H2020 ERC - Synergy Grant 2020-2026

ASsembly and phase Transitions of Ribonucleoprotein Aggregates in neurons: from physiology to pathology

Sommario: Recent works indicate the pathogenic relevance of altered RNA metabolism and aberrant ribonucleoprotein (RNP) assembly in several neurodegenerative diseases, such as Amyotrophic lateral sclerosis. How defective RNPs form, what are their integral components and which events trigger their appearance late in life are still unsolved issues. While emerging evidence indicates that mutations and post-translational modifications of specific RNA-binding proteins (RBPs) induce liquid-solid phase transition in vitro, much less is known about the in vivo properties of RNP assemblies and which role RNA plays in their formation. ASTRA will combine sophisticated imaging-derived RNP complex purification with innovative computational approaches and powerful genetic tools to unravel the biophysical properties and composition of RBP complexes and how they are modified in disease conditions. Through the development of new imaging and optical methods we plan to study how RNPs separate in liquid and solid phases in cells, in tissues (retina) and animal models and to characterize their RNA and protein components in physiological and pathological states. Exploiting the novel finding that non-coding RNAs act as scaffolding molecules for RNP assembly, we will investigate how such RNAs control the dynamic link between RNP formation, intracellular sorting and function. In a genuine interdisciplinary team effort, we will reveal how the architecture and localization of cytoplasmic RNP complexes are controlled in motor neurons and affected in neurodegeneration. We plan to develop novel advanced microscopy methods to monitor formation of aberrant RNPs in vivo and we will explore new molecules to impede pathological cascades driven by RNP assemblies. In conclusion, ASTRA will allow us to gain a comprehensive understanding of RNP function and dysfunction; we will use this knowledge to develop new therapeutic strategies that will impact on several protein-misfolding neurodegenerative diseases.

Total budget: 5.602.894,55€

Total contribution: 5.602.894,55€

H2020 ERC - Advanced Grant 2019-2026

Synthetic photobiology for light controllable active matter

Sommario: From a Physics and Engineering standpoint, swimming bacteria are a formidable example of self-propelled micro-machines. Together with their synthetic counterpart, self-propelled colloids, they represent the “living” atoms of active matter, an exciting branch of contemporary soft matter and statistical mechanics. Differently from synthetic colloids, however, each bacterial cell contains all the molecular machinery that is required to self-replicate, sense the environment, process information and compute responses. Breaking down these biological functions into basic genetic parts has been one of the greatest triumphs of molecular biology. Today, synthetic biologists are assembling these parts into new genetic programs and exploiting bacteria as computing micro-machines. Project SYGMA will employ the synthetic biology toolkit to provide the building blocks for a light controllable active matter having reliable, reconfigurable and interactively tunable dynamical properties. We will first engineer transmembrane photoreceptors to wire RGB external light signals to cellular physical responses like speed, tumbling, growth and death rates. These genetic parts will allow the modular design of customized active particles to build active materials with unprecedented optical control capabilities. Using these new tools we will address, with experiments and theory, fundamental questions like: how fast can we drive particle density using spatiotemporal motility modulations? what is the force on a body suspended in a bath of bacteria with non uniform motility? how do physical forces contribute to morphogenesis in bacterial colonies? Finding quantitative and experimentally validated answers will eventually allow us to engineer structured illumination protocols to mold living microstructures, transport colloidal cargos by shaping active pressure, control swarms of biohybrid microcars and shape bacterial microcolonies.

Total budget: 353.388,75€

Total contribution: 353.388,75€