ERC FUNDED PROJECTS

Changes in climate and land use (e.g., increased grazing pressure), are two main global change components that also act as major desertification drivers. Understanding how drylands will respond to these drivers is crucial because they occupy 41% of the terrestrial surface and are home to over 38% of the world’s human population. Land degradation already affects ~250 million people in the developing world, which rely upon the provision of many ecosystem processes (multifunctionality). This proposal aims to develop a better understanding of the functioning and resilience of drylands (i.e. their ability to respond to and recover from disturbances) to major desertification drivers. Its objectives are to: 1) test how changes in climate and grazing pressure determine spatiotemporal patterns in multifunctionality in global drylands, 2) assess how biotic attributes (e.g., biodiversity, cover) modulate ecosystem resilience to climate change and grazing pressure at various spatial scales, 3) test and develop early warning indicators of desertification, and 4) forecast the onset of desertification and its ecological consequences under different climate and grazing scenarios. I will use various biotic communities/attributes, ecosystem services and spatial scales (from local to global), and will combine approaches from several disciplines. Such comprehensive and highly integrated research endeavor is novel and constitutes a ground breaking advance over current research efforts on desertification. This project will provide a mechanistic understanding on the processes driving multifunctionality under different global change scenarios, as well as key insights to forecast future scenarios for the provisioning of ecosystem services in drylands, and to test and develop early warning indicators of desertification. This is of major importance to attain global sustainability and key Millennium Development Goals, such as the eradication of poverty.

1 894 450 €

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

Naturally-emitted very short-lived halogens (VSLH) have a profound impact on the chemistry and composition of the atmosphere, destroying greenhouse gases and altering aerosol production, which together can change the Earth´s radiative balance. Therefore, natural halogens possess leverage to influence climate, although their contribution to climate change is not well established and most climate models have yet to consider their effects. Also, there is increasing evidence that natural halogens i) impact on the air quality of coastal cities, ii) accelerates the atmospheric deposition of mercury (a toxic heavy metal) and iii) that their natural ocean and ice emissions are controlled by biological and photochemical mechanisms that may respond to climate changes. Motivated by the above, this project aims to quantify the so far unrecognized natural halogen-climate feedbacks and the impact of these feedbacks on global atmospheric oxidizing capacity (AOC) and radiative forcing (RF) across pre-industrial, present and future climates. Answering these questions is essential to predict if these climate-mediated feedbacks can reduce or amplify future climate change. To this end we will develop a multidisciplinary research approach using laboratory and field observations and models interactively that will allow us to peel apart the detailed physical processes behind the contribution of natural halogens to global climate change. Furthermore, the work plan also involves examining past-future climate impacts of natural halogens within a holistic Earth System model, where we will develop the multidirectional halogen interactions in the land-ocean-ice-biosphere-atmosphere coupled system. This will provide a breakthrough in our understanding of the importance of these natural processes for the composition and oxidation capacity of the Earth´s atmosphere and climate, both in the presence and absence of human influence.

1 979 112 €

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

Understanding how organisms adapt to their environments is a long-standing problem in Biology with far-reaching implications: adaptation affects the ability of species to survive in changing environments, host-pathogen interactions, and resistance to pesticides and drugs. Despite recent progress, adaptation is to date a poorly understood process largely due to limitations of current approaches that focus (i) on a priori candidate genes, (ii) on signals of selection at the DNA level without functional validation of the identified candidates, and (iii) on small sets of adaptive mutations that do not represent the variability present in natural populations. As a result, major questions such as what is the relative importance of different types of mutations in adaptation?, and what is the importance of epigenetic changes in adaptive evolution?, remain largely unanswered. To gain a deep understanding of adaptation, we need to systematically identify adaptive mutations across space and time, pinpoint their molecular mechanisms and discover their fitness effects. To this end, Drosophila melanogaster has proven to be an ideal organism. Besides the battery of genetic tools and resources available, D. melanogaster has recently adapted to live in out of Africa environments. We and others have already shown that transposable elements (TEs) have substantially contributed to the adaptation of D. melanogaster to different environmental challenges. Here, we propose to use state-of-the-art techniques, such as Illumina TruSeq sequencing and CRISPR/Cas9 genome editing, to systematically identify and characterize in detail adaptive TE insertions in D. melanogaster natural populations. Only by moving from gathering anecdotic evidence to applying global approaches, we will be able to start constructing a quantitative and predictive theory of adaptation that will be relevant for other species as well.

2 392 521 €

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

Soil dust aerosols are mixtures of different minerals, whose relative abundances, particle size distribution (PSD), shape, surface topography and mixing state influence their effect upon climate. However, Earth System Models typically assume that dust aerosols have a globally uniform composition, neglecting the known regional variations in the mineralogy of the sources. The goal of FRAGMENT is to understand and constrain the global mineralogical composition of dust along with its effects upon climate. The representation of the global dust mineralogy is hindered by our limited knowledge of the global soil mineral content and our incomplete understanding of the emitted dust PSD in terms of its constituent minerals that results from the fragmentation of soil aggregates during wind erosion. The emitted PSD affects the duration of particle transport and thus each mineral’s global distribution, along with its specific effect upon climate. Coincident observations of the emitted dust and soil PSD are scarce and do not characterize the mineralogy. In addition, the existing theoretical paradigms disagree fundamentally on multiple aspects. We will contribute new fundamental understanding of the size-resolved mineralogy of dust at emission and its relationship with the parent soil, based on an unprecedented ensemble of measurement campaigns that have been designed to thoroughly test our theoretical hypotheses. To improve knowledge of the global soil mineral content, we will evaluate and use available remote hyperspectral imaging, which is unprecedented in the context of dust modelling. Our new methods will anticipate the coming innovation of retrieving soil mineralogy through high-quality spaceborne hyperspectral measurements. Finally, we will generate integrated and quantitative knowledge of the role of dust mineralogy in dust-radiation, dust-chemistry and dust-cloud interactions based on modeling experiments constrained with our theoretical innovations and field measurements.

2 000 000 €

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

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

Cardiac toxicity is one of the most frequent serious side effects of cancer therapy, affecting up to 30% of treated patients. Cancer treatment-induced cardiotoxicity (CTiCT) can result in severe heart failure. The trade-off between cancer and chronic heart failure is an immense personal burden with physical and psychological consequences. Current therapies for CTiCT are suboptimal, featuring poor early detection algorithms and nonspecific heart failure treatments. Based on our recently published results and additional preliminary data presented here, we propose that CTiCT is associated with altered mitochondrial dynamics, triggering a cardiomyocyte metabolic reprogramming. MATRIX represents a holistic approach to tackling mitochondrial dysfunction in CTiCT. Our hypothesis is that reverting metabolic reprogramming by shifting mitochondrial substrate utilization could represent a new paradigm in the treatment of early-stage CTiCT. By refining a novel imaging-based algorithm recently developed in our group, we will achieve very early detection of myocardial damage in patients treated with commonly prescribed cancer therapies, long before clinically used parameters become abnormal. Such early detection, not available currently, is crucial for implementation of early therapies. We also hypothesize that in end-stage CTiCT, mitochondrial dysfunction has passed a no-return point, and the failing heart will only be rescued by a strategy to replenish the myocardium with fresh healthy mitochondria. This will be achieved with a radical new therapeutic option: in-vivo mitochondrial transplantation. The MATRIX project has broad translational potential, including a new therapeutic approach to a clinically relevant condition, the development of technology for early diagnosis, and advances in knowledge of basic disease mechanisms.

1 999 375 €

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

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

In neurons, sites of Ca2+ influx and Ca2+ sensors are located within 20-50 nm, in subcellular “Ca2+ nanodomains”. Such tight coupling is crucial for the functional properties of synapses and neuronal excitability. Two key players act together in nanodomains, coupling Ca2+ signal to membrane potential: the voltage-dependent Ca2+ channels (VDCC) and the large conductance Ca2+ and voltage-gated K+ channels (BK). BK channels are characterized by synergistic activation by Ca2+ and membrane depolarization, but the complex molecular mechanism underlying channel function is not adequately understood. Information about the pore region, voltage sensing domain or isolated intracellular domains has been obtained separately using electrophysiology, biochemistry and crystallography. Nevertheless, the specialized behavior of this channel must be studied in the whole protein complex at the membrane in order to determine the complete range of structures and movements critical to its in vivo function. Using a combination of genetics, electrophysiology and spectroscopy, our group has measured for the first time the structural rearrangements accompanying whole BK channel activation at the membrane. From this unique position, our first goal is to fully determine the real time structural dynamics underlying the molecular coupling of Ca2+, voltage and activation of BK channels in the membrane environment, its regulation by accessory subunits and channel effectors. BK subcellular localization and role in Ca2+ nanodomains make these channels perfect candidates as reporters of local changes in [Ca2+] restricted to specific nanodomains close to the neuronal membrane. In our laboratory we have created fluorescent variants of the channel that report BK activity induced by Ca2+ binding, or Ca2+ binding and voltage. Our second aim in this proposal is to optimize and deploy this novel optoelectrical reporters to study physiologically relevant Ca2+-induced processes both in cellular and animal mode

1 999 742 €

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

Finding the mutations, genes and pathways directly involved in cancer is of paramount importance to understand the mechanisms of tumour development and devise therapeutic strategies to overcome the disease. Due to their role in cancer development and maintenance, the proteins encoded by cancer genes are candidate therapeutic targets. Indeed, in recent years we have witnessed the development of successful cancer-targeting therapies to counteract the effect of driver mutations. Although the coding part of the human genome has now largely been explored in the search for cancer driver mutations in most frequent cancer types, the extent of involvement of noncoding mutations in cancer development remains a mystery. The main challenges faced are: 1) the functional role of most noncoding regions is unknown, and 2) tumours often have thousands of somatic mutations, so that distinguishing cancer driver mutations from bystanders is like finding the proverbial needle in a haystack. To overcome these two challenges I propose to analyse the pattern of somatic mutations across thousands of tumours in noncoding regions to identify signals of positive selection. These signals are an indication that mutations in the region have been positively selected during tumour evolution and are thus directly involved in the tumour phenotype. The large scale analysis proposed here will allow us to create a catalogue of noncoding elements involved in different types of cancer upon mutations. We will study in detail a selected set of driver elements to uncover their specific function and role in the tumourigenic process. Furthermore, we will explore possibilities of counteracting their driver effect with targeted drugs. The results of this project may boost our understanding of the biological role of noncoding regions, help to unravel novel molecular causes of cancer and provide novel targeted therapeutic opportunities for cancer patients.

1 995 829 €

Start date: 2016-12-01, End date: 2021-11-30

"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

Just as our experience has its origin in our perceptions, our perceptions are fundamentally shaped by our experience. How does the brain build expectations from experience and how do expectations impact perception? In a Bayesian framework, expectations determine the environment’s prior probability, which combined with stimulus information, can yield optimal decisions. While the accumulation-to-bound model describes temporal integration of sensory inputs and their combination with the prior, we still lack electrophysiological evidence showing neural circuits that integrate previous events adaptively to generate advantageous expectations. I aim to understand (1) how circuits in the cerebral cortex integrate the recent history of stimuli and rewards to generate expectations, (2) how expectations are combined with sensory input across the processing hierarchy to bias decisions and (3) whether the dynamics of the expectation can dominate neuronal and choice variability. I will train rats in a new auditory discrimination task using predictable stimulus sequences that, once learned, are used to compute adaptive priors that improve discrimination. I will perform population recordings and optogenetic manipulations to identify the brain areas involved in the computation of priors in the task. To reveal the circuit mechanisms underlying the observed dynamics I will train a computational network model to classify fluctuating inputs and, by adapting its dynamics to the statistics of the stimulus sequence, accumulate evidence across trials to maximize performance. The model will generalize the accumulation-to-bound model by integrating information across various time scales and will partition choice variability into that caused by the dynamics of the prior or by fluctuations in the stimulus response. My proposal points at a paradigm shift from viewing neuronal variability as a corrupting source of noise to the result of our brain’s inevitable tendency to predict the future.

2 000 000 €

Start date: 2016-09-01, End date: 2021-08-31

In eukaryotes, untranslated regions located at the 3′ end (3’UTRs) of messenger RNAs (mRNAs) have been proved to be key post-transcriptional regulatory elements controlling almost every single biological process. In contrast, in bacteria, most studies regarding post-transcriptional regulation have been mainly focused on specific non-coding RNAs and 5’UTRs, which often carry riboswitches or thermosensors. Remarkably, bacterial 3’UTRs have been largely disregarded and have not been considered as potential regulators. Recently, we found that a 3’UTR modulates biofilm formation in S. aureus through its interaction with the 5’UTR encoded in the same mRNA. This mechanism resembles eukaryotic mRNA circularization. Also, a 3’UTR that contributes to cellular homeostasis by promoting hilD mRNA turnover was recently shown in Salmonella. Although both studies are pioneering showing the potential of bacterial 3’UTRs as regulatory elements, many questions still remain to be answered. Are 3’UTRs roles conserved in bacterial species? Do 3’UTRs contain specific regulatory sequences or secondary RNA structures? Are transcriptional terminator sequences relevant for certain 3’UTRs? Are 3’UTRs specifically recognized by RNA-binding proteins? Might 3’UTRs be responsible for bacterial speciation? Might bacterial 3’UTRs be the ancestors of eukaryotic 3’UTR evolution? To achieve these questions, here we propose a high-throughput analysis based on the development of specialized dual-reporter libraries to identify in vivo functional 3’UTRs by fluorescence-activated cell sorting coupled to RNA sequencing. Also the pool of RNA-binding proteins associated to 3’UTRs will be identified by global MS2-tagging and mass spectrometry. Examples of 3’UTRs belonging to physiologically important genes will be selected to deeply study regulatory mechanisms at the molecular and single cell levels. We expect that this project will largely change the view of post-transcriptional regulation in bacteria.

1 876 778 €

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

The traditional view is that species and their genomes evolve only by vertical descent, leading to evolutionary histories that can be represented by bifurcating lineages. However, modern evolutionary thinking recognizes processes of reticulate evolution, such as horizontal gene transfer or hybridization, which involve total or partial merging of genetic material from two diverged species. Today it is widely recognized that such events are rampant in prokaryotes, but a relevant role in eukaryotes has only recently been acknowledged. Unprecedented genomic and phylogenetic information, and recent work from others and us have shown that reticulate evolution in eukaryotes is more common and have more complex outcomes than previously thought. However, we still have a very limited understanding of what are the impacts at the genomic and evolutionary levels. To address this, I propose to combine innovative computational and experimental approaches. The first goal is to infer patterns of reticulate evolution across the eukaryotic tree, and relate this to current biological knowledge. The second goal is to trace the genomic aftermath of inter-species hybridization at the i) long-term, by analysing available genomes in selected eukaryotic taxa, ii) mid-term, by sequencing lineages of natural fungal hybrids, and iii) short-term, by using re-sequencing and experimental evolution in yeast. A particular focus is placed on elucidating the role of hybridization in the origin of whole genome duplications, and in facilitating the spread of horizontally transferred genes. Finally results from this and other projects will be integrated into emerging theoretical frameworks. Outcomes of this project will profoundly improve our understanding of reticular processes as drivers of eukaryotic genome evolution, and will impact other key aspects of evolutionary theory, ranging from the concept of orthology to the eukaryotic tree of life.

1 986 178 €

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

The cerebral cortex is organized into highly specialized sensory areas. Thus, it is fundamental to understand how these areas acquire and maintain their identity and functional organization. Challenging normal brain development and forcing the brain to the limits of plasticity, offers us the possibility to shed light on these issues. Accordingly, we shall use prenatal sensory deprivation as a model to understand the mechanisms underlying early neuroplasticity, events that could influence the natural organization of sensory cortical areas. Early sensory deprivation produces profound changes in the cortex, provoking the reorganization of both the deprived and the spared cortical territories. Classically, this adaptation is thought to require sensory experience from the intact sensory modalities. However, our recent data from embryonic deprived mice challenge this view, suggesting that a component independent of experience contributes to this reorganization and that the thalamus plays a pivotal role in these events. Hence, we now propose to adopt multidisciplinary and innovative approaches to characterize the structural, genetic and functional rearrangements in the thalamus following embryonic sensory deprivation, and to define the factors and mechanisms that drive cortical specificity. Experimental results from sensory deprived animals in which the thalamus and gene expression is manipulated in vivo, will be integrated to explain when and how neuroplastic cortical adaptations are triggered in the deprived brain. To further understand the rewiring capacity of thalamic neurons and their potential role in sensory restoration, we will adopt a high-risk, high-gain approach to reprogramme nuclei specific thalamic neurons. The novel information obtained will establish how sensory inputs and thalamocortical connections govern cortical activity and architecture, ultimately sculpting perceptual behaviour.

1 966 771 €

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

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

The Mediterranean Sea is an excellent sensor of transient climate conditions at different time scales. Changes in Mediterranean water properties result from complex interactions between the Atlantic inflow, local climate and north and south atmospheric teleconnections. In turn, Mediterranean outflow waters spill into the Atlantic Ocean, thus acting as a net salt and heat source for the Atlantic Meridional Overturning Circulation (AMOC). Climate models anticipate changes in these circulation systems within decades; thus it becomes critical to understand the natural range of variations in the Mediterranean Thermohaline Circulation (MedTHC) and whether these can alter the AMOC. An innovative approach, based on both well-established and newly-developed analytical methods will be applied to characterize, qualitatively and quantitatively, past changes in the MedTHC dynamics. Specific time windows representing very different transient periods (18-14 ka BP; 9.5-6.5 ka BP and the last 2 kyr) will be targeted in order to understand the distinctive role that individual forcing mechanisms exerted in controlling MedTHC changes. Particular emphasis will be placed on building robust regional chronologies and proxy records with unprecedented high-resolution. This approach will combine proxy data from sediment cores and deep-sea corals along the main paths of water masses as they cross the Mediterranean basins and exit into the North Atlantic. This paleo-data analysis will be complemented with novel climate model paleo-simulations to test the sensitivity of the AMOC to changes in Mediterranean outflow under varying AMOC conditions. The main goals are to identify: (1) The natural range of MedTHC variability; (2) The forcings and inter-regional teleconnections driving MedTHC changes; (3) The associated impact onto the AMOC. The assessment of the forcings controlling MedTHC and the ensuing impact on the AMOC will allow us to gauge the consequences of future Mediterranean changes.

2 400 000 €

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

The overreaching goal of my lab is to improve the prognosis of patients with high-risk pediatric brain tumors. To this end, I propose to integrate clinical and lab-based research to develop tumor-targeted oncolytic adenoviruses with the capacity to elicit a therapeutic immune response in those tumors. Our research will use novel and relevant models to accomplish the experimental aims. We have previously worked with Delta-24-RGD (DNX-2401) a replication-competent adenovirus that has been translated to the clinical scenario. In 2017, the first clinical trial phase I with DNX-2401 for newly diagnosed Diffuse Intrinsic Pontine Gliomas (DIPG; a lethal pediatric brain tumor) opened propelled by my team. Preliminary results from the first trials revealed that the intratumoral injection of the virus instigated an initial phase of oncolysis followed by a delayed inflammatory response that ultimately resulted in complete regression in a subset of the patients without associated toxicities. I hypothesized that enhancement of the immune component of the DNX-2401-based therapy will result in the complete regression of the vast majority of pediatric brain tumors. In our specific approach, we propose to understand the immune microenvironment of DIPGs and the response to viral therapy in the context of the trial. Moreover, that knowledge will leverage the design of Delta-24-based adenoviruses to recruit lymphocytes to the tumor with the competence of different type of ligands to activate the tumor infiltrating lymphocytes. I expect that this combinatorial innovative treatment will efficiently challenge the profound and inherent tumor immunosuppression and, in turn, will elicit a robust anti-tumor immune response resulting in the significant improvement of the prognosis and quality of life of patients with pediatric brain tumors. This project has the potential to produce a vertical advance in the field of pediatric oncology.

2 000 000 €

Start date: 2019-03-01, End date: 2024-02-29