ERC FUNDED PROJECTS

Signal transduction in biology relies on the transfer of information across biomolecules by concerted conformational changes that cannot currently be characterized experimentally at high resolution. In CONCERT we will develop a method based on the use of nuclear magnetic resonance spectroscopy in solution that will provide very detailed descriptions of such changes by using the information about structural heterogeneity contained in a parameter that is exquisitely sensitive to molecular shape called residual dipolar coupling measured in steric alignment. To show how this new method will allow the study of information transfer we will determine conformational ensembles that will report on the intra and inter-domain concerted conformational changes that activate the androgen receptor, a large allosteric multi-domain protein that regulates the male phenotype and is a therapeutic target for castration resistant prostate cancer, the condition suffered by prostate cancer patients that have become refractory to hormone therapy, the first line of treatment for this disease. To complement the structural information obtained by nuclear magnetic resonance and, especially, measure the rate of information transfer across the androgen receptor we will carry out in a collaborative fashion high precision single molecule Förster resonance energy transfer and fluorescence correlation spectroscopy experiments on AR constructs labelled with fluorescent dyes. In summary we will develop a method that will make it possible to describe some of the most fascinating biological phenomena, such as allostery and signal transduction, and will, in the long term, be an instrument for the discovery of drugs to treat castration resistant prostate cancer, a late stage of prostate cancer that is incurable and kills ca. 70.000 European men every year.

1 950 000 €

Start date: 2015-07-01, End date: 2020-12-31

Extreme events often cause local-initial damage to the critical elements of building structures, followed by a cascade of further failures in the rest of the building; a phenomenon known as “progressive collapse”. Current design philosophies are based on giving buildings extensive continuity, so that when a critical element fails its load can be re-distributed among the rest of the structure. However, in certain situations (e.g. initial failure of several columns) this extensive continuity introduces undesirable effects and actually increases the risk of progressive collapse. Segmenting a building into individual units connected only by means of fuses would avoid a failure in one zone propagating to others. While such fuses would provide continuity for normal loads or small local-initial failure, they would “isolate” the different parts of the building when otherwise the forces generated by the initial failure would pull down the rest of the structure. Although fuse segmentation is probably the only alternative that can fill the gaps in the present design philosophies, so far, no studies have been carried out on the possibility of applying it to buildings. Endure’s overall aim is to develop a novel fuse-based segmentation design approach to limit or arrest the propagation of failures in building structures subjected to extreme events. The project will be multidisciplinary and highly ambitious, and will achieve its overall aim by: 1) Developing a performance-based approach for the design of fuse-segmented buildings; 2) Designing, manufacturing and testing fuses for segmenting buildings; and 3) Implementing fuses in segmented realistic building prototypes and testing and validating the new fuse-based approach in these structures. Endure will open up a new research area and design approach, and also deliver novel construction procedures. The project will lead to safer buildings, especially in the case of extreme events with severe consequences for building integrity.

2 509 375 €

Start date: 2022-01-01, End date: 2026-12-31

The epithelium is a cohesive two-dimensional layer of cells attached to a fluid-filled fibrous matrix, which lines most free surfaces and cavities of the body. It serves as a protective barrier with tunable permeability, which must retain integrity in a mechanically active environment. Paradoxically, it must also be malleable enough to self-heal and remodel into functional 3D structures such as villi in our guts or tubular networks. Intrigued by these conflicting material properties, the main idea of this proposal is to view epithelial monolayers as living engineering materials. Unlike lipid bilayers or hydrogels, widely used in biotechnology, cultured epithelia are only starting to be integrated in organ-on-chip microdevices. As for any complex inert material, this program requires a fundamental understanding of the structure-property relationships. (1) Regarding their effective in-plane rheology, at short time-scales epithelia exhibit solid-like behavior while at longer times they flow as a consequence of the only qualitatively understood dynamics of the cell-cell junctional network. (2) As for material failure, excessive tension can lead to epithelial fracture, but as we have recently shown, matrix poroelasticity can also cause hydraulic fracture under stretch. However, it is largely unknown how adhesion molecules, membrane, cytoskeleton and matrix interact to give epithelia their robust and flaw-tolerant resilience. (3) Regarding shaping 3D epithelial structures, besides the classical view of chemical patterning, mechanical buckling is emerging as a major morphogenetic driving force, suggesting that it may be possible design 3D epithelial structures in vitro by mechanical self-assembly. Towards understanding (1,2,3), we will combine a broad range of theoretical, computational and experimental methods. Besides providing fundamental mechanobiological understanding, this project will provide a framework to manipulate epithelia in bioinspired technologies.

1 989 875 €

Start date: 2016-09-01, End date: 2022-08-31

Following promising early breakthroughs, progress in the development of high-performance multicomponent organic energy materials has stalled due to a bottleneck in device optimization. FOREMAT will develop a breakthrough technology to overcome this bottleneck by shifting from fabrication-intense to measurement-intense assessment methods, enabling rapid multi-parameter optimization of novel systems. Our goal is to deliver organic material systems with a step-change in performance, bringing them close to the expected market turn point, including panchromatic organic photovoltaics with ca 15% efficiencies and thermoelectric devices that could revolutionize waste heat recovery by their flexibility, lightweight and high power factor. The development of multicomponent materials promises to dramatically improve the cost, efficiency and stability of organic energy devices. For example, they allow to engineer broad-band absorption in photovoltaics matched to the sun’s spectrum, or to create composites that conduct electricity like metals while thermally insulate like cotton yielding thermoelectric devices beyond the state-of-the-art. Despite these advantages, the long time required to evaluate promising organic multinaries currently limits their development. We will circumvent this problem by developing a high-throughput technology that will allow evaluation times up to two orders of magnitude faster saving, at the same time, around 90% of material. To meet these ambitious goals, we will advance novel fabrication tools and create samples bearing a high density of information arising from 2-dimensional gradual variations in relevant parameters that will be sequentially tested with increasing resolution in order to determine optimum values with high precision. This quantitative step will enable a disruptive qualitative change as in depth multidimensional studies will lead to design rationales for multicomponent systems with step-change performance in energy applications.

2 423 894 €

Start date: 2015-10-01, End date: 2022-01-31

HyMAP aims to develop a new generation of multifunctional hybrid photocatalysts and solar photoreactor which would allow the exploitation of at least the 1 % of the sunlight energy for the CO2 photoreduction using water as electron donor. This will imply a CO2 conversion in the range of 12 to 35 Ton/y•ha, depending on product distribution, which represents at least a 20-fold improvement over the state of the art. To achieve this goal, I propose an interdisciplinary research program through which several breakthroughs at different scales will be achieved: Development of efficient multifunctional organic/inorganic semiconductors and metal-organic frameworks photocatalysts with separated reduction/oxidation active sites. The fact of having independent multiple redox sites combined in a single material would maximize charge separation and transport processes, as well as sunlight harvesting. Characterization and modelling of the structural and opto-electronic properties of the proposed materials. Evaluation of the materials in artificial photosynthesis devices. At this stage, a solar photoreactor that would allow good transmission, uniform light distribution and maximize the energy harvesting in the overall spectra will be developed. HYMAP will provide me with an excellent opportunity to lead a consolidated research group. During my scientific career I have demonstrated creative thinking, autonomy and an excellent capacity to carry out state of the art research in heterogeneous catalysis, characterization, modelling and reactor engineering. I have a meritorious research track reflected by a good number of scientific publications, broad professional expertise, innovative project conception and a consolidate network of international collaboration. This, along with my leadership and management abilities, will assure the successful achievement of the mentioned goals of this project. HyMAP is a revised version of a proposal scored with A (2nd stage) of last ERC-CoG call.

2 506 738 €

Start date: 2015-07-01, End date: 2021-06-30

Drought is the first cause of agricultural losses globally, and represents a major threat to food security. Currently, plant biotechnology stands as the most promising strategy to produce crops capable of producing high yields in fed rain conditions. From the study of whole-plants, the main underlying mechanism for responses to drought stress has been uncovered, and multiple drought resistance genes have been engineered into crops. So far, plants with enhanced drought resistance displayed reduced crop yield, which imposes the search of novel approaches to uncouple drought resistance from plant growth. Our laboratory has recently shown, for the first time, that the receptors of Brassinosteroid hormones use cell-specific pathways to allocate different developmental responses during root growth. In particular, we have found that cell-specific components of the stem cell niche have the ability to control cellular responses to stress to promote stem renewal to ensure root growth. Additionally, we have also found that BR mutants are resistant to drought, together opening an exceptional opportunity to investigate the mechanisms that confer drought resistance with cellular specificity in plants. In this project, we will use Brassinosteroid signaling in the Arabidopsis root to investigate the mechanism for drought stress resistance in plant and to design novel molecules able to confer resistance to the drought stress. Finally, we will translate our research results and tools into Sorghum bicolor (Sorghum), a crop cereal of paramount importance in fed rain regions of the planet. Our research will impact in science, providing new avenues for the study of hormone signaling in plants, and in society, by providing sustainable solutions for enhance crop production in limiting water environments.

2 000 000 €

Start date: 2016-11-01, End date: 2022-04-30

Biological systems are robust to perturbations, with many genetic, stochastic and environmental challenges having no or little phenotypic consequence. However, the extent of this robustness varies across individuals, for example the same mutation or treatment may only affect a subset of individuals. The overall objective of this project is to understand the cellular and molecular mechanisms that confer this robustness and why it varies across individuals. We will address three specific questions: 1. Why do inherited mutations have different outcomes in different individuals, even when they are genetically identical and share a common environment? 2. What are the mechanisms during development that confer robustness to mechanical deformation? 3. How can the loss of robustness be exploited to specifically kill cancer cells? To address the first two questions, we will use live imaging procedures that we have developed that make the C. elegans embryo a unique animal system to link early inter-individual variation in gene expression and cellular behaviour to later variation in phenotypes. To address the third question, we will apply our understanding of genetic robustness and genetic interaction networks in model organisms to the comprehensive analysis of cancer genome datasets. The predictions from these hypothesis-driven computational analyses will then be evaluated using wet-lab experiments. Understanding and predicting variation in robustness is both a fundamental challenge for biology and one that is central to the development of personalised and predictive medicine. A patient does not want to know the typical outcome of a mutation or treatment; they want to know what will actually happen to them. The work outlined here will contribute to our basic understanding of robustness and its variation among individuals, and it will also directly tackle the problem of predicting and targeting variation in robustness as a strategy to kill tumour cells.

1 996 812 €

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

The global folding of the chromosome is mediated by Structural Maintenance of Chromosome (SMC) proteins, which stabilize the higher-order chromatin architecture by bringing distant DNA sequences together. Despite over a decade of work on these systems, their mechanism remains unknown, largely because of difficulty in re-capitulating physiological DNA binding and condensation in vitro. Moreover, traditional biochemical approaches are poorly suited for the study of processes that are fundamentally mechanical in nature. However, key breakthroughs, including the discovery that SMC is loaded by Spo0J protein at parS sites in vivo, and that parS sites act as global condensation centres for the chromosome have opened new possibilities to study chromosome organisation using single-molecule (SM) approaches. Importantly, our recent experiments with Magnetic Tweezers (MT) have already revealed a novel function of Spo0J in condensing DNA via a parS-independent binding mechanism. Inspired by these recent discoveries, I have devised a series of novel SM biophysical approaches with the ambitious goal of determining the mechanism of action of SMC complexes, including understanding the role of SMC loaders and SMC accessory subunits, and how these proteins are regulated by ATP binding and hydrolysis for chromosome organisation. The rationale behind this approach is that SM methods are particularly well-suited for monitoring DNA cohesion and condensation where manipulation of individual DNA molecules, measurement of forces, and addition of proteins and buffer solutions can be carefully controlled. High throughput MT will be combined with fast video imaging, optical trapping, and fluorescence; and will be used to interrogate hypothetical models for SMC-DNA interactions. Finally, the novel assays developed here may be applicable to other protein-DNA interactions including variant SMC-like proteins specialized for other biological functions such as DNA repair.

1 894 999 €

Start date: 2016-06-01, End date: 2021-11-30

The environmental concerns over the use of fossil fuels have promoted great interest in generating electric energy from renewable sources such as solar and wind. However, the intermittent nature of those resources demands high performing and cost-effective energy storage systems. Redox Flow Batteries (RFBs) present several advantages, namely, total decoupling of power and energy densities and the possibility of rapid mechanical charging by substituting spent electrolytes with fresh ones. The major issues of the current Vanadium RFBs are the high price and toxicity of vanadium components and the high cost and low performance of the ion-selective membranes they require. MFreeB project proposes to completely remove the problematic membrane of RFBs by developing a disruptive, versatile and scalable concept of Membrane-Free RFB implementing efficient catholytes and anolytes in which the metallic redox pairs are replaced by cheap, abundant and environmental-friendly molecules. In order to achieve this objective, I propose a multi- and interdisciplinary research methodology across a wide range of expertise including fundamental electrochemistry, thermodynamics, physical chemistry, modelling, and mechanical engineering. I will make use of advantages of different electrolytes to develop a versatile concept of Membrane-Free RFB with a wide range of applications. This Consolidator Grant (ERC) would provide adequate support to consolidate my own independent research team and programme. During my scientific career, I have demonstrated creative thinking and excellent capacity to carry out research going beyond the state of the art. My meritorious record of scientific publications (55 ISI articles, h index = 25), project leadership, international collaborations and capacity for supervising and coordinating a research team are presented in the proposal. I am now in an excellent position and research environment to commit and be devoted to this encouraging and challenging project

1 998 407 €

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