ERC FUNDED PROJECTS

Neurons are morphologically complex cells that rely on highly compartmentalized signaling to coordinate cellular functions. The endocytic pathway is a crucial trafficking route by which neurons integrate, spatially process and transfer information. Endosomal trafficking in axons and dendrites ensures that required molecules and signaling complexes are present where and when they are functionally needed thus fulfilling essential roles in neuronal physiology. Our recent work has revealed the presence of mRNAs and ribosomes on endosomes in axons, raising the exciting possibility that these motile organelles also directly modulate the local proteome by controlling de novo protein synthesis. However, the mechanisms by which endosomes regulate mRNA translation in neurons is unknown. Moreover, the roles of endosome-mediated control of protein synthesis in neuronal development and function have not been investigated. Here, we propose to bridge this knowledge gap by elucidating links between the endocytic pathway and local protein synthesis in neurons, focusing on their functional relationship in axons. By combining genome-wide analysis, genetic tools, state-of-the-art imaging techniques and the use of Xenopus and mouse vertebrate models, we plan to address the following fundamental questions: (i) What are the mRNAs associated with endosomes and does endosomal trafficking regulate their axonal localization? (ii) Does the endocytic pathway mediate the selective translation of axonal mRNAs in response to extracellular factors? (iii) What are the endosome-associated RNA-binding proteins, and what is the effect of perturbing these associations on axonal development and maintenance in vivo? (iv) Does impaired endosomal regulation of axonal mRNA localization and translation cause axonopathies? Answering these questions will set strong foundations for this new area of research and can provide a new angle in our comprehension of neuropathies in need of novel therapeutic strategies.

1 499 563 €

Start date: 2020-09-01, End date: 2025-08-31

Additive manufacturing and Automated Fibre Placement (AFP) processes brought to the emergence of a new class of fibre-reinforced materials; namely, the Variable Angle Tow (VAT) composites. AFP machines allow the fibres to be relaxed along curvilinear paths within the lamina, thus implying a point-wise variation of the material properties. In theory, the designer can conceive VAT structures with unexplored capabilities and tailor materials with optimized stiffness-to-weight ratios. In practise, steering brittle fibres, generally made of glass or carbon, is not trivial. Printing must be performed at the right combination of temperature, velocity, curvature radii and pressure to preserve the integrity of fibres. The lack of information on how the effect of these parameters propagates through the scales, from fibres to the final structure, represents the missing piece in the puzzle of VAT composites, which today are either costly or difficult to design because affected by unpredictable failure mechanisms and unwanted defects (gaps, overlaps, and fibre kinking). This proposal is for an exploratory study into a radical new approach to the problem of design, manufacturing and analysis of tow-steered printed composite materials. The program will act as a pre-echo, a precursor, to: 1) implement global/local models for the simulation and analysis of VATs with unprecedented accuracy from fibre-matrix to component scales; 2) develop a (hybrid) metamodeling platform based on machine learning for defect sensitivity and optimization; and 3) set new rules and best-practices to design for manufacturing. A 5-year, highly inter-disciplinary programme is planned, encompassing structural mechanics, numerical calculus, 3D printing and AFP, measurements and testing of advanced composites, data science and artificial intelligence, and constrained optimization problems to finally fill the gap between the design and the digital manufacturing chain of advanced printed materials.

1 477 901 €

Start date: 2019-10-01, End date: 2025-01-31

The threat of climate change calls for a rapid transition to a low-carbon society. Aligning the financial system with climate stability is a crucial prerequisite for achieving decarbonisation while preserving economic prosperity and societal welfare. However, we currently lack a comprehensive understanding of how the institutional and behavioural features of financial systems may affect the speed and shape of the low-carbon transition. Additionally, the coevolving socioeconomic, financial and environmental repercussions of such a large-scale societal transformation have not yet been systematically analysed. The SMOOTH project will lay the foundations of an innovative macro-financial analytical framework to provide essential insights on the links between financial systems and decarbonisation dynamics. Methodologically, I will introduce a breakthrough by linking macroeconomic analysis with an original evidence-based representation of investment decisions based on forward-looking expectations of transition pathways. In the course of five years, this integrated modelling framework will enable the first comprehensive assessment of the transition financial drivers and obstacles, and their implications for growth, financial stability, employment, private/public debt and functional distribution, with a focus on Europe. Building on this knowledge, a harmonised set of policies aimed at achieving a rapid and smooth transition can be designed. I will go beyond the current state of the art by integrating the analysis of fiscal policies with monetary policies and financial regulation, and investigating their institutional requirements and implications. SMOOTH will create a new interdisciplinary field of research integrating elements from macroeconomic modelling, climate economics, behavioural finance, socio-technical transition theory and political science, lifting the analytical power of transition modelling to a new level and opening up novel avenues for future research.

1 499 956 €

Start date: 2020-09-01, End date: 2025-08-31

CD4+ T cells are crucial component of our immune system: they support distinct types of proinflammatory responses key for pathogen clearance, maintain tolerance and suppress harmful inflammation. To perform this multitude of functions, naïve CD4+ T cells first undergo activation through direct contact with dendritic cells (DCs), a highly heterogeneous compartment including several populations of migratory and resident cells. These interactions lead to selection of antigen specific T cell clones, followed by their proliferation and differentiation into distinct subsets showing specialized effector programs or polarizations. Despite the essential role of dendritic cells in the activation and polarization of naïve CD4+ T cells, we have limited information available on both the identity of DC involved in priming and the molecular messages exchanged upon DC-CD4+ T cell interaction in different types of response. Recently, I developed an innovative technology that allows us for the first time to label interactions between immune cells in vivo. This method, which we called LIPSTIC, relies on the labeling of genetically engineered receptor–ligand pairs mediated by the enzyme Sortase A. After the enzymatic reaction takes place in vivo, the history of ligand–receptor interactions is revealed by the presence of reporter tags easily detected by flow cytometry. This proposal aims to determine how interactions between dendritic cells and T cells instruct CD4+ T cells toward distinct fates using LIPSTIC and by implementing other technologies designed ad hoc to measure and understand the biological consequences of relevant cell-cell interactions on T cell fate decision. The combined approaches described here will contribute to the characterization of the molecular signals governing CD4+ T cell response in vivo.

1 500 000 €

Start date: 2020-03-01, End date: 2025-08-31