ERC FUNDED PROJECTS

Blood and lymphatic vessels have been the subject of intense investigation due to their important role in cancer development and in cardiovascular diseases. The significant advance in the methods used to modify and analyse gene function have allowed us to obtain a much better understanding of the molecular mechanisms involved in the regulation of the biology of blood vessels. However, there are two key aspects that significantly diminish our capacity to understand the function of gene networks and their intersections in vivo. One is the long time that is usually required to generate a given double mutant vertebrate tissue, and the other is the lack of single-cell genetic and phenotypic resolution. We have recently performed an in vivo comparative transcriptome analysis of highly angiogenic endothelial cells experiencing different VEGF and Notch signalling levels. These are two of the most important molecular mechanisms required for the adequate differentiation, proliferation and sprouting of endothelial cells. Using the information generated from this analysis, the overall aim of the proposed project is to characterize the vascular function of some of the previously identified genes and determine how they functionally interact with these two signalling pathways. We propose to use novel inducible genetic tools that will allow us to generate a spatially and temporally regulated fluorescent cell mosaic matrix for quantitative analysis. This will enable us to analyse with unprecedented speed and resolution the function of several different genes simultaneously, during vascular development, homeostasis or associated diseases. Understanding the genetic epistatic interactions that control the differentiation and behaviour of endothelial cells, in different contexts, and with high cellular definition, has the potential to unveil new mechanisms with high biological and therapeutic relevance.

1 481 375 €

Start date: 2015-03-01, End date: 2020-02-29

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

Learning to read is probably one of the most exciting discoveries in our life. Using a longitudinal approach, the research proposed examines how the human brain responds to two major challenges: (a) the instantiation a complex cognitive function for which there is no genetic blueprint (learning to read in a first language, L1), and (b) the accommodation to new statistical regularities when learning to read in a second language (L2). The aim of the present research project is to identify the neural substrates of the reading process and its constituent cognitive components, with specific attention to individual differences and reading disabilities; as well as to investigate the relationship between specific cognitive functions and the changes in neural activity that take place in the course of learning to read in L1 and in L2. The project will employ a longitudinal design. We will recruit children before they learn to read in L1 and in L2 and track reading development with both cognitive and neuroimaging measures over 24 months. The findings from this project will provide a deeper understanding of (a) how general neurocognitive factors and language specific factors underlie individual differences – and reading disabilities– in reading acquisition in L1 and in L2; (b) how the neuro-cognitive circuitry changes and brain mechanisms synchronize while instantiating reading in L1 and in L2; (c) what the limitations and the extent of brain plasticity are in young readers. An interdisciplinary and multi-methodological approach is one of the keys to success of the present project, along with strong theory-driven investigation. By combining both we will generate breakthroughs to advance our understanding of how literacy in L1 and in L2 is acquired and mastered. The research proposed will also lay the foundations for more applied investigations of best practice in teaching reading in first and subsequent languages, and devising intervention methods for reading disabilities.

2 487 000 €

Start date: 2012-05-01, End date: 2017-04-30

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

"Our research group has worked over the years at the interface between cancer and ageing, with a strong emphasis on mouse models. More recently, we became interested in cellular reprogramming because we hypothesized that understanding cellular plasticity could yield new insights into cancer and ageing. Indeed, during the previous ERC Advanced Grant, we made relevant contributions to the fields of cellular reprogramming (Nature 2013), cellular senescence (Cell 2013), cancer (Cancer Cell 2012), and ageing (Cell Metabolism 2012). Now, we take advantage of our diverse background and integrate the above processes. Our unifying hypothesis is that cellular plasticity lies at the basis of tissue regeneration (“adaptive cellular plasticity”), as well as at the origin of cancer (“maladaptive gain of cellular plasticity”) and ageing (“maladaptive loss of cellular plasticity”). A key experimental system will be our “reprogrammable mice” (with inducible expression of the four Yamanaka factors), which we regard as a tool to induce cellular plasticity in vivo. The project is divided as follows: Objective #1 – Cellular plasticity and cancer: role of tumour suppressors in in vivo de-differentiation and reprogramming / impact of transient de-differentiation on tumour initiation / lineage tracing of Oct4 to determine whether a transient pluripotent-state occurs during cancer. Objective #2 – Cellular plasticity in tissue regeneration and ageing: impact of transient de-differentiation on tissue regeneration / contribution of the damage-induced microenvironment to tissue regeneration / impact of transient de-differentiation on ageing. Objective #3: New frontiers in cellular plasticity: chemical manipulation of cellular plasticity in vivo / new states of pluripotency / characterization of in vivo induced pluripotency and its unique properties. We anticipate that the completion of this project will yield new fundamental insights into cancer, regeneration and ageing."

2 488 850 €

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

Whole genome sequencing is quickly becoming a routine clinical instrument. However, our ability to decipher DNA variants is still largely limited to protein-coding exons, which comprise 1% of the genome. Most known Mendelian mutations are in exons, yet genetic testing still fails to show causal coding mutations in more than 50% of well-characterized Mendelian disorders. This defines a pressing need to interpret noncoding genome sequences, and to establish the role of noncoding mutations in Mendelian disease. A recent case study harnessed whole genome sequencing, epigenomics, and functional genomics to show that mutations in an enhancer cause most cases of neonatal diabetes due to pancreas agenesis. This example raises major questions: (i) what is the overall impact of penetrant regulatory mutations in human diabetes? (ii) do regulatory mutations cause distinct forms of diabetes? (iii) more generally, can we develop a strategy to systematically tackle regulatory variation in Mendelian disease? The current project will address these questions with unique resources. First, we have created epigenomic and functional perturbation resources to interpret the regulatory genome in embryonic pancreas and adult pancreatic islets. Second, we have collected an unprecedented international cohort of patients with a phenotype consistent with monogenic diabetes, yet lacking mutations in known gene culprits after genetic testing, and therefore with increased likelihood of harboring noncoding mutations. Third, we have developed a prototype platform to sequence regulatory mutations in a large number of patients. These resources will be combined with innovative strategies to uncover causal enhancer mutations underlying Mendelian diabetes. If successful, this project will expand the diagnostic spectrum of diabetes, it will discover new genetic regulators of diabetes-relevant networks, and will provide a framework to understand regulatory variation in Mendelian disease.

2 243 746 €

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

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

In recent years, my laboratory, as well as others, have established the observation that epigenetic disruption, particularly in the DNA methylation and histone modification patterns, contributes to the initiation and progression of human tumors (Esteller, Nat Rev Genet 2007; Esteller, N Engl J Med 2008; Esteller, Nat Rev Biotech, In Press, 2010). Even more recently, it has been recognized that microRNAs, small non-coding RNAs that are thought to regulate gene expression by sequence-specific base pairing in mRNA targets, also play a key role in the biology of the cell, and that they can also have an impact in the development of many diseases, including cancer (le Sage and Agami, 2006; Blenkiron and Miska, 2007). However, there is little understanding about epigenetic modifications that might regulate the activity of microRNAs and other non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs), Piwi-interacting RNAs (piRNAs), small-interfering RNAs (siRNAs), transcribed ultraconserved regions (T-UCRs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), long interspersed ncRNAs (lincRNAs), promoter-associated RNAs (PASRs and PALRs) and terminator-associated sRNAs (TASRs) (Calin et al., 2007; Mercer, et al., 2009; Ghildiyal & Zamore, 2009; Jacquier, 2009). Our ignorance in this respect is even more significant if we consider these questions in the domain of cancer. Making best use of our expertise in several of these fields, my group will tackle the study of the epigenetic modifications that regulate ncRNA expression and how the DNA methylation and histone modifications profiles of these loci might become distorted in human cancer. These findings could have profound consequences not only in the understading of tumor biology, but in the design of better molecular staging, diagnosis and treatments of human malignancies.

2 497 240 €

Start date: 2011-04-01, End date: 2016-03-31

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

Infant cancer is very distinct to adult cancer and it is progressively seen as a developmental disease. An intriguing infant cancer is the t(4;11) acute lymphoblastic leukemia (ALL) characterized by the hallmark rearrangement MLL-AF4 (MA4), and associated with dismal prognosis. The 100% concordance in twins and its prenatal onset suggest an extremely rapid disease progression. Many key issues remain elusive: Is MA4 leukemogenic? Which are other relevant oncogenic drivers? Which is the nature of the cell transformed by MA4? Which is the leukemia-initiating cell (LIC)? Does this ALL follow a hierarchical or stochastic cancer model? How to explain therapy resistance and CNS involvement? To what extent do genetics vs epigenetics contribute this ALL? These questions remain a challenge due to: 1) the absence of prospective studies on diagnostic/remission-matched samples, 2) the lack of models which faithfully reproduce the disease and 3) a surprising genomic stability of this ALL. I hypothesize that a Multilayer-Omics to function approach in patient blasts and early human hematopoietic stem/progenitor cells (HSPC) is required to fully scrutinize the biology underlying this life-threatening leukemia. I will perform genome-wide studies on the mutational landscape, DNA and H3K79 methylation profiles, and transcriptome on a uniquely available, large cohort of diagnostic/remission-matched samples. Omics data integration will provide unprecedented information about oncogenic drivers which must be analyzed in ground-breaking functional assays using patient blasts and early HSPCs carrying a CRISPR/Cas9-mediated locus/allele-specific t(4;11). Serial xenografts combined with exome-seq in paired diagnostic samples and xenografts will identify the LIC and determine whether variegated genetics may underlie clonal functional heterogeneity. This project will provide a precise understanding and a disease model for MA4+ ALL, offering a platform for new treatment strategies.

2 000 000 €

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

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

We have recently identified metastasis-initiating cells (MICs) in several types of tumors (Nature, 2017)1. Intriguingly, MICs: (i) are exclusive in their ability to generate metastases when transplanted; (ii) express the fatty acid channel CD36 and have a unique lipid metabolic signature; (iii) are exquisitely sensitive to the levels of fat in circulation, thus providing a link between the predisposition of metastasis and dietary fat; (iv) are highly sensitive to CD36 inhibition, which almost completely abolishes their metastatic potential. We still do not know how MICs promote metastasis or how MICs are influenced by dietary fat. In particular: (A) where are MICs located within the tumor, and does this location influence their behavior? How and where do they attach and expand at metastatic sites? (B) Why are MICs so sensitive to specific dietary lipids, and how do these lipids promote metastasis at the molecular and cellular levels? (C) Is the prolonged consumption of a high-fat diet a risk factor for developing metastatic tumors? If so, what are the underlying genetic and epigenetic causes for this effect? Can we revert these causes? To answer these questions, we will combine state-of-the-art in vivo functional models of metastasis, with quantitative metabolomics and proteomics, epigenetic and geographical position (3D) single-cell transcriptomic studies, as well as integrative computational analyses, using preclinical models and patientderived carcinomas of melanoma, oral cancer and breast cancer. We expect our project to provide fundamental insights into the mechanisms of metastasis, and how they are influenced by diet. This is highly relevant as 1) large quantities of fatty acids are typically consumed in Western diets; and 2) metastasis is the leading cause of cancer-related deaths. We also tackle a timely medical unmet need by exploring the therapeutic anti-metastatic potential of targeting fatty acid metabolism in cancer patients.

2 370 625 €

Start date: 2018-08-01, End date: 2023-07-31

Concepts of large bodies of glacial ice and liquid standing water, a robust hydrological cycle, and a rich Martian history of climate change are part of the current consensus model for early Mars. However, questions still poorly constrained include: a precise understanding of the inventory of water during the first billion years of Mars history and its early evolution on both global and local scales; whether liquid or solid H2O dominated, for what duration of time and where the water resided; what were the host-rock weathering rates and patterns and the physicochemical parameters defining such interactions; what specific landforms and mineralogies were generated during those periods; and what implications all these processes had on the possible inception of life on Mars. These fundamental questions represent large uncertainties and knowledge gaps. Therefore, a quantitative understanding of the basic characteristics of water on early Mars is very much needed and is the focus of this proposal. This application outlines a plan for my research in the next five years, and explains how I propose to fully characterize the aqueous environments of early Mars through a quantitative and truly interdisciplinary investigation. Spacecraft mission-derived datasets will be consistently used to test hypotheses through paleogeomorphological reconstructions, geochemical modeling, mineralogical studies, and astrobiological investigations. The derived results will produce hard constraints on the physical evolution, chemical alteration and habitability of surface and near-surface aqueous environments on early Mars. The planned investigations will benefit from the combination of working with first-hand data from ongoing Mars missions and with the state-of-the-art laboratory tools at the host institution. The final expected result will be a complete understanding of the physicochemical nature of water on early Mars, also opening new paths for the astrobiological exploration of the planet.

1 998 368 €

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

The world around us is immensely rich in sensory information, which we perceive through a varied range of different sensory systems (enabling us to feel, hear, see…). Yet, our perceptual experience is not a sensory piecemeal, but a unitary phenomenon brought about by Multisensory Integration mechanisms. MSI is in charge of binding sensory input to create faithful and coherent representations of the environment, an ability that confers important advantages in terms of optimizing behavioural outcomes. For example, people often find it easier to speak with someone when they can see their partner’s face, as lip and facial movements compensate for acoustic noise. The novelty of the project is that it focuses on internal processes, and in particular attention, to be of utmost importance during MSI. Attention enables efficient allocation of limited cognitive and neural resources, and therefore it plays a paramount role in perception, cognition and action. The aim is to understand the interplay between attention and the mechanisms of multisensory integration. Unravelling this interplay presents important challenges but, in return, promises to provide very important insights into how perception is accomplished by the human mind and brain. In particular, the driving hypothesis underlying the present proposal is that objects of perception are multi-sensory defined events, and that attention plays a key role in building up and maintaining these perceptual representations. The strategy is to address this dynamic interplay between MSI and Attention by addressing a set of key specific research questions by means of converging methodological approaches. I propose to undertake this task with the help of a multidisciplinary team of researchers of different backgrounds, and a set of research methods including a behavioural approach (psychophysics in healthy adult humans, developmental studies and neuropsychology) combined with selective use of brain imaging stimulation.

1 450 672 €

Start date: 2011-04-01, End date: 2016-09-30

Mitochondrial defects are associated with aging and age-related pathology, but the molecular mechanisms regulating mitochondrial function during ageing are poorly understood. The most relevant genetic pathway regulating ageing is the insulin/IGF-1 signalling (IIS) pathway. The mitochondrial prohibitin (PHB) complex influences cellular metabolism and mitochondrial biogenesis, affecting ageing in opposite ways in wild-type animals and IIS-defective C. elegans mutants. The aim of the proposed research programme is to shed light on the intricate communication between mitochondria and cell-signalling networks in the regulation of ageing. Our specific objectives are: 1-Elucidate the cellular signalling pathways involved in the metabolic responses to mitochondrial dysfunction upon PHB depletion in wild type animals and IIS-defective mutants, using genome-wide RNAi screens, 2-Conduct a comprehensive metabolic profiling of wild type and IIS mutants in the presence and absence of prohibitins and 3-Identify genetic suppressors of prohibitins by performing forward genetic suppressor screens. As an ultimate goal, genes discovered in C. elegans will be tested in vertebrate assays for a conserved role in ageing. We will implement an interdisciplinary approach that combines the genetic power of C. elegans with state-of-the-art metabolomic approaches as well as automated sorting and optical imaging technologies to monitor fat content and mitochondrial biogenesis, in a genome-wide scale, in vivo. The fine-tuning of cellular metabolism, by integration of diverse signalling inputs is the molecular basis of longevity. This project represents a truly integrative and innovative approach to identify cellular signalling pathways involved in mediating lifespan-extending metabolism adjustments, and what these metabolic adjustments entail. These studies will provide fundamental insights to understand the ageing process and to combat ageing-related diseases.

1 424 640 €

Start date: 2012-06-01, End date: 2018-05-31

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

"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

Ras genes are some of the best-studied genes in biomedical research due to their central role in mitogenic signaling and their oncogenic activation in one third of all human tumors. More recently, Ras genes have also been implicated in developmental disorders including Costello and Noonan syndromes. In spite of this wealth of information, we still do not know the role of Ras proteins in adult homeostasis and, more importantly, how their misregulation affects human health. The latter is of paramount importance in order to develop efficacious therapies against tumors carrying Ras oncogenes - an achievement that could save thousands of lives worldwide. We propose to address these issues using genetic approaches in mouse models. We aim to systemically ablate all Ras genes in adult mice as well as in selective tissues to understand their role in normal homeostasis. We also propose to characterize mouse models for developmental disorders induced by hyperactive Ras proteins. These models should help us to better understand these human disorders as well as tools to test potential therapeutic strategies. Finally, we propose to use K-Ras driven mouse tumor models for human PDA and NSCLC to address key questions that may be directly translated to the clinic. In the case of PDA, we propose to study the contribution of the inflammatory response induced by pancreatitis to tumor development. In the case of NCSLC, we propose to isolate cancer initiating cells in an attempt to reveal the earliest events in tumor development. Moreover, we intend to use this tumor model to validate druggable Ras downstream effectors as therapeutic targets. The results derived from these studies should provide key information to design forthcoming clinical trials that will benefit cancer patients.

2 496 192 €

Start date: 2010-04-01, End date: 2015-03-31

This project will investigate the nature, structure and significance of conscious agency along three related fronts. First, although philosophers have emphasized the importance of various aspects of consciousness for human agency, work on conscious agency within philosophy remains unsystematic. Cross-talk regarding the phenomena at issue hampers progress, as does a lack of significant attention to the richness of the phenomenology that accompanies human agency. In response, we will develop a new account of the nature and mechanistic underpinnings of agentive phenomenology. Second, although psychology’s recent progress in explaining agentive capacities – e.g., metacognition, cognitive control, attention, perception, decision-making, and motor acuity – is impressive, insights regarding the importance of consciousness for these capacities need to be made explicit, and leveraged to construct a next generation model of action control. In response, we will map the phenomenology of agency onto the structure and function of action control capacities, with special focus on three areas: the role of explicit knowledge and its signatures within consciousness, the function of phenomenal states for cognitive control resource allocation, and the relationships between conscious intentions and perceptual feedback. Third, we will deploy the tools of experimental philosophy – that is, the use of psychological methods to study philosophical questions – in two novel areas. First, we will complement and advance this project’s philosophical work by experimentally investigating agentive phenomenology. Second, we will explore the practical and moral significance of conscious agency, by determining what aspects of conscious agency drive commonsense moral thinking about responsibility for action.

1 064 712 €

Start date: 2018-05-01, End date: 2023-04-30

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

Language is the most amazing skill that humans possess. It allows social interaction, can make us cry, laugh and transmit our most complex thoughts. Comprehending the cognitive processes involved in language learning is of critical importance for our understanding of why under certain conditions language learning is impaired. However, current language learning research has often offered limited explanations bounded within the language domain, ignoring the importance of other cognitive functions. The present project breaks these limits and presents an integrative approach at the edge of different research fields to understand the role of attention during language acquisition. Because speech is a sequence of sounds that unfold in time the present proposal integrates this long ignored temporal dimension. The aim of the project is thus to understand the involvement of the temporal orienting brain networks in language learning and how the attentional system may be tuned to the acquisition of words and rules. Three specific objectives will be fulfilled: (i) delineating the temporal attention mechanisms and brain networks involved in language learning, (ii) uncovering the developmental relationship in infants between these specific attentional mechanisms and word and rule learning, and (iii) understanding how the deficits in temporal orienting and the lesions in its brain networks may lead to similar deficits in language acquisition. This project uses a combination of novel methods allowing linking structural and functional measures (analysis of oscillatory activity following EEG variations during learning, fMRI – structural MRI white matter tractography and TMS) in different populations (brain-damaged patients, infants and healthy adults).

1 485 600 €

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