Project acronym ALLELECHOKER
Project DNA binding proteins for treatment of gain of function mutations
Researcher (PI) Enrico Maria Surace
Host Institution (HI) FONDAZIONE TELETHON
Country Italy
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary Zinc finger (ZF) and transcription activator-like effector (TALE) based technologies are been allowing the tailored design of “artificial” DNA-binding proteins targeted to specific and unique DNA genomic sequences. Coupling DNA binding proteins to effectors domains enables the constitution of DNA binding factors for genomic directed transcriptional modulation or targeted genomic editing. We have demonstrated that pairing a ZF DNA binding protein to the transcriptional repressor Kruppel-associated box enables in vivo, the transcriptional repression of one of the most abundantly expressed gene in mammals, the human rhodopsin gene (RHO). We propose to generate RHO DNA binding silencers (“AlleleChoker”), which inactivate RHO either by transcriptional repression or targeted genome modification, irrespectively to wild-type or mutated alleles (mutational-independent approach), and combine RHO endogenous silencing to RHO replacement (silencing-replacement strategy). With this strategy in principle a single bimodal bio-therapeutic will enable the correction of any photoreceptor disease associated with RHO mutation. Adeno-associated viral (AAV) vector-based delivery will be used for photoreceptors gene transfer. Specifically our objectives are: 1) Construction of transcriptional repressors and nucleases for RHO silencing. Characterization and comparison of RHO silencing mediated by transcriptional repressors (ZFR/ TALER) or nucleases (ZFN/ TALEN) to generate genomic directed inactivation by non-homologous end-joining (NHEJ), and refer these results to RNA interference (RNAi) targeted to RHO; 2) RHO silencing in photoreceptors. to determine genome-wide DNA binding specificity of silencers, chromatin modifications and expression profile on human retinal explants; 3) Tuning silencing and replacement. To determine the impact of gene silencing-replacement strategy on disease progression in animal models of autosomal dominant retinitis pigmentosa (adRP) associated to RHO mutations
Summary
Zinc finger (ZF) and transcription activator-like effector (TALE) based technologies are been allowing the tailored design of “artificial” DNA-binding proteins targeted to specific and unique DNA genomic sequences. Coupling DNA binding proteins to effectors domains enables the constitution of DNA binding factors for genomic directed transcriptional modulation or targeted genomic editing. We have demonstrated that pairing a ZF DNA binding protein to the transcriptional repressor Kruppel-associated box enables in vivo, the transcriptional repression of one of the most abundantly expressed gene in mammals, the human rhodopsin gene (RHO). We propose to generate RHO DNA binding silencers (“AlleleChoker”), which inactivate RHO either by transcriptional repression or targeted genome modification, irrespectively to wild-type or mutated alleles (mutational-independent approach), and combine RHO endogenous silencing to RHO replacement (silencing-replacement strategy). With this strategy in principle a single bimodal bio-therapeutic will enable the correction of any photoreceptor disease associated with RHO mutation. Adeno-associated viral (AAV) vector-based delivery will be used for photoreceptors gene transfer. Specifically our objectives are: 1) Construction of transcriptional repressors and nucleases for RHO silencing. Characterization and comparison of RHO silencing mediated by transcriptional repressors (ZFR/ TALER) or nucleases (ZFN/ TALEN) to generate genomic directed inactivation by non-homologous end-joining (NHEJ), and refer these results to RNA interference (RNAi) targeted to RHO; 2) RHO silencing in photoreceptors. to determine genome-wide DNA binding specificity of silencers, chromatin modifications and expression profile on human retinal explants; 3) Tuning silencing and replacement. To determine the impact of gene silencing-replacement strategy on disease progression in animal models of autosomal dominant retinitis pigmentosa (adRP) associated to RHO mutations
Max ERC Funding
1 354 840 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym ANOREP
Project Targeting the reproductive biology of the malaria mosquito Anopheles gambiae: from laboratory studies to field applications
Researcher (PI) Flaminia Catteruccia
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PERUGIA
Country Italy
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Anopheles gambiae mosquitoes are the major vectors of malaria, a disease with devastating consequences for
human health. Novel methods for controlling the natural vector populations are urgently needed, given the
evolution of insecticide resistance in mosquitoes and the lack of novel insecticidals. Understanding the
processes at the bases of mosquito biology may help to roll back malaria. In this proposal, we will target
mosquito reproduction, a major determinant of the An. gambiae vectorial capacity. This will be achieved at
two levels: (i) fundamental research, to provide a deeper knowledge of the processes regulating reproduction
in this species, and (ii) applied research, to identify novel targets and to develop innovative approaches for
the control of natural populations. We will focus our analysis on three major players of mosquito
reproduction: male accessory glands (MAGs), sperm, and spermatheca, in both laboratory and field settings.
We will then translate this information into the identification of inhibitors of mosquito fertility. The
experimental activities will be divided across three objectives. In Objective 1, we will unravel the role of the
MAGs in shaping mosquito fertility and behaviour, by performing a combination of transcriptional and
functional studies that will reveal the multifaceted activities of these tissues. In Objective 2 we will instead
focus on the identification of the male and female factors responsible for sperm viability and function.
Results obtained in both objectives will be validated in field mosquitoes. In Objective 3, we will perform
screens aimed at the identification of inhibitors of mosquito reproductive success. This study will reveal as
yet unknown molecular mechanisms underlying reproductive success in mosquitoes, considerably increasing
our knowledge beyond the state-of-the-art and critically contributing with innovative tools and ideas to the
fight against malaria.
Summary
Anopheles gambiae mosquitoes are the major vectors of malaria, a disease with devastating consequences for
human health. Novel methods for controlling the natural vector populations are urgently needed, given the
evolution of insecticide resistance in mosquitoes and the lack of novel insecticidals. Understanding the
processes at the bases of mosquito biology may help to roll back malaria. In this proposal, we will target
mosquito reproduction, a major determinant of the An. gambiae vectorial capacity. This will be achieved at
two levels: (i) fundamental research, to provide a deeper knowledge of the processes regulating reproduction
in this species, and (ii) applied research, to identify novel targets and to develop innovative approaches for
the control of natural populations. We will focus our analysis on three major players of mosquito
reproduction: male accessory glands (MAGs), sperm, and spermatheca, in both laboratory and field settings.
We will then translate this information into the identification of inhibitors of mosquito fertility. The
experimental activities will be divided across three objectives. In Objective 1, we will unravel the role of the
MAGs in shaping mosquito fertility and behaviour, by performing a combination of transcriptional and
functional studies that will reveal the multifaceted activities of these tissues. In Objective 2 we will instead
focus on the identification of the male and female factors responsible for sperm viability and function.
Results obtained in both objectives will be validated in field mosquitoes. In Objective 3, we will perform
screens aimed at the identification of inhibitors of mosquito reproductive success. This study will reveal as
yet unknown molecular mechanisms underlying reproductive success in mosquitoes, considerably increasing
our knowledge beyond the state-of-the-art and critically contributing with innovative tools and ideas to the
fight against malaria.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
Project acronym AXONENDO
Project Endosomal control of local protein synthesis in axons
Researcher (PI) Jean-Michel Cioni
Host Institution (HI) OSPEDALE SAN RAFFAELE SRL
Country Italy
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary 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.
Summary
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.
Max ERC Funding
1 499 563 €
Duration
Start date: 2020-09-01, End date: 2025-08-31
Project acronym BIHSNAM
Project Bio-inspired Hierarchical Super Nanomaterials
Researcher (PI) Nicola Pugno
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TRENTO
Country Italy
Call Details Starting Grant (StG), PE8, ERC-2011-StG_20101014
Summary "Nanomaterials such as carbon nanotubes or graphene sheets represent the future of material science, due to their potentially exceptional mechanical properties. One great drawback of all artificial materials, however, is the decrease of strength with increasing toughness, and viceversa. This problem is not encountered in many biological nanomaterials (e.g. spider silk, bone, nacre). Other biological materials display exceptional adhesion or damping properties, and can be self-cleaning or self-healing. The “secret” of biomaterials seems to lie in “hierarchy”: several levels can often be identified (2 in nacre, up to 7 in bone and dentine), from nano- to micro-scale.
The idea of this project is to combine Nature and Nanotechnology to design hierarchical composites with tailor made characteristics, optimized with respect to both strength and toughness, as well as materials with strong adhesion/easy detachment, smart damping, self-healing/-cleaning properties or controlled energy dissipation. For example, one possible objective is to design the “world’s toughest composite material”. The potential impact and importance of these goals on materials science, the high-tech industry and ultimately the quality of human life could be considerable.
In order to tackle such a challenging design process, the PI proposes to adopt ultimate nanomechanics theoretical tools corroborated by continuum or atomistic simulations, multi-scale numerical parametric simulations and Finite Element optimization procedures, starting from characterization experiments on biological- or nano-materials, from the macroscale to the nanoscale. Results from theoretical, numerical and experimental work packages will be applied to a specific case study in an engineering field of particular interest to demonstrate importance and feasibility, e.g. an airplane wing with a considerably enhanced fatigue resistance and reduced ice-layer adhesion, leading to a 10 fold reduction in wasted fuel."
Summary
"Nanomaterials such as carbon nanotubes or graphene sheets represent the future of material science, due to their potentially exceptional mechanical properties. One great drawback of all artificial materials, however, is the decrease of strength with increasing toughness, and viceversa. This problem is not encountered in many biological nanomaterials (e.g. spider silk, bone, nacre). Other biological materials display exceptional adhesion or damping properties, and can be self-cleaning or self-healing. The “secret” of biomaterials seems to lie in “hierarchy”: several levels can often be identified (2 in nacre, up to 7 in bone and dentine), from nano- to micro-scale.
The idea of this project is to combine Nature and Nanotechnology to design hierarchical composites with tailor made characteristics, optimized with respect to both strength and toughness, as well as materials with strong adhesion/easy detachment, smart damping, self-healing/-cleaning properties or controlled energy dissipation. For example, one possible objective is to design the “world’s toughest composite material”. The potential impact and importance of these goals on materials science, the high-tech industry and ultimately the quality of human life could be considerable.
In order to tackle such a challenging design process, the PI proposes to adopt ultimate nanomechanics theoretical tools corroborated by continuum or atomistic simulations, multi-scale numerical parametric simulations and Finite Element optimization procedures, starting from characterization experiments on biological- or nano-materials, from the macroscale to the nanoscale. Results from theoretical, numerical and experimental work packages will be applied to a specific case study in an engineering field of particular interest to demonstrate importance and feasibility, e.g. an airplane wing with a considerably enhanced fatigue resistance and reduced ice-layer adhesion, leading to a 10 fold reduction in wasted fuel."
Max ERC Funding
1 004 400 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym BioMNP
Project Understanding the interaction between metal nanoparticles and biological membranes
Researcher (PI) Giulia Rossi
Host Institution (HI) UNIVERSITA DEGLI STUDI DI GENOVA
Country Italy
Call Details Starting Grant (StG), PE3, ERC-2015-STG
Summary The BioMNP objective is the molecular-level understanding of the interactions between surface functionalized metal nanoparticles and biological membranes, by means of cutting-edge computational techniques and new molecular models.
Metal nanoparticles (NP) play more and more important roles in pharmaceutical and medical technology as diagnostic or therapeutic devices. Metal NPs can nowadays be engineered in a multitude of shapes, sizes and compositions, and they can be decorated with an almost infinite variety of functionalities. Despite such technological advances, there is still poor understanding of the molecular processes that drive the interactions of metal NPs with cells. Cell membranes are the first barrier encountered by NPs entering living organisms. The understanding and control of the interaction of nanoparticles with biological membranes is therefore of paramount importance to understand the molecular basis of the NP biological effects.
BioMNP will go beyond the state of the art by rationalizing the complex interplay of NP size, composition, functionalization and aggregation state during the interaction with model biomembranes. Membranes, in turn, will be modelled at an increasing level of complexity in terms of lipid composition and phase. BioMNP will rely on cutting-edge simulation techniques and facilities, and develop new coarse-grained models grounded on finer-level atomistic simulations, to study the NP-membrane interactions on an extremely large range of length and time scales.
BioMNP will benefit from important and complementary experimental collaborations, will propose interpretations of the available experimental data and make predictions to guide the design of functional, non-toxic metal nanoparticles for biomedical applications. BioMNP aims at answering fundamental questions at the crossroads of physics, biology and chemistry. Its results will have an impact on nanomedicine, toxicology, nanotechnology and material sciences.
Summary
The BioMNP objective is the molecular-level understanding of the interactions between surface functionalized metal nanoparticles and biological membranes, by means of cutting-edge computational techniques and new molecular models.
Metal nanoparticles (NP) play more and more important roles in pharmaceutical and medical technology as diagnostic or therapeutic devices. Metal NPs can nowadays be engineered in a multitude of shapes, sizes and compositions, and they can be decorated with an almost infinite variety of functionalities. Despite such technological advances, there is still poor understanding of the molecular processes that drive the interactions of metal NPs with cells. Cell membranes are the first barrier encountered by NPs entering living organisms. The understanding and control of the interaction of nanoparticles with biological membranes is therefore of paramount importance to understand the molecular basis of the NP biological effects.
BioMNP will go beyond the state of the art by rationalizing the complex interplay of NP size, composition, functionalization and aggregation state during the interaction with model biomembranes. Membranes, in turn, will be modelled at an increasing level of complexity in terms of lipid composition and phase. BioMNP will rely on cutting-edge simulation techniques and facilities, and develop new coarse-grained models grounded on finer-level atomistic simulations, to study the NP-membrane interactions on an extremely large range of length and time scales.
BioMNP will benefit from important and complementary experimental collaborations, will propose interpretations of the available experimental data and make predictions to guide the design of functional, non-toxic metal nanoparticles for biomedical applications. BioMNP aims at answering fundamental questions at the crossroads of physics, biology and chemistry. Its results will have an impact on nanomedicine, toxicology, nanotechnology and material sciences.
Max ERC Funding
1 131 250 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym BONEPHAGY
Project Defining the role of the FGF – autophagy axis in bone physiology
Researcher (PI) Carmine SETTEMBRE
Host Institution (HI) FONDAZIONE TELETHON
Country Italy
Call Details Starting Grant (StG), LS4, ERC-2016-STG
Summary Autophagy is a fundamental cellular catabolic process deputed to the degradation and recycling of a variety of intracellular materials. Autophagy plays a significant role in multiple human physio-pathological processes and is now emerging as a critical regulator of skeletal development and homeostasis. We have discovered that during postnatal development in mice, the growth factor FGF18 induces autophagy in the chondrocyte cells of the growth plate to regulate the secretion of type II collagen, a major component of cartilaginous extracellular matrix. The FGF signaling pathways play crucial roles during skeletal development and maintenance and are deregulated in many skeletal disorders. Hence our findings may offer the unique opportunity to uncover new molecular mechanisms through which FGF pathways regulate skeletal development and maintenance and to identify new targets for the treatment of FGF-related skeletal disorders. In this grant application we propose to study the role played by the different FGF ligands and receptors on autophagy regulation and to investigate the physiological relevance of these findings in the context of skeletal growth, homeostasis and maintenance. We will also investigate the intracellular machinery that links FGF signalling pathways to the regulation of autophagy. In addition, we generated preliminary data showing an impairment of autophagy in chondrocyte models of Achondroplasia (ACH) and Thanathoporic dysplasia, two skeletal disorders caused by mutations in FGFR3. We propose to study the role of autophagy in the pathogenesis of FGFR3-related dwarfisms and explore the pharmacological modulation of autophagy as new therapeutic approach for achondroplasia. This application, which combines cell biology, mouse genetics and pharmacological approaches, has the potential to shed light on new mechanisms involved in organismal development and homeostasis, which could be targeted to treat bone and cartilage diseases.
Summary
Autophagy is a fundamental cellular catabolic process deputed to the degradation and recycling of a variety of intracellular materials. Autophagy plays a significant role in multiple human physio-pathological processes and is now emerging as a critical regulator of skeletal development and homeostasis. We have discovered that during postnatal development in mice, the growth factor FGF18 induces autophagy in the chondrocyte cells of the growth plate to regulate the secretion of type II collagen, a major component of cartilaginous extracellular matrix. The FGF signaling pathways play crucial roles during skeletal development and maintenance and are deregulated in many skeletal disorders. Hence our findings may offer the unique opportunity to uncover new molecular mechanisms through which FGF pathways regulate skeletal development and maintenance and to identify new targets for the treatment of FGF-related skeletal disorders. In this grant application we propose to study the role played by the different FGF ligands and receptors on autophagy regulation and to investigate the physiological relevance of these findings in the context of skeletal growth, homeostasis and maintenance. We will also investigate the intracellular machinery that links FGF signalling pathways to the regulation of autophagy. In addition, we generated preliminary data showing an impairment of autophagy in chondrocyte models of Achondroplasia (ACH) and Thanathoporic dysplasia, two skeletal disorders caused by mutations in FGFR3. We propose to study the role of autophagy in the pathogenesis of FGFR3-related dwarfisms and explore the pharmacological modulation of autophagy as new therapeutic approach for achondroplasia. This application, which combines cell biology, mouse genetics and pharmacological approaches, has the potential to shed light on new mechanisms involved in organismal development and homeostasis, which could be targeted to treat bone and cartilage diseases.
Max ERC Funding
1 586 430 €
Duration
Start date: 2017-01-01, End date: 2022-06-30
Project acronym BRAIN-ACT
Project Biohybrid Synapses for Interactive Neuronal Networks
Researcher (PI) Francesca Santoro
Host Institution (HI) FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Country Italy
Call Details Starting Grant (StG), PE8, ERC-2020-STG
Summary BRAIN-ACT aims to develop the next generation of interactive biohybrid devices which will couple biological neuronal networks to organic artificial neurons. For the first time, neurons will interact with the device by active mechanical reshaping which will transduce in the maintenance of the electrical network connection strength (long term potentiation –LTP). This will be achieved by a) processing dynamic electroactive materials b) engineering the neuromorphic abiotic surface with biological synaptic receptors and c) intergrate an in vitro biohybrid synapses array to investigate the interplay at the interface between neuronal cells and their synaptic activity with dynamic electrically-smart materials.
BRAIN-ACT will pave the way for a new class of chip-based smart bioelectronic devices which will ‘have a shape of a neuron and act like a neuron’.
Over 10 million people are affected by neurodegenerative diseases like Parkinson’s and Alzheimer’s worldwide and show significant loss of functionalities in their daily life. Those are mainly related to faulty connections within the brain which reflects neuronal miscommunication regulated by billions of individual connections among pairs called synapses. The ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity is called synaptic plasticity and is regulated through electrical and biomechanical signals exchanged by neurons pairs. In vitro bioelectronic platforms have been devoted to monitor and stimulate those signals across neuronal network areas to characterize electrical activity and connectivity in a passive manner.
BRAIN-ACT will revolutionize the study of in vitro neuronal networks through active mechanical reshaping to establish optimal electrical signal exchange among neuronal cells. More broadly, the proposed project will define the fundamental conditions to unleash the potential of neuromorphic devices as implantable materials in to the brain.
Summary
BRAIN-ACT aims to develop the next generation of interactive biohybrid devices which will couple biological neuronal networks to organic artificial neurons. For the first time, neurons will interact with the device by active mechanical reshaping which will transduce in the maintenance of the electrical network connection strength (long term potentiation –LTP). This will be achieved by a) processing dynamic electroactive materials b) engineering the neuromorphic abiotic surface with biological synaptic receptors and c) intergrate an in vitro biohybrid synapses array to investigate the interplay at the interface between neuronal cells and their synaptic activity with dynamic electrically-smart materials.
BRAIN-ACT will pave the way for a new class of chip-based smart bioelectronic devices which will ‘have a shape of a neuron and act like a neuron’.
Over 10 million people are affected by neurodegenerative diseases like Parkinson’s and Alzheimer’s worldwide and show significant loss of functionalities in their daily life. Those are mainly related to faulty connections within the brain which reflects neuronal miscommunication regulated by billions of individual connections among pairs called synapses. The ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity is called synaptic plasticity and is regulated through electrical and biomechanical signals exchanged by neurons pairs. In vitro bioelectronic platforms have been devoted to monitor and stimulate those signals across neuronal network areas to characterize electrical activity and connectivity in a passive manner.
BRAIN-ACT will revolutionize the study of in vitro neuronal networks through active mechanical reshaping to establish optimal electrical signal exchange among neuronal cells. More broadly, the proposed project will define the fundamental conditions to unleash the potential of neuromorphic devices as implantable materials in to the brain.
Max ERC Funding
1 859 062 €
Duration
Start date: 2021-09-01, End date: 2026-08-31
Project acronym BRIDGE
Project Bridging the gap between Gas Emissions and geophysical observations at active volcanoes
Researcher (PI) Alessandro Aiuppa
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PALERMO
Country Italy
Call Details Starting Grant (StG), PE10, ERC-2012-StG_20111012
Summary In spite of their significance in a variety of volcanological aspects, gas observations at volcanoes have lagged behind geophysical studies for a long time. This has primarily reflected the inherent technical limitations met by gas geochemists in capturing volcanic gas properties (chemistry and flux) at high-rate (1 Hz), and using permanent instrumental arrays. The poor temporal resolution of volcanic gas observations has, in addition, precluded the real-time analysis of fast-occurring volcanic processes, as those occurring shortly prior to eruptions, therefore generally limiting the use of gas geochemistry in volcanic hazard assessment. However, the recent progresses made by modern multi-component/high frequency measurement techniques now open the way for decisive step ahead in the current state-of-the-art to be finally attempted.
The BRIDGE research proposal has the ambitious goals to bridge the existing technological gap between geochemical and geophysical observations at volcanoes. This will be achieved by designing, setting up, and deploying in the field, innovative instruments for 1 Hz observations of volcanic SO2 and CO2 fluxes. From this, the co-acquired volcanic gas and geophysical information will be then combined within a single interpretative framework, therefore contributing to fill our current gap of knowledge on fast (timescales of seconds/minutes) degassing processes, and to deeper exploration of the role played by gas exsolution from (and migration through) silicate liquids as effective source mechanism of the physical signals (e.g., LP and VLP seismicity, and tremor) measured at volcanoes. Finally, this combined volcanic gas-geophysical approach will be used to yield improved modelling/understanding of a variety of volcanic features, including modes/rates of gas separation from magmas, mechanisms of gas flow in conduits, and trigger mechanisms of explosive volcanic eruptions.
Summary
In spite of their significance in a variety of volcanological aspects, gas observations at volcanoes have lagged behind geophysical studies for a long time. This has primarily reflected the inherent technical limitations met by gas geochemists in capturing volcanic gas properties (chemistry and flux) at high-rate (1 Hz), and using permanent instrumental arrays. The poor temporal resolution of volcanic gas observations has, in addition, precluded the real-time analysis of fast-occurring volcanic processes, as those occurring shortly prior to eruptions, therefore generally limiting the use of gas geochemistry in volcanic hazard assessment. However, the recent progresses made by modern multi-component/high frequency measurement techniques now open the way for decisive step ahead in the current state-of-the-art to be finally attempted.
The BRIDGE research proposal has the ambitious goals to bridge the existing technological gap between geochemical and geophysical observations at volcanoes. This will be achieved by designing, setting up, and deploying in the field, innovative instruments for 1 Hz observations of volcanic SO2 and CO2 fluxes. From this, the co-acquired volcanic gas and geophysical information will be then combined within a single interpretative framework, therefore contributing to fill our current gap of knowledge on fast (timescales of seconds/minutes) degassing processes, and to deeper exploration of the role played by gas exsolution from (and migration through) silicate liquids as effective source mechanism of the physical signals (e.g., LP and VLP seismicity, and tremor) measured at volcanoes. Finally, this combined volcanic gas-geophysical approach will be used to yield improved modelling/understanding of a variety of volcanic features, including modes/rates of gas separation from magmas, mechanisms of gas flow in conduits, and trigger mechanisms of explosive volcanic eruptions.
Max ERC Funding
1 496 222 €
Duration
Start date: 2012-10-01, End date: 2016-09-30
Project acronym CellKarma
Project Dissecting the regulatory logic of cell fate reprogramming through integrative and single cell genomics
Researcher (PI) Davide CACCHIARELLI
Host Institution (HI) FONDAZIONE TELETHON
Country Italy
Call Details Starting Grant (StG), LS2, ERC-2017-STG
Summary The concept that any cell type, upon delivery of the right “cocktail” of transcription factors, can acquire an identity that otherwise it would never achieve, revolutionized the way we approach the study of developmental biology. In light of this, the discovery of induced pluripotent stem cells (IPSCs) and cell fate conversion approaches stimulated new research directions into human regenerative biology. However, the chance to successfully develop patient-tailored therapies is still very limited because reprogramming technologies are applied without a comprehensive understanding of the molecular processes involved.
Here, I propose a multifaceted approach that combines a wide range of cutting-edge integrative genomic strategies to significantly advance our understanding of the regulatory logic driving cell fate decisions during human reprogramming to pluripotency.
To this end, I will utilize single cell transcriptomics to isolate reprogramming intermediates, reconstruct their lineage relationships and define transcriptional regulators responsible for the observed transitions (AIM 1). Then, I will dissect the rules by which transcription factors modulate the activity of promoters and enhancer regions during reprogramming transitions, by applying synthetic biology and genome editing approaches (AIM 2). Then, I will adopt an alternative approach to identify reprogramming modulators by the analysis of reprogramming-induced mutagenesis events (AIM 3). Finally, I will explore my findings in multiple primary reprogramming approaches to pluripotency, with the ultimate goal of improving the quality of IPSC derivation (Aim 4).
In summary, this project will expose novel determinants and yet unidentified molecular barriers of reprogramming to pluripotency and will be essential to unlock the full potential of reprogramming technologies for shaping cellular identity in vitro and to address pressing challenges of regenerative medicine.
Summary
The concept that any cell type, upon delivery of the right “cocktail” of transcription factors, can acquire an identity that otherwise it would never achieve, revolutionized the way we approach the study of developmental biology. In light of this, the discovery of induced pluripotent stem cells (IPSCs) and cell fate conversion approaches stimulated new research directions into human regenerative biology. However, the chance to successfully develop patient-tailored therapies is still very limited because reprogramming technologies are applied without a comprehensive understanding of the molecular processes involved.
Here, I propose a multifaceted approach that combines a wide range of cutting-edge integrative genomic strategies to significantly advance our understanding of the regulatory logic driving cell fate decisions during human reprogramming to pluripotency.
To this end, I will utilize single cell transcriptomics to isolate reprogramming intermediates, reconstruct their lineage relationships and define transcriptional regulators responsible for the observed transitions (AIM 1). Then, I will dissect the rules by which transcription factors modulate the activity of promoters and enhancer regions during reprogramming transitions, by applying synthetic biology and genome editing approaches (AIM 2). Then, I will adopt an alternative approach to identify reprogramming modulators by the analysis of reprogramming-induced mutagenesis events (AIM 3). Finally, I will explore my findings in multiple primary reprogramming approaches to pluripotency, with the ultimate goal of improving the quality of IPSC derivation (Aim 4).
In summary, this project will expose novel determinants and yet unidentified molecular barriers of reprogramming to pluripotency and will be essential to unlock the full potential of reprogramming technologies for shaping cellular identity in vitro and to address pressing challenges of regenerative medicine.
Max ERC Funding
1 497 250 €
Duration
Start date: 2018-03-01, End date: 2023-08-31
Project acronym CGT HEMOPHILIA A
Project Cell and gene therapy based strategies to correct the bleeding phenotype in Hemophilia A
Researcher (PI) Antonia Follenzi
Host Institution (HI) UNIVERSITA DEGLI STUDI DEL PIEMONTE ORIENTALE AMEDEO AVOGADRO
Country Italy
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Currently, haemophilia A cannot be cured. To prevent major bleeding episodes in haemophilia, human Factor VIII (FVIII) protein must be frequently administered as prophylaxis or on demand. This treatment is complicated by its high cost and development of antibodies that neutralize FVIII activity in 20 to 30% of the patients. Therefore, permanent solutions in the form of cell and gene therapy are very attractive for haemophilia A. Recently, we demonstrated in a murine model that liver sinusoidal endothelial cells (LSEC) produce and secrete FVIII, although not exclusively. We have also found that these mice can be treated by reconstitution with wild-type bone marrow, indicating that bone marrow-derived cells, of hematopoietic, mesenchymal or even endothelial origin, can produce and secrete FVIII. Based on these findings in mice, I propose that human LSEC, umbilical cord blood cells, and bone marrow cells might be suitable sources of FVIII to be used for cell replacement therapy for haemophilia A. To advance opportunities for cell and gene therapies in haemophilia A and for identifying additional cell sources of FVIII, I intend to explore whether replacement of liver endothelium and bone marrow in immnocompromised Haemophilia A mice with healthy human cells will provide therapeutic correction. Recently, the possibility of reprogramming mature somatic cells to generate induced pluripotent stem (iPS) cells has enabled the derivation of disease-specific pluripotent cells, thus providing unprecedented experimental platforms to treat human diseases. Therefore, I intend to study whether the generation of patient-specific iPS cells may be applied to cell and gene therapy of coagulation disorders and in particular for the treatment of Haemophilia A. Studies with these novel target cells may impact significantly the future course of Haemophilia A by providing proof-of feasibility of a novel therapy strategies.
Summary
Currently, haemophilia A cannot be cured. To prevent major bleeding episodes in haemophilia, human Factor VIII (FVIII) protein must be frequently administered as prophylaxis or on demand. This treatment is complicated by its high cost and development of antibodies that neutralize FVIII activity in 20 to 30% of the patients. Therefore, permanent solutions in the form of cell and gene therapy are very attractive for haemophilia A. Recently, we demonstrated in a murine model that liver sinusoidal endothelial cells (LSEC) produce and secrete FVIII, although not exclusively. We have also found that these mice can be treated by reconstitution with wild-type bone marrow, indicating that bone marrow-derived cells, of hematopoietic, mesenchymal or even endothelial origin, can produce and secrete FVIII. Based on these findings in mice, I propose that human LSEC, umbilical cord blood cells, and bone marrow cells might be suitable sources of FVIII to be used for cell replacement therapy for haemophilia A. To advance opportunities for cell and gene therapies in haemophilia A and for identifying additional cell sources of FVIII, I intend to explore whether replacement of liver endothelium and bone marrow in immnocompromised Haemophilia A mice with healthy human cells will provide therapeutic correction. Recently, the possibility of reprogramming mature somatic cells to generate induced pluripotent stem (iPS) cells has enabled the derivation of disease-specific pluripotent cells, thus providing unprecedented experimental platforms to treat human diseases. Therefore, I intend to study whether the generation of patient-specific iPS cells may be applied to cell and gene therapy of coagulation disorders and in particular for the treatment of Haemophilia A. Studies with these novel target cells may impact significantly the future course of Haemophilia A by providing proof-of feasibility of a novel therapy strategies.
Max ERC Funding
1 123 000 €
Duration
Start date: 2011-05-01, End date: 2017-04-30
