cause one or more of the 3 cancers. The discovery of such causations will open up research towards directed antimicrobial treatment.

2 233 740 €

Start date: 2011-07-01, End date: 2016-06-30

It is now widely accepted that tumors are composed of heterogeneous population of cells, which contribute to many aspects of treatment resistance observed in clinic. Despite the acknowledgment of the tumor cell heterogeneity, little evidence was shown about complexity and dynamics of this heterogeneity in vivo, mainly because of lacking flexible genetic tools which allow sophisticated analysis in primary tumors. We recently developed a very efficient mouse somatic brain tumor model which have a full penetrance of high grade glioma development. Combination of this model with several transgenic mouse lines allow us to isolate and track different population of cells in primary tumors, most importantly, we also confirmed that this can be done on single cell level. Here I propose to use this set of valuable genetic tools to dissect the cellular heterogeneity in mouse gliomas. First we will perform several single cell lineage tracing experiment to demonstrate the contribution of brain tumor stem cell, tumor progenitors as well as the relatively differentiated cells, which will provide a complete data sets of clonal dynamics of different tumor cell types. Second we will further perform this tracing experiment with the presence of conventional chemotherapy. Third we will perform single cell RNA sequencing experiment to capture the molecular signature, which determines the cellular heterogeneity, discovered by single cell tracing. This result will be further validated by analysis of this molecular signatures in human primary tumors. We will also use our established in vivo target validation approach to manipulate the candidate molecular regulators to establish the functional correlation between molecular signature and phenotypic heterogeneity. This project will greatly improve our understanding of tumor heterogeneity, and possibly provide novel approaches and strategies of targeting human glioblastomas.

2 000 000 €

Start date: 2015-06-01, End date: 2020-05-31

The demand for donated organs vastly outnumbers the supply, leading each year to the death of thousands of people and the suffering of millions more. Engineered tissues and organs following Tissue Engineering approaches are a possible solution to this problem. However, a prevascularization solution to irrigate complex engineered tissues and assure their survival after transplantation is currently elusive. In the human body, complex organs and tissues irrigation is achieved by a network of blood vessels termed capillary bed which suggests such a structure is needed in engineered tissues. Previous approaches to engineer capillary beds reached different levels of success but none yielded a fully functional one due to the inability in simultaneously addressing key elements such as correct angiogenic cell populations, a suitable matrix and dynamic conditions that mimic blood flow. CapBed aims at proposing a new technology to fabricate in vitro capillary beds that include a vascular axis that can be anastomosed with a patient circulation. Such capillary beds could be used as prime tools to prevascularize in vitro engineered tissues and provide fast perfusion of those after transplantation to a patient. Cutting edge techniques will be for the first time integrated in a disruptive approach to address the requirements listed above. Angiogenic cell sheets of human Adipose-derived Stromal Vascular fraction cells will provide the cell populations that integrate the capillaries and manage its intricate formation, as well as the collagen required to build the matrix that will hold the capillary beds. Innovative fabrication technologies such as 3D printing and laser photoablation will be used for the fabrication of the micropatterned matrix that will allow fluid flow through microfluidics. The resulting functional capillary beds can be used with virtually every tissue engineering strategy rendering the proposed strategy with massive economical, scientific and medical potential

1 499 940 €

Start date: 2018-11-01, End date: 2023-10-31

The possibility of having a unique device that converts thermal and photonics energy into electrical energy and simultaneously stores it, is something dreamed by the PI since the beginning of her research career. To achieve that goal, this project aims to gather, in a single substrate, solar cells with up-conversion nanoparticles, thermoelectrics and graphene super-capacitor, all made of thin films. These three main components will be developed separately and integrated sequentially. The innovation proposed is not limited to the integration of components, but rely in ground-breaking concepts: 1) thermoelectric elements based on thin film (TE-TF) oxides; 2) plasmonic nanoparticles for up conversion of near infrared radiation to visible emission in solar cells; 3) graphene super-capacitors; 4) integration and optimization of all components in a single CapTherPV device. This ambitious project will bring new insights at large area, low cost and flexible energy harvesting and comes from an old idea of combining energy conversion and storage that has been pursued by the PI. She started her career in amorphous silicon thin film solar cells, later she started the development of thin film batteries and more recently started a research line in thermoelectric films. If approved, this project will give financial support to consolidate the research being carried out and will give independence to the PI in terms of resources and creative think. More importantly, will facilitate the concretization of the dream that has been pursued with hard work.

1 999 375 €

Start date: 2015-07-01, End date: 2020-06-30

Celiac disease affects at least 1% of the world population. Its onset is triggered by gluten, a common dietary protein, however, its etiology is poorly understood. More than 80% of patients are not properly diagnosed and they therefore do not follow a gluten-free diet, thereby increasing their risk for disease-associated complications and early death. A better understanding of the disease biology would improve the diagnosis, prevention, and treatment of celiac disease. This project investigates the disease mechanisms in celiac disease by using predisposing genes and genetic variants as disease initiating factors. Specifically, it will investigate if long, intergenic non-coding RNAs (lincRNAs) are causally involved in celiac disease pathogenesis by regulating protein-coding genes and pathways associated with the disease. This project is based on two important observations by my group: (1) Our genetic studies, which led to identifying 39 celiac disease risk loci, suggest that the mechanism underlying the disease is largely governed by dysregulation of gene expression. (2) We uncovered a previously unrecognized role for lincRNAs that provides clues as to exactly how genetic variation causes disease, as this class of biologically important RNA molecules regulate gene expression. The research will be performed in CD4+ T cells, a severely affected cell type in disease pathology. I will first use celiac disease-associated protein-coding genes to delineate their regulatory pathways and then study the transcriptional programs of lincRNAs present in celiac disease loci. Next I will combine the information and investigate if the expressed lincRNAs modulate the pathways and affect T cell function, thereby discovering if lincRNAs are a missing link between non-coding genetic variation and protein-coding genes. Our findings may well lead to potential therapeutic targets and provide a solid scientific basis for new diagnostic markers, particularly biomarkers, based on genetics.

2 319 914 €

Start date: 2013-02-01, End date: 2018-11-30

Aging worldwide population demands new solutions to permanently restore damaged tissues, thus reducing healthcare costs. Regenerative medicine offers alternative therapies for tissue repair. Although first clinical trials revealed excellent initial response after implantation of these engineered tissues, long-term follow-ups demonstrated that degeneration and lack of integration with the surrounding tissues occur. Causes are related to insufficient cell-material interactions and loss of cell potency when cultured in two-dimensional substrates, among others. Stem cells are a promising alternative due to their differentiation potential into multiple lineages. Yet, better control over cell-material interactions is necessary to maintain tissue engineered constructs in time. It is crucial to control stem cell quiescence, proliferation and differentiation in three-dimensional scaffolds while maintaining cells viable in situ. Stem cell activity is controlled by a complex cascade of signals called “niche”, where the extra-cellular matrix (ECM) surrounding the cells play a major role. Designing scaffolds inspired by this cellular niche and its ECM may lead to engineered tissues with instructive properties characterized by enhanced homeostasis, stability and integration with the surrounding milieu. This research proposal aims at engineering constructs where scaffolds work as stem cell delivery systems actively controlling cell quiescence, proliferation, and differentiation. This challenge will be approached through a biomimetic design inspired by the mesenchymal stem cell niche. Three different scaffolds will be combined to achieve this purpose: (i) a scaffold designed to maintain cell quiescence; (ii) a scaffold designed to promote cell proliferation; and (iii) a scaffold designed to control cell differentiation. To prove the design criteria the evaluation of stem cell quiescence, proliferation, and differentiation will be assessed for musculoskeletal regenerative therapies.

1 500 000 €

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

The concept that any cell type, upon delivery of the right “cocktail” of transcription factors, can acquire an identity that otherwise it would never achieve, revolutionized the way we approach the study of developmental biology. In light of this, the discovery of induced pluripotent stem cells (IPSCs) and cell fate conversion approaches stimulated new research directions into human regenerative biology. However, the chance to successfully develop patient-tailored therapies is still very limited because reprogramming technologies are applied without a comprehensive understanding of the molecular processes involved. Here, I propose a multifaceted approach that combines a wide range of cutting-edge integrative genomic strategies to significantly advance our understanding of the regulatory logic driving cell fate decisions during human reprogramming to pluripotency. To this end, I will utilize single cell transcriptomics to isolate reprogramming intermediates, reconstruct their lineage relationships and define transcriptional regulators responsible for the observed transitions (AIM 1). Then, I will dissect the rules by which transcription factors modulate the activity of promoters and enhancer regions during reprogramming transitions, by applying synthetic biology and genome editing approaches (AIM 2). Then, I will adopt an alternative approach to identify reprogramming modulators by the analysis of reprogramming-induced mutagenesis events (AIM 3). Finally, I will explore my findings in multiple primary reprogramming approaches to pluripotency, with the ultimate goal of improving the quality of IPSC derivation (Aim 4). In summary, this project will expose novel determinants and yet unidentified molecular barriers of reprogramming to pluripotency and will be essential to unlock the full potential of reprogramming technologies for shaping cellular identity in vitro and to address pressing challenges of regenerative medicine.

1 497 250 €

Start date: 2018-03-01, End date: 2023-02-28

Faithful chromosome segregation in all eukaryotes relies on centromeres, the chromosomal sites that recruit kinetochore proteins and mediate spindle attachment during cell division. Fundamental to centromere function is a histone H3 variant, CenH3, that initiates kinetochore assembly on centromeric DNA. CenH3 is conserved throughout most eukaryotes; its deletion is lethal in all organisms tested. These findings established the paradigm that CenH3 is an absolute requirement for centromere function. My recent findings undermined this paradigm of CenH3 essentiality. I showed that CenH3 was lost independently in four lineages of insects. These losses are concomitant with dramatic changes in their centromeric architecture, in which each lineage independently transitioned from monocentromeres (where microtubules attach to a single chromosomal region) to holocentromeres (where microtubules attach along the entire length of the chromosome). Here, I aim to characterize this unique CenH3-deficient chromosome segregation pathway. Using proteomic and genomic approaches in lepidopteran cell lines, I will determine the mechanism of CenH3-independent kinetochore assembly that led to the establishment of their holocentric architecture. Using comparative genomic approaches, I will determine whether this kinetochore assembly pathway has recurrently evolved over the course of 400 million years of evolution and its impact on the chromosome segregation machinery. My discovery of CenH3 loss in holocentric insects establishes a new class of centromeres. My research will reveal how CenH3 that is essential in most other eukaryotes, could have become dispensable in holocentric insects. Since the evolution of this CenH3-independent chromosome segregation pathway is associated with the independent rises of holocentric architectures, my research will also provide the first insights into the transition from a monocentromere to a holocentromere.

1 497 500 €

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