ERC FUNDED PROJECTS

The objective of this project is to overcome current limitations for antibody production that are inherent to the extant immune system of vertebrates. This will be done by creating an all-in-one artificial/synthetic counterpart based exclusively on prokaryotic parts, devices and modules. To this end, ARISYS will exploit design concepts, construction hierarchies and standardization notions that stem from contemporary Synthetic Biology for the assembly and validation of (what we believe is) the most complex artificial biological system ventured thus far. This all-bacterial immune-like system will not only simplify and make affordable the manipulations necessary for antibody generation, but will also permit the application of such binders by themselves or displayed on bacterial cells to biotechnological challenges well beyond therapeutic and health-related uses. The work plan involves the assembly and validation of autonomous functional modules for [i] displaying antibody/affibody (AB) scaffolds attached to the surface of bacterial cells, [ii] conditional diversification of target-binding sequences of the ABs, [iii] contact-dependent activation of gene expression, [iv] reversible bi-stable switches, and [v] clonal selection and amplification of improved binders. These modules composed of stand-alone parts and bearing well defined input/output functions, will be assembled in the genomic chassis of streamlined Escherichia coli and Pseudomonas putida strains. The resulting molecular network will make the ABs expressed and displayed on the cell surface to proceed spontaneously (or at the user's decision) through subsequent cycles of affinity and specificity maturation towards antigens or other targets presented to the bacterial population. In this way, a single, easy-to-handle (albeit heavily engineered) strain will govern all operations that are typically scattered in a multitude of separate methods and apparatuses for AB production.

2 422 271 €

Start date: 2013-05-01, End date: 2019-04-30

A new generation of galaxy surveys will soon start measuring the spatial distribution of millions of galaxies over a broad range of redshifts, offering an imminent opportunity to discover new physics. A detailed comparison of these measurements with theoretical models of galaxy clustering may reveal a new fundamental particle, a breakdown of General Relativity, or a hint on the nature of cosmic acceleration. Despite a large progress in the analytic treatment of structure formation in recent years, traditional clustering models still suffer from large uncertainties. This limits cosmological analyses to a very restricted range of scales and statistics, which will be one of the main obstacles to reach a comprehensive exploitation of future surveys. Here I propose to develop a novel simulation--based approach to predict galaxy clustering. Combining recent advances in computational cosmology, from cosmological N--body calculations to physically-motivated galaxy formation models, I will develop a unified framework to directly predict the position and velocity of individual dark matter structures and galaxies as function of cosmological and astrophysical parameters. In this formulation, galaxy clustering will be a prediction of a set of physical assumptions in a given cosmological setting. The new theoretical framework will be flexible, accurate and fast: it will provide predictions for any clustering statistic, down to scales 100 times smaller than in state-of-the-art perturbation--theory--based models, and in less than 1 minute of CPU time. These advances will enable major improvements in future cosmological constraints, which will significantly increase the overall power of future surveys maximising our potential to discover new physics.

1 484 240 €

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

BIOFORCE has a highly ambitious applied objective: to create transgenic cereal plants that will provide a near-complete micronutrient complement (vitamins A, C, E, folate and essential minerals Ca, Fe, Se and Zn) for malnourished people in the developing world, as well as built-in resistance to insects and parasitic weeds. This in itself represents a striking advance over current efforts to address food insecurity using applied biotechnology in the developing world. We will also address fundamental mechanistic aspects of multi-gene/pathway engineering through transcriptome and metabolome profiling. Fundamental science and applied objectives will be achieved through the application of an exciting novel technology (combinatorial genetic transformation) developed and patented by my research group. This allows the simultaneous transfer of an unlimited number of transgenes into plants followed by library-based selection of plants with appropriate genotypes and phenotypes. All transgenes integrate into one locus ensuring expression stability over multiple generations. This proposal represents a new line of research in my laboratory, founded on incremental advances in the elucidation of transgene integration mechanisms in plants over the past two and a half decades. In addition to scientific issues, BIOFORCE address challenges such as intellectual property, regulatory and biosafety issues and crucially how the fruits of our work will be taken up through philanthropic initiatives in the developing world while creating exploitable opportunities elsewhere. BIOFORCE is comprehensive and it provides a complete package that stands to make an unprecedented contribution to food security in the developing world, while at the same time generating new knowledge to streamline and simplify multiplex gene transfer and the simultaneous modification of multiple complex plant metabolic pathways

2 290 046 €

Start date: 2009-04-01, End date: 2014-03-31

This project will be aimed at obtaining a deeper insight into the physical processes taking place in astrophysical magnetized plasmas. To study these scenarios I will employ different numerical codes as virtual tools that enable me to experiment on computers (virtual labs) with distinct initial and boundary conditions. Among the kind of sources I am interested to consider, I outline the following: Gamma-Ray Bursts (GRBs), extragalactic jets from Active Galactic Nuclei (AGN), magnetars and collapsing stellar cores. A number of important questions are still open regarding the fundamental properties of these astrophysical sources (e.g., collimation, acceleration mechanism, composition, high-energy emission, gravitational wave signature). Additionally, there are analytical issues on the formalism in relativistic dynamics not resolved yet, e.g., the covariant extension of resistive magnetohydrodynamics (MHD). All these problems are so complex that only a computational approach is feasible. I plan to study them by means of relativistic and Newtonian MHD numerical simulations. A principal focus of the project will be to assess the relevance of magnetic fields in the generation, collimation and ulterior propagation of relativistic jets from the GRB progenitors and from AGNs. More generally, I will pursue the goal of understanding the process of amplification of seed magnetic fields until they become dynamically relevant, e.g., using semi-global and local simulations of representative boxes of collapsed stellar cores. A big emphasis will be put on including all the relevant microphysics (e.g. neutrino physics), non-ideal effects (particularly, reconnection physics) and energy transport due to neutrinos and photons to account for the relevant processes in the former systems. A milestone of this project will be to end up with a numerical tool that enables us to deal with General Relativistic Radiation Magnetohydrodynamics problems in Astrophysics.

1 497 000 €

Start date: 2011-03-01, End date: 2017-02-28

The actual view of cellular transformation and cancer progression supports the notion that cancer cells must undergo metabolic reprogramming in order to survive in a hostile environment. This field has experienced a renaissance in recent years, with the discovery of cancer genes regulating metabolic homeostasis, in turn being accepted as an emergent hallmark of cancer. Prostate cancer presents one of the highest incidences in men mostly in developed societies and exhibits a significant association with lifestyle environmental factors. Prostate cancer recurrence is thought to rely on a subpopulation of cancer cells with low-androgen requirements, high self-renewal potential and multidrug resistance, defined as cancer-initiating cells. However, whether this cancer cell fraction presents genuine metabolic properties that can be therapeutically relevant remains undefined. In CancerMetab, we aim to understand the potential benefit of monitoring and manipulating metabolism for prostate cancer prevention, detection and therapy. My group will carry out a multidisciplinary strategy, comprising cellular systems, genetic mouse models of prostate cancer, human epidemiological and clinical studies and bioinformatic analysis. The singularity of this proposal stems from the approach to the three key aspects that we propose to study. For prostate cancer prevention, we will use our faithful mouse model of prostate cancer to shed light on the contribution of obesity to prostate cancer. For prostate cancer detection, we will overcome the consistency issues of previously reported metabolic biomarkers by adding robustness to the human studies with mouse data integration. For prostate cancer therapy, we will focus on a cell population for which the metabolic requirements and the potential of targeting them for therapy have been overlooked to date, that is the prostate cancer-initiating cell compartment.

1 498 686 €

Start date: 2013-11-01, End date: 2019-10-31

Over many years, our research group has explored the complex relationship between cancer and ageing. As part of this work, we have generated mouse models of protease deficiency which are protected from cancer but exhibit accelerated ageing. Further studies with these mice have allowed us to unveil novel mechanisms of both normal and pathological ageing, to discover two new human progeroid syndromes, and to develop therapies for the Hutchinson-Gilford progeria syndrome, now in clinical trials. We have also integrated data from many laboratories to first define The hallmarks of ageing and the current possibilities for Metabolic control of longevity. Now, we propose to leverage our extensive experience in this field to further explore the relative relevance of cell-intrinsic and -extrinsic mechanisms of ageing. Our central hypothesis is that ageing derives from the combination of both systemic and cell-autonomous deficiencies which lead to the characteristic loss of fitness associated with this process. Accordingly, it is necessary to integrate multiple approaches to understand the mechanisms underlying ageing. This integrative and multidisciplinary project is organized around three major aims: 1) to characterize critical cell-intrinsic alterations which drive ageing; 2) to investigate ageing as a systemic process; and 3) to design intervention strategies aimed at expanding longevity. To fully address these objectives, we will use both hypothesis-driven and unbiased approaches, including next-generation sequencing, genome editing, and cell reprogramming. We will also perform in vivo experiments with mouse models of premature ageing, genomic and metagenomic studies with short- and long-lived organisms, and functional analyses with human samples from both progeria patients and centenarians. The information derived from this project will provide new insights into the molecular mechanisms of ageing and may lead to discover new opportunities to extend human healthspan.

2 456 250 €

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

A hallmark of cancer is tumor cell heterogeneity, which results from combinations of multiple genetic and epigenetic alterations within an individual tumor. In contrast, we have recently discovered that most human colorectal cancers (CRCs) are composed of mixtures of phenotypically distinct tumor cells organized into a stem cell hierarchy that displays a striking resemblance to the healthy colonic epithelium. We showed that long-term regeneration potential of tumor cells is largely influenced by the position that they occupy within the tumor's hierarchy. To analyze the organization of CRCs without the constraints imposed by tumor cell transplantation experiments, we have developed a method that allows for the first time tracking and manipulating the fate of specific cell populations in whole human tumors. This technology is based on editing the genomes of primary human CRCs cultured in the form of tumor organoids using Zinc-Finger Nucleases to knock-in either lineage tracing or cell ablation alleles in genes that define colorectal cancer stem cells (CRC-SCs) or differentiated-like tumor cells. Edited tumor organoids generate CRCs in mice that reproduce the tumor of origin while carrying the desired genetic modifications. This technological advance opens the gate to perform classical genetic and developmental analysis in human tumors. We will exploit this advantage to address fundamental questions about the cell heterogeneity and organization of human CRCs that cannot be tackled through currently existing experimental approaches such as: Are CRC-SCs the only tumor cell population with long term regenerating potential? Can we cure CRC with anti-CRC-SC specific therapies? Will tumor cell plasticity contribute to the regeneration of the CRC-SC pool after therapy? Do quiescent-SCs regenerate CRC tumors after standard chemotherapy? Can we identify these cells? How do common genetic alterations in CRC influence the CRC hierarchy? Do they affect the stem cell phenotype?

2 499 405 €

Start date: 2014-04-01, End date: 2019-03-31

For many years, mitochondria were viewed as semiautonomous organelles, required only for cellular energetics. This view has been displaced by the concept that mitochondria are fully integrated into the life of the cell and that mitochondrial function and stress response rapidly affect other organelles, and even other tissues. A recent discovery from my lab demonstrated that mitochondrial metabolism regulates lysosomal degradation (Cell Metabolism, 2015), thus opening the way to investigate the mechanism behind communication between these organelles and its consequences for homeostasis. With this proposal, we want to assess how mitochondrial crosstalk with endolysosomal compartment controls cellular homeostasis and how mitochondrial dysfunction in certain tissues may account for systemic effects on the rest of the organism. EndoMitTalk will deliver significant breakthroughs on (1) the molecular mediators of endolysosomal-mitochondria communication, and how deregulation of this crosstalk alters cellular (2), and organism homeostasis (3). Our central goals are: 1a,b. To identify metabolic and physical connections mediating endolysosomal-mitochondria crosstalk; 2a. To decode the consequences of altered interorganelle communication in cellular homeostasis 2b. To study the therapeutic potential of improving lysosomal function in respiration-deficient cells; 3a. To assess how unresolved organelle dysfunction and metabolic stresses exclusively in immune cells affects organism homeostasis and lifespan. 3b. To decipher the molecular mediators by which organelle dysfunction in T cells contributes to age-associated diseases, with special focus in cardiorenal and metabolic syndromes. In sum, EndoMitTalk puts forward an ambitious and multidisciplinary but feasible program with the wide purpose of understanding and improving clinical interventions in mitochondrial diseases and age-related pathologies.

1 498 625 €

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

Galactic stellar nuclei are very common in all types of galaxies and are marked by the presence of nuclear star clusters, the densest and most massive star clusters in the present-day Universe. Their formation is still an unresolved puzzle. The centre of the Milky Way contains a massive black hole and a stellar nucleus and is orders of magnitude closer than any comparable target. It is the only galactic nucleus and the most extreme astrophysical environment that we can examine on scales of milli-parsecs. It is therefore a crucial laboratory for studying galactic nuclei and their role in the context of galaxy evolution. Yet, suitable data that would allow us to examine the stellar component of the Galactic Centre exist for less than 1% of its projected area. Moreover, the well-explored regions are extraordinary, like the central parsec around the massive black hole, and therefore probably not representative for the overall environment. Fundamental questions on the stellar population, structure and assembly history of the Galactic Centre remain therefore unanswered. This project aims at addressing the open questions by obtaining accurate, high-angular resolution, multi-wavelength near-infrared photometry for an area of several 100 pc^2, a more than ten-fold increase compared to the current state of affairs. The Galactic Centre presents unique observational challenges because of a combination of high extinction and extreme stellar crowding. It is therefore not adequately covered by existing or upcoming imaging surveys. I present a project that is specifically tailored to overcome these observational challenges. In particular, I have developed a key technique to obtain the necessary sensitive, high-angular resolution images with a stable point spread function over large, crowded fields. It works with a range of existing ground-based instruments and will serve to complement existing data to provide a global and detailed picture of the stellar nucleus of the Milky Way.

1 547 657 €

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

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: 2021-10-31

Cancer is caused by somatically acquired changes in the DNA. Some of these changes fall in “cancer genes”, conferring clonal selective advantage to the cells that carry the mutant alleles. Identifying these genes/pathways is of vital importance for a correct understanding of cancer biology as well as for the diagnosis and treatment of human malignancies. In this respect, the use of genetically modified mice has been extremely useful in the past for characterizing the molecular pathways involved in cancer progression. The remarkable progress made during the last two decades on the genetic modification of mouse genomes offers unique opportunities to investigate different aspects of tumor molecular behavior, impossible to study on human samples. Recently, the advent of next-generation sequencing technologies has provided new strategies for the systematic genome-wide identification of somatic changes in cancer cell genomes. Using these technologies, we and others have characterized the high intra-tumor heterogeneity observed in some human tumors. Although the exact significance of this heterogeneity is uncertain, it seems to be responsible for key aspects in the management of cancer patients such as metastasis predisposition and tissue specificity or treatment resistance. Taking advantage of next-generation sequencing, we propose to finely characterize the intra-tumor heterogeneity evolution during the progression of tumors induced in a mouse model of pancreatic cancer, as well as, for the first time, to purify the different cell populations these primary tumors are composed of. A complete genomic and transcriptomic characterization of these populations followed by posterior functional assays will help us to identify the genes/pathways involved in tumor progression as well as metastatic potential and its tissue specificity. This new knowledge could finally contribute to a better understanding of cancer and to the design of more efficient anti-tumor therapies

1 498 850 €

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

The goal of this project is to develop new types of biosensors based on two different approaches: (i) a new bioanalytic microsystem platform for cell growth, manipulation and analysis using on-chip integrated microtubes and (ii) the use of synthetic self-propelled nanomotors for bioanalytical and biosensing applications. Based on the novel “Lab-in-a-tube” concept, we will design a multifunctional device for the capturing, growth and sensing of single cell behaviours inside “glass” microtubes to be employed for diverse biological applications. We will decorate the walls of the microtubes with proteins from the extracellular matrix enabling the long-term study of cellular changes such as mitosis time, spindle reorientation, DNA damage and cellular differentiation. These microtubes are fabricated by the well-established rolled-up nanotechnology developed in the host institution. Moreover, the multifunctionality of the “Lab-in-a-tube” platform will be extended by integrating different modules into a single microtubular unit, bringing up several applications such as optofluidics(bio)sensors, electrodes for electrochemical control and sensing, and magnetic biodetection. At the IIN institute in IFW Dresden, we are pioneers on the fabrication of catalytic microjet engines (microbots) and their use for transporting different kinds of objects in vitro into a fluid. The remote controlled motion of these autonomous microbots and the transport of microobjects and cells to specific targets within lab-on-a-chip systems is possible. Their walls can be biofunctionalized with enzymes, antibodies or DNA, the catalytic microbots representing a novel and unique tool for biosensing, environmental and biomedical applications. Our next step is to use biocompatible fuels to propel these microbots with the final aim of transporting and delivering drugs in vivo.The separation of cancer cells, bacteria and other biomaterials to build up new tissues or to replace disease cells are also aimed.

1 499 880 €

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

Recent reports suggest that early microbial colonization has an important role for in promoting health. This may contribute to reduce the risk of chronic diseases such as obesity, allergies and inflammatory conditions. Advances in understanding host-microbe interactions imply that maternal microbiota plays a crucial role on health programming. This process begins in utero and it is modulated by mode of delivery and diet. My research has shown that i) specific shifts in milk microbial composition are associated with lactation time and mode of delivery, ii) milk microbes drive the infant microbiota composition; iii) maternal microbiota dysbiosis may be transferred to the infant. However, factors defining maternal microbiota and its biological role upon infant’s health are not yet fully understood. Hence, this project aims to characterize maternal microbes to be transferred to neonates and determine their function in infant health programming. The specific aims are:(1) understanding how the maternal microbiome is influenced by host and environmental factors;(2) characterizing the microbial core and bioactive compounds transmitted to the offspring mainly via breastfeeding and their key roles in the microbial modulation and host response;(3) understanding the interactions among breast milk bioactive compounds and their role in infant health;(4) shedding light on how maternal microbes influence the infant immune system & (5)development of new dietary strategies and therapies based on microbial replacement and modulation. To achieve these objectives, a systems biology approach by means of state-of-the-art techniques and new methodologies based on subpopulation enrichment by flow cytometer-sorter to study host–microbe interactions will be used. Results obtained will demonstrate the interaction between infant nutrition, microbes and host response in early life and its key role in health programming, enabling new applications in the field of personalized nutrition & medicine.

1 499 979 €

Start date: 2015-06-01, End date: 2020-12-31

Plant nutrition is essential to understand any physiological process in plant biology, as well as to improve crops, and agricultural practices. The root microbiome plays an important role in plant nutrition. The best characterized microbiome elements are two plant endosymbionts: arbuscular mycorrhizal fungi (AMF) and rhizobia. AMF are responsible for delivering most of the mineral nutrients required by the host plant. Similarly, rhizobia in legume nodules provide the vast majority of the nitrogen requirements. Given their importance for plant nutrition a significant effort in understanding macronutrient exchange among the symbionts has been made. However, very little is known about metal micronutrient exchange. This is in contrast to the role of metals as essential nutrients for life (30-50 % of the proteins are metalloproteins) and to the yield-limiting effect that low soil metal bioavailability has worldwide. AMF are a source of metals, transferring the incorporated metals to the host,. Nitrogen-fixing rhizobia in mature nodules act as metal sinks, since the main enzymes required are highly expressed metalloproteins. We hypothesize that by changing the expression levels of the metal transporters involved, we will increase nitrogen fixation rates and increase plant metal uptake, resulting in higher crop production and fruit metal biofortification. Towards this goal, we will answer: i) How are metals incorporated from the AMF into the plant?, ii) How are metals delivered to the nodule?, iii) How are metals recovered from senescent nodules?, and iv) How does the natural variation of symbiotic-specific metal transporters affect yields and metal content of the fruit? In this project, we will use a multidisciplinary approach that involves metallotranscriptomics, plant physiology and molecular biology, and state-of-the art synchrotron based X-ray fluorescence to study metal distributions.

1 499 405 €

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

Nutrient-sensing by POMC neurons is a critical process to monitor the metabolic status of the organism and to coordinate adaptive neuroendocrine, behavioural and metabolic effectors of energy balance. Mitochondria, as central commanders of cellular energy production and primary sources of bioenergetic signals, are logical candidates to play a key role in metabolic control. However, a comprehensive understanding of the mitochondria as nutrient-sensors and modulators of systemic energy homeostasis is lacking. MITOSENSING hypothesizes that dedicated mitochondrial networks in POMC neurons are able to sense, integrate and respond to alterations in the nutritional milieu and engage physiological actions to maintain energy balance. Thus, defects in these mitochondrial nutrient-sensing programs in this subset of neurons underlie the development of metabolic conditions such as obesity and type-2 diabetes (T2D). To test it, we will pursue three aims: 1) to identify transcriptionally-modulated mitochondrial nutrient-sensing programs in POMC neurons; 2) to investigate whether disruption of specific nutrient-sensing programs in POMC neurons cause metabolic disorders; 3) to investigate whether the development of lifestyle-associated metabolic disorders are caused by defective mitochondrial nutrient-sensing programs in POMC neurons. By providing neuron-specific, integrative, functional and mechanistic in vivo strategies, MITOSENSING will represent a major step forward into the understanding of mitochondria as a nutrient-sensing entity, the gene programs involved and their physiological regulatory functions in the context of energy balance control. Adequate coordination of neuronal nutrient-sensing with energy balance control is critical to sustain life, and thus understanding the molecular mechanisms governing these physiological programs will have an enormous scientific impact and also potential therapeutical implications for obesity and T2D.

1 999 573 €

Start date: 2017-04-01, End date: 2022-03-31

Engineering bacteria to deliver therapeutic agents or to present antigens for vaccination is an emerging area of research with great clinical potential. The most challenging issue in this field is the selection of the right bacteria to engineer, commonly known as “chassis”. The best chassis depends on the application but there is a common drawback in bacteria used nowadays: their complexity and the lack of quantitative information for many reactions which limits genome engineering to classical trial and error approaches. In this project, we want to engineer the genome-reduced bacterium M. pneumoniae using a whole-cell model that will drive the rational to create a chassis for human and animal therapy. Its small size (816 Kbases), the lack of cell wall, and the vast amount of comprehensive quantitative –omics datasets makes this bacterium one of the best candidates for chassis design. By combining bioinformatics, -omics, and biochemistry approaches with genome engineering tools, systems biology analyses, and computational whole-cell models, MYCOCHASSIS aims to: i) develop a whole cell-model based on organism-specific experimental data that will be validated experimentally and that can predict the impact of genome modifications; ii) implement genome engineering tools to delete non-essential pathogenic and virulent elements predicted by the whole-cell model to engineer a therapeutical chassis; iii) using the whole-cell model design and engineer genes and circuits to improve growth rate in a defined medium. iv) as a proof of concept introduce orthogonal gene circuits to secrete peptides and enzymes capable of dissolving in vitro biofilms made by the lung pathogens Pseudomonas aeruginosa and Staphylococus aureus. This project will validate the usefulness of whole-cell models for synthetic biology by modelling multiple genomic modifications orientated to facilitate engineering of biological systems.

2 454 522 €

Start date: 2015-11-01, End date: 2020-10-31

Obesity is associated with increased risk for epithelial tumors such as hepatocellular carcinoma (HCC). It is not known, however, whether obesity increases the risk for HCC simply because it promotes cirrhosis, a general risk factor for HCC, or through other mechanisms that operate independently of cirrhosis. Among these, obesity is associated with a chronic inflammatory state, with the release of cytokines such as IL-6 and TNFalpha, well-known HCC mediators. Obesity is normally linked to diabetes and in consequence, to hyperinsulinemia. This increase in circulating insulin levels is suggested to be a factor that contributes to cancer. Moreover, the increase in free fatty acids (FFA) in blood among obese patients promotes a compensatory response from liver that activates the transcription of genes required for beta-oxidation, leading to a reduction in non-physiological stores of lipids in the liver. This increase in beta-oxidation could result in oxidative stress, inflammation and the production of lipid peroxidation bioproducts, which are known mutagens. The precise mechanisms whereby FFA and cytosolic triglycerides exert their effects, resulting in the diabetic phenotype, remain poorly understood. Emerging evidence nonetheless links microRNA (miRNA) with lipid metabolism, suggesting that these small RNAs mediate this increase in beta-oxidation. Our goal is to study how the components of the obesity state (inflammation, steatosis hyperinsulinemia and microRNA control of gene regulation) affect HCC development. We will use several mouse models in which one or more of these factors are reduced following induction of metabolic disease. We will also determine whether specific miRNAs that are down- or upregulated in the liver of mice on a high fat diet are implicated in HCC development.

1 498 043 €

Start date: 2010-12-01, End date: 2016-11-30

p53 is a transcriptional factor modulating numerous biological actions. Although it is best known for its role in cancer development, it is now evident that it is implicated in metabolism. More specifically, p53 modulates energy metabolism and homeostasis through their effects on adipocyte development and function. However, nothing is known about the potential metabolic function of p53 in the central nervous system. Neuronal networks within the central nervous system play a crucial role in the regulation of food intake, body weight, and glucose homeostasis, so the main objective of this project will be to evaluate the potential of brain p53 as anti-obesity and/or anti-diabetic drug candidate. Our project will dissect precisely which specific components of energy balance are altered after central disruption or rescue of p53 signalling in selective neuronal populations, as well as the molecular pathways mediating these actions. More precisely, we will disrupt the central p53 signalling specifically in hypothalamic POMC and AgRP neurons, which are crucial for energy and glucose homeostasis. We will also generate and characterize mice lacking p53 in dopamine neurons that are essential for mechanisms related with the reward of food. Once we know which specific areas are crucial for the central actions of p53, we will complete the experiments rescuing p53 expression in selective neuronal populations (POMC, AgRP or dopamine neurons) of p53 null mice. We will also investigate the interaction between p53 with leptin and ghrelin, likely the two more important hormones in the regulation of energy balance, which act through homeostatic and hedonic mechanisms. Understanding the precise role and mechanisms regulated by central p53 on energy balance may open new avenues for the identification of potential anti-obesity drug targets directed towards specific molecular pathways.

1 477 680 €

Start date: 2011-12-01, End date: 2017-05-31

Oxygen (O2) is essential for life on Earth. This proposal deals with the study of the molecular mechanisms underlying acute O2 sensing by cells, a long-standing issue that is yet to be elucidated. In recent years, the discovery of hypoxia inducible transcription factors and their regulation by the O2-dependent hydroxylases has provided a solid framework for understanding genetic responses to sustained (chronic) hypoxia. However the mechanisms of acute O2 sensing, necessary for the activation of rapid, life-saving, compensatory respiratory and cardiovascular reflexes (e.g. hyperventilation and sympathetic activation), are unknown. While the primary goal of the project is to characterize the molecular mechanisms underlying acute O2 sensing by arterial chemoreceptors (carotid body –CB- and adrenal medulla –AM-), we will also extend our study to other organs (e.g. pulmonary and systemic arteries) of the homeostatic acute O2-sensing system. We will investigate the role of mitochondria, in particular complex I (MCI), in acute O2 sensing. Previous data from our group demonstrated that rotenone, a MCI blocker, selectively occludes responsiveness to hypoxia in CB cells. In addition, our unpublished data indicate that sensitivity to hypoxia (but not to other stimuli) is lost in mice with genetic disruption of MCI genes in CB and AM cells. We have shown that the adult CB is a plastic organ that contains a population of multipotent neural stem cells. Hence, another objective of the project is to study the role of these stem cells in CB modulation (over- or infra-activation), which may participate in the pathogenesis of diseases. In the past, our group has made seminal contributions to unveiling the cellular bases of arterial chemoreception. The discovery of stem cells in the CB and the generation of new genetically modified mouse models, put us in a leading position to elucidate the molecular bases of acute O2 sensing and their biomedical implications.

2 843 750 €

Start date: 2015-11-01, End date: 2020-10-31

Future, large galaxy surveys (such as BOSS, DES, LSST, EUCLID, ADEPT etc.) will cover of the order of 10000 square degrees on the sky, with the primary science goal to unravel the nature of the physics responsible for the current accelerated expansion of the universe. This acceleration likely involves new physics which could imply ether a modification of our understanding of particles and fields (if the acceleration is caused by a new negative pressure-component) or a change in our understanding of space and time (by modifying Einstein's General Relativity laws). The unprecedented and exquisite data provided by these surveys will make possible also other interesting science with implications for fundamental physics (e.g., inflation, neutrino properties) and astrophysics (e.g., biasing, galaxy formation). The success of future large-scale galaxy surveys evidently requires a correct interpretation of their data. The current proposal, which benefits from the interaction of Cosmology, astrophysics and particle physics, aims at building up a set of robust tools to maximize the physics extracted from large-scale structure data. Such an interplay is mandatory to ensure a suitable modeling of the observables and a meaningful comparison with the theoretical predictions. The PI is involved with surveys such as BOSS, ADEPT and LSST and for the past year has been leading a working group with the goal of bringing together particle physicists and cosmology to better understand dark energy. The methods developed in the proposal presented here are expected to be used by the international community involved in future surveys. This would imply a big step for Spanish groups joining or even leading future Cosmology or Astro-particle physics projects.

1 395 000 €

Start date: 2009-11-01, End date: 2015-10-31

To cope with abiotic stresses plants require an extensive molecular regulation of gene expression. In plants, translation is a key step in the control of gene expression under abiotic stress conditions. This translational regulation involves (1) a global inhibition of protein synthesis and (2) an efficient and selective translation of certain mRNAs, generally codifying proteins involved in the abiotic stress response. Although in plants the mechanisms involved in the onset of this dual regulation are currently unknown, some evidences point out that cap independent translation, via recognition of internal ribosome entry sites (IRES) within the mRNAs efficiently translated, could be the clue for the selective protein synthesis observed under such conditions. In this proposal we aim to further characterize the cellular IRESs operating under abiotic stress conditions in plants and to exploit the identified cellular IRESs as biotechnological tools to allow the efficient and selective translation of mRNAs of interest under abiotic stress conditions. In plants, no IRES trans-acting factors (ITAFs) and only two cellular IRESs have been identified so far. Therefore, the systematic identification of new cellular IRESs, the identification for the first time of ITAFs and the study of how they can control IRES activity-specificity under abiotic stress conditions are important steps forward in the knowledge of how plants adapt to environmental stresses. In addition, the pioneering use of the identified cellular IRESs as a tool to tightly and specifically control the expression of proteins of interest under abiotic stress conditions will open up a new perspective for the study of abiotic stress in plants and for the generation of plants with increased tolerance to such conditions.

1 237 500 €

Start date: 2010-12-01, End date: 2017-05-31

"Thousands of cancer patients worldwide are taking RANKL inhibitors for the management of bone metastasis, based on the key role of RANKL and its receptor, RANK, in osteoclasts. RANK signaling has multiple divergent effects in immunity and inflammation, both in the generation of active immune responses, as well as in the induction of tolerance. We showed that RANK overexpression induces stemness and interferes with differentiation in non transformed mammary epithelial cells and promotes mammary tumorigenesis, acting as a paracrine mediator of progesterone. However, the therapeutic potential of inhibiting RANK signaling once tumors develop and its effects on tumor immunity remain unexplored. Our proposal tackles novel concepts: Is RANK a better therapeutic target than RANKL? Does RANK induce ""stemness"" in other epithelia and solid tumors and how? Does RANK regulate the tumor-immune cell crosstalk? Would inhibition of RANK signaling in tumor and immune cells result in synergistic or opposing effects on tumor outcome? We hypotesize that RANK activation in solid tumors expands the cancer stem cells pool and induces an immnunosuppressive environment leading to tumor recurrence and metastasis. In PLEIO-RANK we aim to: 1. Define the contribution of RANK to the epithelial hierarchy in mammary, skin and colon, during homeostasis and tumorigenesis, undertaking lineage tracing approaches. 2. Dissect the impact of RANK loss in the epithelial or the immune compartment in tumor outcome, exploiting tissue inducible models, in breast cancer and solid tumors driven by chronic inflammation. 3. Validate the clinical implications of our findings using patient derived xenografts and human tumor samples. Based on the results of our proposal RANK inhibition could become a unique targeted therapy able to reduce metastasis and mortality in solid tumors for its pleiotropic antitumor effects in cancer stem cells, immune cells and their crosstalk. "

1 999 960 €

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

The precise synthesis of nano-devices with tailored complex structures and properties is a requisite for their use in nanotechnology and medicine. Nowadays, the technology for the generation of these devices lacks the precision to determine their properties, and is accomplished mostly by “trial and error” experimental approaches. Bottom-up self-assembly that relies on highly specific biomolecular interactions of small and simple components, is an attractive approach for nanostructure templating. Here, we propose to overcome aforementioned challenges by using self-assembling protein building blocks as templates for nanofabrication. In nature, protein assemblies govern sophisticated structures and functions, which are inspiration to engineer novel assemblies by exploiting the same set of tools and interactions to create nanostructures with numerous potential applications in synthetic biology and nanotechnology. We hypothesize that we can rationally assemble a variety functional nanostructures by the logical combination of simple protein building blocks with specified properties. We propose to use a designed repeat protein scaffold for which we acquired a deep understanding of its molecular structure, stability, function, and inherent assembly properties. Only few conserved residues define the structure of the building block, which allow us to mutate its sequence to modulate assembly properties and to introduce reactive functionalities without compromising the structure of the scaffolding molecule. First, we will design a collection of protein-based nanostructures. Then, we will introduce reactive functionalities to create hybrid nanostructures with nanoparticles, metals and electro-active molecules. Finally, these conjugates will be used to build nano-devices such as nanocircuits, catalysts and electroactive materials. The outcome of this project will be a modular versatile platform for the fabrication of multiple protein-based hybrid functional nanostructures.

1 718 850 €

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

Global food security will remain a worldwide concern for the next 50 years and beyond. Agricultural production undergoes an increasing pressure by global anthropogenic changes, including rising population, increased protein demands and climatic extremes. Because of the immediate and dynamic nature of these changes, productivity monitoring measures are urgently needed to ensure both the stability and continued increase of the global food supply. Europe has expressed ambitions to keep its fingers on the pulse of its agricultural lands. In response to that, this proposal - named SENTIFLEX - is dedicated to developing a European vegetation productivity monitoring facility based on the synergy of Sentinel-3 (S3) with FLEX satellite fluorescence data. ESA's 8th Earth Explorer FLEX is the first mission specifically designed to globally measure Sun-Induced chlorophyll Fluorescence (SIF) emission from terrestrial vegetation. These two European Earth observation missions offer immense possibilities to increase our knowledge of the basic functioning of the Earth’s vegetation, i.e., the photosynthetic activity of plants resulting in carbon fixation. Two complementary approaches are envisioned to realize quantification of photosynthesis through satellite SIF and S3. First, the work seeks to advance the science in establishing and consolidating relationships between canopy-leaving SIF and unbiased estimates of photosynthesis of the plants, thereby disentangling the role of dynamic vegetative and atmospheric variables. Second, consolidated relationships between SIF and photosynthesis will be used to build a FLEX-S3 data processing assimilation scheme through process-based vegetation models that will deliver spatiotemporally highly resolved information on Europe’s vegetation productivity. To streamline all these datasets into a prototype vegetation productivity monitoring facility, new data processing concepts will be introduced such as the emulation of radiative transfer models.

1 499 587 €

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

The basic mechanisms of stem cell malfunction during aging are poorly understood even though they underlie the regenerative decline of most organs and tissues as we age. Based on our recent contributions (Nature 2014, Nature 2016), the fields of tissue regeneration and aging converge on the key role of the quiescent state, the preferred state of stem cells in low turnover tissues such as skeletal muscle. Our unifying hypothesis is that stem-cell quiescence maintenance, which requires active proteostasis (protein homeostasis), lies at the basis of stemness, and that its substitution by a senescence state in aging impairs regeneration. How these variables connect to drive stem cell aging is not known. Crucial experimental systems in this proposal are sensitive reporter mice for proteostasis, senescence and quiescence/fate in aging muscle stem cells. The project is divided as follows: Objective 1. Proteostasis and stem cell quiescence maintenance: tracing proteostasis in quiescent stem cells from autophagy and chaperone-mediated autophagy (CMA) reporter mice during aging / impact of autophagy/CMA loss on quiescence and regeneration / molecular regulators of proteostasis. Objective 2. Proteostasis and quiescent stem cell heterogeneity and fate: asymmetric segregation of proteotoxic waste as an instructor of stem cell heterogeneity and regenerative fate. Objective 3. The quiescence-to-senescence-switch in aging muscle stem cells: tracing and isolating senescent stem cells in senescence-cell reporter mice during aging / impact of senescent cell ablation on regenerating aged muscle. Objective 4. Circadian regulation in the quiescent stem-cell state: impact of aging on circadian rhythms and consequences for quiescence maintenance and regeneration. We expect that completion of these objectives will provide new fundamental knowledge on stem-cell biology, regeneration and aging.

2 499 949 €

Start date: 2017-11-01, End date: 2022-10-31

Angiogenesis inhibition has proven to be a successful anti-cancer therapeutic approach and anti-angiogenic therapies are currently approved as standard therapy in several types of cancer for their clinically validated beneficial extension of overall survival, progression-free survival and/or time-to-progression in these cancer patients. Nevertheless, in preclinical mouse models of cancer, although these therapies also show significant anti-tumour effects and overall survival benefit, these therapies are also triggering increased tumour local invasion, with more distant dissemination and emergence of metastasis (overall tumour malignization). The clinical relevance of this malignization effect in patients that are currently being treated with antiangiogenic drugs still remains elusive, but the frequent tumour relapses and acquired resistance to therapy in some patients strongly suggests this insidious event should be exhaustively evaluated. In this sense, many laboratories are rapidly advancing in the study of the molecular players and signalling pathways implicated in this event, although an important limitation of all these approaches is that they are all based on Tumour-centered studies of the causes of malignization and are not taking into account the Tumour Stroma contribution to tumour invasion and metastasis. Thus, we postulate that the tumour stroma indeed plays a critical role in malignization after anti-angiogenic therapies and its specific mechanisms should be determined in order to target these stromal components to impede tumour malignization after antiangiogenic therapies. STROMALIGN is a groundbreaking project designed to overcome these current limitations from a novel perspective: instead of focusing on the genetically instable and highly adaptive tumour cell component, we rather postulate that the tumour stroma plays a critical role in malignization after anti-angiogenic therapies and its targeting could offer significant advantages of less adaptation/resistance, and broader applicability to several different tumour types. Thus, we will initially dissect the mechanisms of stromal contribution to this malignization effect, followed by pharmacological targeting this event in transgenic and recently developed Tumorgraft mouse models of cancer, and later on applying this knowledge to the clinical setting in samples from two approved clinical studies with anti-angiogenic therapies currently ongoing at our Hospital. By starting at the biology of animal models and later on validating these findings in the clinical setting we will tackle this current biomedical challenge by finding new stromal targets of malignancy that will ultimately benefit anti-angiogenic treated patients in the clinic.

1 495 796 €

Start date: 2012-06-01, End date: 2017-05-31

Wheat is one of the most important food crops in the world and understanding its genetics and genome organisation is of great value for genetics and plant breeding purposes. Despite is genome complexity (polyploidy), hexaploid and tetraploid wheats behave as diploids during meiosis. This means that each chromosome only recognises its identical (homologue) to pair and not the related chromosomes (homeologues). There are several pairing homologous (Ph) genes controlling chromosome pairing in wheat during meiosis. The strongest effect is associated with the Ph1 locus, which is located on the long arm on chromosome 5B. Ph1 appears to sense homology prior to the chromosomes coming into contact with each other at early meiosis. Thus, if the chromosomes are true homologues, they perfectly recognise each other, chromatin remodelling is synchronized and allows pairing and recombination to occur. If the chromosomes are homoeologous (related), remodelling is not synchronized and the chromosomes fail to pair and recombine. In the absence of Ph1, all chromosomes can remodel without the requirement for the presence of an identical or near identical chromosome, and this increases the chance of pairing between related chromosomes in addition to pairing between true homologues. In this project we want to analyse deeper this Ph1 behaviour and we also want to exploit ph1 mutants as a tool for wheat breeding programs to promote inter-specific recombination between related wild species. In fact, Hordeum chilense (wild barley with interesting agronomic traits for wheat breeding) introgressions will be developed into durum wheat to transfer desirable agronomic traits from this wild barley into wheat, like resistance to diseases or the increment in carotene content. Introgression lines will be crosses with ph1 mutants to promote inter-specific recombination H. chilense-wheat, reduce the size of the H. chilense chromosome fragment. New wheat varieties will be generated.

600 000 €

Start date: 2010-01-01, End date: 2015-12-31

B cells are one of the main players of immunity, responsible for the production of immunoglobulins (Igs). In 2011, I was granted an ERC Starting grant to undertake the phenotypical and functional characterization of teleost B lymphocytes based on the hypothesis that they do not behave as mammalian B2 cells (conventional B cells) but closely resemble mammalian innate B1 lymphocytes involved in extrafollicular T-independent (TI) responses. Since then, my laboratory has gathered considerable evidences that strengthen this hypothesis. These studies were mostly carried out in central lymphoid compartments, but did not address how teleost B1-like cells regulate the delicate balance between immunity and tolerance at mucosal interfaces, in species lacking follicular structures. In this new project, I want to pursue my studies on B lymphocyte functionality, focusing on how teleost mucosal B cells are regulated, still under the assumption that fish B lymphocytes resemble better a B1 model. We will study how fish B cells differentiate to antibody secreting cells (ASCs) and establish extrafollicular long-term memory, taking into account novel results in mammals that have challenged traditional paradigms and revealed that long-term immunological memory can be established through TI IgM B1-like responses. Furthermore, we will also study the role of IgD in the gills, as previous studies from my group suggest that this Ig plays a key role in the regulation of immunity in this specific mucosa, as it seems to do in humans in areas such as the upper respiratory tract. Addressing how fish B cells mount a protective mucosal immune response in the absence of T cell help from organized follicles could provide new mechanistic insights into IgM and IgD responses emerging in humans. From a practical view, our work will contribute to understand why satisfactory mucosal vaccination is still an unreached goal for most diseases in both mammals and fish, despite their strong demand.

1 866 046 €

Start date: 2017-04-01, End date: 2022-03-31

Ripening is the critical step for the development of flavour quality in fruit. This character has significantly declined in many fleshy fruits over recent decades, primarily due to the focus of current breeding programs on agronomic traits such as production, firmness, and postharvest shelf life. This strategy has caused a tunnelling effect on genetic variability in many crops. This is particularly significant in strawberry, where current cultivars are derived from a narrow germplasm stock. A notable feature of strawberry fruit is that undergoes a non-climacteric ripening program independent of the hormone ethylene, in contrast to well studied climacteric fruits such as tomato, where ethylene plays a central role. Therefore, improving fruit flavour in present strawberry varieties requires two important breakthroughs: 1) a precise understanding of non-climacteric fruit ripening regulation that will allow the targeting of relevant quality genes, and 2) the identification of unexploited allelic variants from wild germplasm to be introgressed through the generation of novel breeding lines. The first objective will be achieved by (i) focusing on the sequenced, diploid Fragaria vesca, a wild relative of the cultivated strawberry that will serve as a model, (ii) identifying key transcription factors (TFs) regulating fruit ripening by generating a stage- and tissue-specific gene expression map, (iii) using a candidate gene approach and reverse genetics based on gene silencing and TILLING to verify the role of these TFs, and (iv) defining the gene regulatory networks controlling the ripening process via integration of transcriptomic, metabolomic and ChIP-Seq data obtained from the stably silenced and/or TILLED lines. Finally, TRANSFR-Q plans to use this knowledge, combined with the identification of novel alleles from a core collection of Fragaria germplasm, to transfer flavour quality characters into current strawberry cultivars.

1 500 000 €

Start date: 2015-06-01, End date: 2021-05-31