Project acronym ALLELECHOKER
Project DNA binding proteins for treatment of gain of function mutations
Researcher (PI) Enrico Maria Surace
Host Institution (HI) FONDAZIONE TELETHON
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 BioLEAP
Project Biotechnological optimization of light use efficiency in algae photobioreactors
Researcher (PI) Tomas Morosinotto
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PADOVA
Call Details Starting Grant (StG), LS9, ERC-2012-StG_20111109
Summary New renewable energy source are highly needed to compensate exhausting fossil fuels reserves and reduce greenhouse gases emissions. Some species of algae have an interesting potential as feedstock for the production of biodiesel thanks to their ability to accumulate large amount of lipids. Strong research efforts are however needed to fulfil this potential and address many issues involving optimization of cultivation systems, biomass harvesting and algae genetic improvement. This proposal aims to address one of these issues, the optimization of algae light use efficiency. Light, in fact, provides the energy supporting algae growth and must be exploited with the highest possible efficiency to achieve sufficient productivity.
In a photobioreactor algae are highly concentrated and this cause a inhomogeneous light distribution with a large fraction of the cells exposed to very low light or even in the dark. Algae are also actively mixed and they can abruptly move from dark to full illumination and vice versa. This proposal aims to assess how alternation of dark/light cycles affect algae growth and functionality of photosynthetic apparatus both in batch and continuous cultures. In collaboration with the Chemical Engineering department, experimental data will be exploited to build a model describing the photobioreactor, a fundamental tool to improve its design.
The other main scope of this proposal is the isolation of genetically improved strains more suitable to the artificial environment of a photobioreactor. A first part of the work of setting up protocols for transformation will be followed by a second phase for generation and selection of mutants with altered photosynthetic performances. Transcriptome analyses in different light conditions will also be instrumental to identify genes to be targeted by genetic engineering.
Summary
New renewable energy source are highly needed to compensate exhausting fossil fuels reserves and reduce greenhouse gases emissions. Some species of algae have an interesting potential as feedstock for the production of biodiesel thanks to their ability to accumulate large amount of lipids. Strong research efforts are however needed to fulfil this potential and address many issues involving optimization of cultivation systems, biomass harvesting and algae genetic improvement. This proposal aims to address one of these issues, the optimization of algae light use efficiency. Light, in fact, provides the energy supporting algae growth and must be exploited with the highest possible efficiency to achieve sufficient productivity.
In a photobioreactor algae are highly concentrated and this cause a inhomogeneous light distribution with a large fraction of the cells exposed to very low light or even in the dark. Algae are also actively mixed and they can abruptly move from dark to full illumination and vice versa. This proposal aims to assess how alternation of dark/light cycles affect algae growth and functionality of photosynthetic apparatus both in batch and continuous cultures. In collaboration with the Chemical Engineering department, experimental data will be exploited to build a model describing the photobioreactor, a fundamental tool to improve its design.
The other main scope of this proposal is the isolation of genetically improved strains more suitable to the artificial environment of a photobioreactor. A first part of the work of setting up protocols for transformation will be followed by a second phase for generation and selection of mutants with altered photosynthetic performances. Transcriptome analyses in different light conditions will also be instrumental to identify genes to be targeted by genetic engineering.
Max ERC Funding
1 257 600 €
Duration
Start date: 2012-10-01, End date: 2017-09-30
Project acronym BIORECAR
Project Direct cell reprogramming therapy in myocardial regeneration through an engineered multifunctional platform integrating biochemical instructive cues
Researcher (PI) Valeria CHIONO
Host Institution (HI) POLITECNICO DI TORINO
Call Details Consolidator Grant (CoG), PE8, ERC-2017-COG
Summary In BIORECAR I will develop a new breakthrough multifunctional biomaterial-based platform for myocardial regeneration after myocardial infarction, provided with biochemical cues able to enhance the direct reprogramming of human cardiac fibroblasts into functional cardiomyocytes.
My expertise in bioartificial materials and biomimetic scaffolds and the versatile chemistry of polyurethanes will be the key elements to achieve a significant knowledge and technological advancement in cell reprogramming therapy, opening the way to the future translation of the therapy into the clinics.
I will implement this advanced approach through the design of a novel 3D in vitro tissue-engineered model of human cardiac fibrotic tissue, as a tool for testing and validation, to maximise research efforts and reduce animal tests.
I will adapt novel nanomedicine approaches I have recently developed for drug release to design innovative cell-friendly and efficient polyurethane nanoparticles for targeted reprogramming of cardiac fibroblasts.
I will design an injectable bioartificial hydrogel based on a blend of a thermosensitive polyurethane and a natural component selected among a novel cell-secreted natural polymer mixture (“biomatrix”) recapitulating the complexity of cardiac extracellular matrix or one of its main protein constituents. Such multifunctional hydrogel will deliver in situ agents stimulating recruitment of cardiac fibroblasts together with the nanoparticles loaded with reprogramming therapeutics, and will provide biochemical signalling to stimulate efficient conversion of fibroblasts into mature cardiomyocytes.
First-in-field biomaterials-based innovations introduced by BIORECAR will enable more effective regeneration of functional myocardial tissue respect to state-of-the art approaches. BIORECAR innovation is multidisciplinary in nature and will be accelerated towards future clinical translation through my clinical, scientific and industrial collaborations.
Summary
In BIORECAR I will develop a new breakthrough multifunctional biomaterial-based platform for myocardial regeneration after myocardial infarction, provided with biochemical cues able to enhance the direct reprogramming of human cardiac fibroblasts into functional cardiomyocytes.
My expertise in bioartificial materials and biomimetic scaffolds and the versatile chemistry of polyurethanes will be the key elements to achieve a significant knowledge and technological advancement in cell reprogramming therapy, opening the way to the future translation of the therapy into the clinics.
I will implement this advanced approach through the design of a novel 3D in vitro tissue-engineered model of human cardiac fibrotic tissue, as a tool for testing and validation, to maximise research efforts and reduce animal tests.
I will adapt novel nanomedicine approaches I have recently developed for drug release to design innovative cell-friendly and efficient polyurethane nanoparticles for targeted reprogramming of cardiac fibroblasts.
I will design an injectable bioartificial hydrogel based on a blend of a thermosensitive polyurethane and a natural component selected among a novel cell-secreted natural polymer mixture (“biomatrix”) recapitulating the complexity of cardiac extracellular matrix or one of its main protein constituents. Such multifunctional hydrogel will deliver in situ agents stimulating recruitment of cardiac fibroblasts together with the nanoparticles loaded with reprogramming therapeutics, and will provide biochemical signalling to stimulate efficient conversion of fibroblasts into mature cardiomyocytes.
First-in-field biomaterials-based innovations introduced by BIORECAR will enable more effective regeneration of functional myocardial tissue respect to state-of-the art approaches. BIORECAR innovation is multidisciplinary in nature and will be accelerated towards future clinical translation through my clinical, scientific and industrial collaborations.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym CA2PVM
Project Multi-field and multi-scale Computational Approach to design and durability of PhotoVoltaic Modules
Researcher (PI) Marco Paggi
Host Institution (HI) SCUOLA IMT (ISTITUZIONI, MERCATI, TECNOLOGIE) ALTI STUDI DI LUCCA
Call Details Starting Grant (StG), PE8, ERC-2012-StG_20111012
Summary "Photovoltaics (PV) based on Silicon (Si) semiconductors is one the most growing technology in the World for renewable, sustainable, non-polluting, widely available clean energy sources. Theoretical and applied research aims at increasing the conversion efficiency of PV modules and their lifetime. The Si crystalline microstructure has an important role on both issues. Grain boundaries introduce additional resistance and reduce the conversion efficiency. Moreover, they are prone to microcracking, thus influencing the lifetime. At present, the existing standard qualification tests are not sufficient to provide a quantitative definition of lifetime, since all the possible failure mechanisms are not accounted for. In this proposal, an innovative computational approach to design and durability assessment of PV modules is put forward. The aim is to complement real tests by virtual (numerical) simulations. To achieve a predictive stage, a challenging multi-field (multi-physics) computational approach is proposed, coupling the nonlinear elastic field, the thermal field and the electric field. To model real PV modules, an adaptive multi-scale and multi-field strategy will be proposed by introducing error indicators based on the gradients of the involved fields. This numerical approach will be applied to determine the upper bound to the probability of failure of the system. This statistical assessment will involve an optimization analysis that will be efficiently handled by a Mathematica-based hybrid symbolic-numerical framework. Standard and non-standard experimental testing on Si cells and PV modules will also be performed to complement and validate the numerical approach. The new methodology based on the challenging integration of advanced physical and mathematical modelling, innovative computational methods and non-standard experimental techniques is expected to have a significant impact on the design, qualification and lifetime assessment of complex PV systems."
Summary
"Photovoltaics (PV) based on Silicon (Si) semiconductors is one the most growing technology in the World for renewable, sustainable, non-polluting, widely available clean energy sources. Theoretical and applied research aims at increasing the conversion efficiency of PV modules and their lifetime. The Si crystalline microstructure has an important role on both issues. Grain boundaries introduce additional resistance and reduce the conversion efficiency. Moreover, they are prone to microcracking, thus influencing the lifetime. At present, the existing standard qualification tests are not sufficient to provide a quantitative definition of lifetime, since all the possible failure mechanisms are not accounted for. In this proposal, an innovative computational approach to design and durability assessment of PV modules is put forward. The aim is to complement real tests by virtual (numerical) simulations. To achieve a predictive stage, a challenging multi-field (multi-physics) computational approach is proposed, coupling the nonlinear elastic field, the thermal field and the electric field. To model real PV modules, an adaptive multi-scale and multi-field strategy will be proposed by introducing error indicators based on the gradients of the involved fields. This numerical approach will be applied to determine the upper bound to the probability of failure of the system. This statistical assessment will involve an optimization analysis that will be efficiently handled by a Mathematica-based hybrid symbolic-numerical framework. Standard and non-standard experimental testing on Si cells and PV modules will also be performed to complement and validate the numerical approach. The new methodology based on the challenging integration of advanced physical and mathematical modelling, innovative computational methods and non-standard experimental techniques is expected to have a significant impact on the design, qualification and lifetime assessment of complex PV systems."
Max ERC Funding
1 483 980 €
Duration
Start date: 2012-12-01, End date: 2017-11-30
Project acronym CABUM
Project An investigation of the mechanisms at the interaction between cavitation bubbles and contaminants
Researcher (PI) Matevz DULAR
Host Institution (HI) UNIVERZA V LJUBLJANI
Call Details Consolidator Grant (CoG), PE8, ERC-2017-COG
Summary A sudden decrease in pressure triggers the formation of vapour and gas bubbles inside a liquid medium (also called cavitation). This leads to many (key) engineering problems: material loss, noise and vibration of hydraulic machinery. On the other hand, cavitation is a potentially a useful phenomenon: the extreme conditions are increasingly used for a wide variety of applications such as surface cleaning, enhanced chemistry, and waste water treatment (bacteria eradication and virus inactivation).
Despite this significant progress a large gap persists between the understanding of the mechanisms that contribute to the effects of cavitation and its application. Although engineers are already commercializing devices that employ cavitation, we are still not able to answer the fundamental question: What precisely are the mechanisms how bubbles can clean, disinfect, kill bacteria and enhance chemical activity? The overall objective of the project is to understand and determine the fundamental physics of the interaction of cavitation bubbles with different contaminants. To address this issue, the CABUM project will investigate the physical background of cavitation from physical, biological and engineering perspective on three complexity scales: i) on single bubble level, ii) on organised and iii) on random bubble clusters, producing a progressive multidisciplinary synergetic effect.
The proposed synergetic approach builds on the PI's preliminary research and employs novel experimental and numerical methodologies, some of which have been developed by the PI and his research group, to explore the physics of cavitation behaviour in interaction with bacteria and viruses.
Understanding the fundamental physical background of cavitation in interaction with contaminants will have a ground-breaking implications in various scientific fields (engineering, chemistry and biology) and will, in the future, enable the exploitation of cavitation in water and soil treatment processes.
Summary
A sudden decrease in pressure triggers the formation of vapour and gas bubbles inside a liquid medium (also called cavitation). This leads to many (key) engineering problems: material loss, noise and vibration of hydraulic machinery. On the other hand, cavitation is a potentially a useful phenomenon: the extreme conditions are increasingly used for a wide variety of applications such as surface cleaning, enhanced chemistry, and waste water treatment (bacteria eradication and virus inactivation).
Despite this significant progress a large gap persists between the understanding of the mechanisms that contribute to the effects of cavitation and its application. Although engineers are already commercializing devices that employ cavitation, we are still not able to answer the fundamental question: What precisely are the mechanisms how bubbles can clean, disinfect, kill bacteria and enhance chemical activity? The overall objective of the project is to understand and determine the fundamental physics of the interaction of cavitation bubbles with different contaminants. To address this issue, the CABUM project will investigate the physical background of cavitation from physical, biological and engineering perspective on three complexity scales: i) on single bubble level, ii) on organised and iii) on random bubble clusters, producing a progressive multidisciplinary synergetic effect.
The proposed synergetic approach builds on the PI's preliminary research and employs novel experimental and numerical methodologies, some of which have been developed by the PI and his research group, to explore the physics of cavitation behaviour in interaction with bacteria and viruses.
Understanding the fundamental physical background of cavitation in interaction with contaminants will have a ground-breaking implications in various scientific fields (engineering, chemistry and biology) and will, in the future, enable the exploitation of cavitation in water and soil treatment processes.
Max ERC Funding
1 904 565 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
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
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: 2023-02-28
Project acronym COSMOS
Project Computational Simulations of MOFs for Gas Separations
Researcher (PI) Seda Keskin Avci
Host Institution (HI) KOC UNIVERSITY
Call Details Starting Grant (StG), PE8, ERC-2017-STG
Summary Metal organic frameworks (MOFs) are recently considered as new fascinating nanoporous materials. MOFs have very large surface areas, high porosities, various pore sizes/shapes, chemical functionalities and good thermal/chemical stabilities. These properties make MOFs highly promising for gas separation applications. Thousands of MOFs have been synthesized in the last decade. The large number of available MOFs creates excellent opportunities to develop energy-efficient gas separation technologies. On the other hand, it is very challenging to identify the best materials for each gas separation of interest. Considering the continuous rapid increase in the number of synthesized materials, it is practically not possible to test each MOF using purely experimental manners. Highly accurate computational methods are required to identify the most promising MOFs to direct experimental efforts, time and resources to those materials. In this project, I will build a complete MOF library and use molecular simulations to assess adsorption and diffusion properties of gas mixtures in MOFs. Results of simulations will be used to predict adsorbent and membrane properties of MOFs for scientifically and technologically important gas separation processes such as CO2/CH4 (natural gas purification), CO2/N2 (flue gas separation), CO2/H2, CH4/H2 and N2/H2 (hydrogen recovery). I will obtain the fundamental, atomic-level insights into the common features of the top-performing MOFs and establish structure-performance relations. These relations will be used as guidelines to computationally design new MOFs with outstanding separation performances for CO2 capture and H2 recovery. These new MOFs will be finally synthesized in the lab scale and tested as adsorbents and membranes under practical operating conditions for each gas separation of interest. Combining a multi-stage computational approach with experiments, this project will lead to novel, efficient gas separation technologies based on MOFs.
Summary
Metal organic frameworks (MOFs) are recently considered as new fascinating nanoporous materials. MOFs have very large surface areas, high porosities, various pore sizes/shapes, chemical functionalities and good thermal/chemical stabilities. These properties make MOFs highly promising for gas separation applications. Thousands of MOFs have been synthesized in the last decade. The large number of available MOFs creates excellent opportunities to develop energy-efficient gas separation technologies. On the other hand, it is very challenging to identify the best materials for each gas separation of interest. Considering the continuous rapid increase in the number of synthesized materials, it is practically not possible to test each MOF using purely experimental manners. Highly accurate computational methods are required to identify the most promising MOFs to direct experimental efforts, time and resources to those materials. In this project, I will build a complete MOF library and use molecular simulations to assess adsorption and diffusion properties of gas mixtures in MOFs. Results of simulations will be used to predict adsorbent and membrane properties of MOFs for scientifically and technologically important gas separation processes such as CO2/CH4 (natural gas purification), CO2/N2 (flue gas separation), CO2/H2, CH4/H2 and N2/H2 (hydrogen recovery). I will obtain the fundamental, atomic-level insights into the common features of the top-performing MOFs and establish structure-performance relations. These relations will be used as guidelines to computationally design new MOFs with outstanding separation performances for CO2 capture and H2 recovery. These new MOFs will be finally synthesized in the lab scale and tested as adsorbents and membranes under practical operating conditions for each gas separation of interest. Combining a multi-stage computational approach with experiments, this project will lead to novel, efficient gas separation technologies based on MOFs.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym DDRNA
Project A novel direct role of non coding RNA in DNA damage response activation
Researcher (PI) Fabrizio D'adda Di Fagagna
Host Institution (HI) IFOM FONDAZIONE ISTITUTO FIRC DI ONCOLOGIA MOLECOLARE
Call Details Advanced Grant (AdG), LS1, ERC-2012-ADG_20120314
Summary DNA, if damaged, cannot be replaced. If not replaceable, it must be repaired. The so-called “DNA damage response” (DDR) is a coordinate set of evolutionary conserved events that arrest the cell-cycle (DNA damage checkpoint function) in proliferating cells and attempts DNA repair. Until DNA damage has not been repaired in full, cell proliferation is not resumed in normal cells.
DNA damage is a physiological event. Ageing and cancer are both associated with DNA damage accumulation. In the past, we contribute to better understand the mechanisms and the consequences of DNA damage generation and DDR activation in both settings.
We have recently identified a completely hitherto undiscovered level of control of DDR activation, so far considered a proteinaceous only signaling cascade. We have discovered that short RNA species are detectable at DNA damage sites and are necessary for DDR activation at DNA lesions. These RNA species are generated by an evolutionary-conserved RNA processing machinery. However, they serve purposes never reported before.
We believe that our findings change radically our understanding of DDR modulation in mammals and disclose a fertile unspoilt ground for exciting investigations.
Summary
DNA, if damaged, cannot be replaced. If not replaceable, it must be repaired. The so-called “DNA damage response” (DDR) is a coordinate set of evolutionary conserved events that arrest the cell-cycle (DNA damage checkpoint function) in proliferating cells and attempts DNA repair. Until DNA damage has not been repaired in full, cell proliferation is not resumed in normal cells.
DNA damage is a physiological event. Ageing and cancer are both associated with DNA damage accumulation. In the past, we contribute to better understand the mechanisms and the consequences of DNA damage generation and DDR activation in both settings.
We have recently identified a completely hitherto undiscovered level of control of DDR activation, so far considered a proteinaceous only signaling cascade. We have discovered that short RNA species are detectable at DNA damage sites and are necessary for DDR activation at DNA lesions. These RNA species are generated by an evolutionary-conserved RNA processing machinery. However, they serve purposes never reported before.
We believe that our findings change radically our understanding of DDR modulation in mammals and disclose a fertile unspoilt ground for exciting investigations.
Max ERC Funding
2 329 200 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
Project acronym DEPTH
Project DEsigning new Paths in The differentiation Hyperspace
Researcher (PI) Giovanni Cesareni
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA TOR VERGATA
Call Details Advanced Grant (AdG), LS2, ERC-2012-ADG_20120314
Summary The adult human organism contains heterogeneous reservoirs of pluripotent stem cells characterized by a diversified differentiation potential. Understanding their biology at a system level would advance our ability to selectively activate and control their differentiation potential. Aside from the basic implications this would represent a substantial progress in regenerative medicine by providing a rational framework for using small molecules to control cell trans-determination and reprogramming.
Here we propose a combined experimental and modelling approach to assemble a predictive model of mesoderm stem cell differentiation. Different cell states are identified by a vector in the differentiation hyperspace, the coordinates of the vector being the activation levels of a large number of nodes of a logic model linking the cell signalling network to the transcription regulatory network.
The premise of this proposal is that differentiation is equivalent to rewiring the cell regulatory network as a consequence of induced perturbation of the gene expression program. This process can be rationally controlled by perturbing specific nodes of the signalling network that in turn control transcription factor activation. We will develop this novel strategy using the mesoangioblast ex vivo differentiation system. Mesoangioblasts are one of the many different types of mesoderm stem/progenitor cells that exhibit myogenic potential. Ex vivo, they readily differentiate into striated muscle. However, under appropriate conditions they can also differentiate, into smooth muscle and adipocytes, albeit less efficiently. We will start by assembling, training and optimizing different predictive models for the undifferentiated mesoangioblast. Next by a combination of experiments and modelling approaches we will learn how, by perturbing the signalling models with different inhibitors and activators we can rewire the cell networks to induce trans-determination or reprogramming.
Summary
The adult human organism contains heterogeneous reservoirs of pluripotent stem cells characterized by a diversified differentiation potential. Understanding their biology at a system level would advance our ability to selectively activate and control their differentiation potential. Aside from the basic implications this would represent a substantial progress in regenerative medicine by providing a rational framework for using small molecules to control cell trans-determination and reprogramming.
Here we propose a combined experimental and modelling approach to assemble a predictive model of mesoderm stem cell differentiation. Different cell states are identified by a vector in the differentiation hyperspace, the coordinates of the vector being the activation levels of a large number of nodes of a logic model linking the cell signalling network to the transcription regulatory network.
The premise of this proposal is that differentiation is equivalent to rewiring the cell regulatory network as a consequence of induced perturbation of the gene expression program. This process can be rationally controlled by perturbing specific nodes of the signalling network that in turn control transcription factor activation. We will develop this novel strategy using the mesoangioblast ex vivo differentiation system. Mesoangioblasts are one of the many different types of mesoderm stem/progenitor cells that exhibit myogenic potential. Ex vivo, they readily differentiate into striated muscle. However, under appropriate conditions they can also differentiate, into smooth muscle and adipocytes, albeit less efficiently. We will start by assembling, training and optimizing different predictive models for the undifferentiated mesoangioblast. Next by a combination of experiments and modelling approaches we will learn how, by perturbing the signalling models with different inhibitors and activators we can rewire the cell networks to induce trans-determination or reprogramming.
Max ERC Funding
2 639 804 €
Duration
Start date: 2013-04-01, End date: 2018-09-30
Project acronym IceCommunities
Project Reconstructing community dynamics and ecosystem functioning after glacial retreat
Researcher (PI) Gentile Francesco FICETOLA
Host Institution (HI) UNIVERSITA DEGLI STUDI DI MILANO
Call Details Consolidator Grant (CoG), LS8, ERC-2017-COG
Summary Glaciers show a pattern of retreat at the global scale. Increasing areas are exposed and colonized by multiple organisms, but lack of global studies hampers a complete understanding of the future of recently deglaciated terrains. What will be the fate of these areas? How do animals, plants and microorganisms colonize them? How do they interact to perform successful colonization? Which are the climatic, geological and biogeographical processes determining colonization patterns? How does ecosystem functioning evolves through time? Until now, the complete reconstruction of soil communities was hampered by the complexity of identification of organisms, thus analyses at broad geographical and taxonomic scale have been so far impossible. IceCommunities will combine innovative methods and a global approach to boost our understanding of the evolution of ecosystems in recently deglaciated areas. I will investigate chronosequences ranging from recently deglaciated terrains to late successional stages of soil pedogenesis. Through environmental DNA metabarcoding I will identify species from multiple taxonomic groups (bacteria, fungi, protists, soil invertebrates, plants), to obtain a complete reconstruction of biotic communities along glacier forelands over multiple mountain areas across the globe. This will allow measuring the rate of colonization at an unprecedented detail. Information on assemblages will be combined with analyses of soil, landscape and climate to identify the drivers of community changes. I will also identify the impact of eco-geographical factors (climate, regional pool of potential colonizers) on colonization. Analysis of functional traits will allow reconstructing how functional diversity emerges during community formation, and how it scales to the functioning of food webs. IceCommunities will help to predict the future development of these increasingly important ecosystems, providing a supported rationale for the appropriate management of these areas
Summary
Glaciers show a pattern of retreat at the global scale. Increasing areas are exposed and colonized by multiple organisms, but lack of global studies hampers a complete understanding of the future of recently deglaciated terrains. What will be the fate of these areas? How do animals, plants and microorganisms colonize them? How do they interact to perform successful colonization? Which are the climatic, geological and biogeographical processes determining colonization patterns? How does ecosystem functioning evolves through time? Until now, the complete reconstruction of soil communities was hampered by the complexity of identification of organisms, thus analyses at broad geographical and taxonomic scale have been so far impossible. IceCommunities will combine innovative methods and a global approach to boost our understanding of the evolution of ecosystems in recently deglaciated areas. I will investigate chronosequences ranging from recently deglaciated terrains to late successional stages of soil pedogenesis. Through environmental DNA metabarcoding I will identify species from multiple taxonomic groups (bacteria, fungi, protists, soil invertebrates, plants), to obtain a complete reconstruction of biotic communities along glacier forelands over multiple mountain areas across the globe. This will allow measuring the rate of colonization at an unprecedented detail. Information on assemblages will be combined with analyses of soil, landscape and climate to identify the drivers of community changes. I will also identify the impact of eco-geographical factors (climate, regional pool of potential colonizers) on colonization. Analysis of functional traits will allow reconstructing how functional diversity emerges during community formation, and how it scales to the functioning of food webs. IceCommunities will help to predict the future development of these increasingly important ecosystems, providing a supported rationale for the appropriate management of these areas
Max ERC Funding
1 845 773 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
