Project acronym CARDYADS
Project Controlling Cardiomyocyte Dyadic Structure
Researcher (PI) William Edward Louch
Host Institution (HI) UNIVERSITETET I OSLO
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Contraction and relaxation of cardiac myocytes, and thus the whole heart, are critically dependent on dyads. These functional junctions between t-tubules, which are invaginations of the surface membrane, and the sarcoplasmic reticulum allow efficient control of calcium release into the cytosol, and also its removal. Dyads are formed gradually during development and break down during disease. However, the precise nature of dyadic structure is unclear, even in healthy adult cardiac myocytes, as are the triggers and consequences of altering dyadic integrity. In this proposal, my group will investigate the precise 3-dimensional arrangement of dyads and their proteins during development, adulthood, and heart failure by employing CLEM imaging (PALM and EM tomography). This will be accomplished by developing transgenic mice with fluorescent labels on four dyadic proteins (L-type calcium channel, ryanodine receptor, sodium-calcium exchanger, SERCA), and by imaging tissue from explanted normal and failing human hearts. The signals responsible for controlling dyadic formation, maintenance, and disruption will be determined by performing high-throughput sequencing to identify novel genes involved with these processes in several established model systems. Particular focus will be given to investigating left ventricular wall stress and stretch-dependent gene regulation as controllers of dyadic integrity. Candidate genes will be manipulated in cell models and transgenic animals to promote dyadic formation and maintenance, and reverse dyadic disruption in heart failure. The consequences of dyadic structure for function will be tested experimentally and with mathematical modeling to examine effects on cardiac myocyte calcium homeostasis and whole-heart function. The results of this project are anticipated to yield unprecedented insight into dyadic structure, regulation, and function, and to identify novel therapeutic targets for heart disease patients.
Summary
Contraction and relaxation of cardiac myocytes, and thus the whole heart, are critically dependent on dyads. These functional junctions between t-tubules, which are invaginations of the surface membrane, and the sarcoplasmic reticulum allow efficient control of calcium release into the cytosol, and also its removal. Dyads are formed gradually during development and break down during disease. However, the precise nature of dyadic structure is unclear, even in healthy adult cardiac myocytes, as are the triggers and consequences of altering dyadic integrity. In this proposal, my group will investigate the precise 3-dimensional arrangement of dyads and their proteins during development, adulthood, and heart failure by employing CLEM imaging (PALM and EM tomography). This will be accomplished by developing transgenic mice with fluorescent labels on four dyadic proteins (L-type calcium channel, ryanodine receptor, sodium-calcium exchanger, SERCA), and by imaging tissue from explanted normal and failing human hearts. The signals responsible for controlling dyadic formation, maintenance, and disruption will be determined by performing high-throughput sequencing to identify novel genes involved with these processes in several established model systems. Particular focus will be given to investigating left ventricular wall stress and stretch-dependent gene regulation as controllers of dyadic integrity. Candidate genes will be manipulated in cell models and transgenic animals to promote dyadic formation and maintenance, and reverse dyadic disruption in heart failure. The consequences of dyadic structure for function will be tested experimentally and with mathematical modeling to examine effects on cardiac myocyte calcium homeostasis and whole-heart function. The results of this project are anticipated to yield unprecedented insight into dyadic structure, regulation, and function, and to identify novel therapeutic targets for heart disease patients.
Max ERC Funding
2 000 000 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym DENOVOSTEM
Project DE NOVO GENERATION OF SOMATIC STEM CELLS: REGULATION AND MECHANISMS OF CELL PLASTICITY
Researcher (PI) Stefano Piccolo
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PADOVA
Call Details Advanced Grant (AdG), LS4, ERC-2014-ADG
Summary The possibility to artificially induce and expand in vitro tissue-specific stem cells (SCs) is an important goal for regenerative medicine, to understand organ physiology, for in vitro modeling of human diseases and many other applications. Here we found that this goal can be achieved in the culture dish by transiently inducing expression of YAP or TAZ - nuclear effectors of the Hippo and biomechanical pathways - into primary/terminally differentiated cells of distinct tissue origins. Moreover, YAP/TAZ are essential endogenous factors that preserve ex-vivo naturally arising SCs of distinct tissues.
In this grant, we aim to gain insights into YAP/TAZ molecular networks (upstream regulators and downstream targets) involved in somatic SC reprogramming and SC identity. Our studies will entail the identification of the genetic networks and epigenetic changes controlled by YAP/TAZ during cell de-differentiation and the re-acquisition of SC-traits in distinct cell types. We will also investigate upstream inputs establishing YAP/TAZ activity, with particular emphasis on biomechanical and cytoskeletal cues that represent overarching regulators of YAP/TAZ in tissues.
For many tumors, it appears that acquisition of an immature, stem-like state is a prerequisite for tumor progression and an early step in oncogene-mediated transformation. YAP/TAZ activation is widespread in human tumors. However, a connection between YAP/TAZ and oncogene-induced cell plasticity has never been investigated. We will also pursue some intriguing preliminary results and investigate how oncogenes and chromatin remodelers may link to cell mechanics, and the plasticity of the differentiated and SC states by controlling YAP/TAZ.
In sum, this research should advance our understanding of the cellular and molecular basis underpinning organ growth, tissue regeneration and tumor initiation.
Summary
The possibility to artificially induce and expand in vitro tissue-specific stem cells (SCs) is an important goal for regenerative medicine, to understand organ physiology, for in vitro modeling of human diseases and many other applications. Here we found that this goal can be achieved in the culture dish by transiently inducing expression of YAP or TAZ - nuclear effectors of the Hippo and biomechanical pathways - into primary/terminally differentiated cells of distinct tissue origins. Moreover, YAP/TAZ are essential endogenous factors that preserve ex-vivo naturally arising SCs of distinct tissues.
In this grant, we aim to gain insights into YAP/TAZ molecular networks (upstream regulators and downstream targets) involved in somatic SC reprogramming and SC identity. Our studies will entail the identification of the genetic networks and epigenetic changes controlled by YAP/TAZ during cell de-differentiation and the re-acquisition of SC-traits in distinct cell types. We will also investigate upstream inputs establishing YAP/TAZ activity, with particular emphasis on biomechanical and cytoskeletal cues that represent overarching regulators of YAP/TAZ in tissues.
For many tumors, it appears that acquisition of an immature, stem-like state is a prerequisite for tumor progression and an early step in oncogene-mediated transformation. YAP/TAZ activation is widespread in human tumors. However, a connection between YAP/TAZ and oncogene-induced cell plasticity has never been investigated. We will also pursue some intriguing preliminary results and investigate how oncogenes and chromatin remodelers may link to cell mechanics, and the plasticity of the differentiated and SC states by controlling YAP/TAZ.
In sum, this research should advance our understanding of the cellular and molecular basis underpinning organ growth, tissue regeneration and tumor initiation.
Max ERC Funding
2 498 934 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym ENSURE
Project Exploring the New Science and engineering unveiled by Ultraintense ultrashort Radiation interaction with mattEr
Researcher (PI) Matteo Passoni
Host Institution (HI) POLITECNICO DI MILANO
Call Details Consolidator Grant (CoG), PE8, ERC-2014-CoG
Summary With the ENSURE project I aim at attaining ground-breaking results in the field of superintense laser-driven ion acceleration, proposing a multidisciplinary research program in which theoretical, numerical and experimental research will be coherently developed in a team integrating in an unprecedented way advanced expertise from materials engineering and nanotechnology, laser-plasma physics, computational science. The aim will be to bring this topic from the realm of fundamental basic science into a subject having realistic engineering applications.
The discovery in 2000 of brilliant, multi-MeV, collimated ion sources from targets irradiated by intense laser pulses stimulated great interest worldwide, due to the ultra-compact spatial scale of the accelerator and ion beam properties. The laser-target system provides unique appealing features to fundamental physics which can be studied in a small lab. At the same time, laser-ion beams could have future potential in many technological areas. This is boosting the development of new labs and facilities all over Europe, but to support these efforts, crucial challenges need to be faced to make these applications a reality.
The goals of ENSURE are: i) design and production of nanoengineered targets, with properties tailored to achieve optimized ion acceleration regimes. This will be pursued exploiting advanced techniques of material science & nanotechnology ii) design of laser-ion beams for novel, key applications in nuclear and materials engineering iii) realization of engineering-oriented ion acceleration experiments, in advanced facilities iv) synergic development of all the required theoretical support for i,ii,iii).
The results of the project can determine a unique impact in the research on laser-driven ion acceleration in Europe, providing new directions to support the attainment, in the next future, of concrete applications of great societal relevance, in medical, energy and materials areas.
Summary
With the ENSURE project I aim at attaining ground-breaking results in the field of superintense laser-driven ion acceleration, proposing a multidisciplinary research program in which theoretical, numerical and experimental research will be coherently developed in a team integrating in an unprecedented way advanced expertise from materials engineering and nanotechnology, laser-plasma physics, computational science. The aim will be to bring this topic from the realm of fundamental basic science into a subject having realistic engineering applications.
The discovery in 2000 of brilliant, multi-MeV, collimated ion sources from targets irradiated by intense laser pulses stimulated great interest worldwide, due to the ultra-compact spatial scale of the accelerator and ion beam properties. The laser-target system provides unique appealing features to fundamental physics which can be studied in a small lab. At the same time, laser-ion beams could have future potential in many technological areas. This is boosting the development of new labs and facilities all over Europe, but to support these efforts, crucial challenges need to be faced to make these applications a reality.
The goals of ENSURE are: i) design and production of nanoengineered targets, with properties tailored to achieve optimized ion acceleration regimes. This will be pursued exploiting advanced techniques of material science & nanotechnology ii) design of laser-ion beams for novel, key applications in nuclear and materials engineering iii) realization of engineering-oriented ion acceleration experiments, in advanced facilities iv) synergic development of all the required theoretical support for i,ii,iii).
The results of the project can determine a unique impact in the research on laser-driven ion acceleration in Europe, providing new directions to support the attainment, in the next future, of concrete applications of great societal relevance, in medical, energy and materials areas.
Max ERC Funding
1 887 500 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym IDEal reSCUE
Project Integrated DEsign and control of Sustainable CommUnities during Emergencies
Researcher (PI) Gian Paolo Cimellaro
Host Institution (HI) POLITECNICO DI TORINO
Call Details Starting Grant (StG), PE8, ERC-2014-STG
Summary Integrated DEsign and control of Sustainable CommUnities during Emergencies
Summary
Integrated DEsign and control of Sustainable CommUnities during Emergencies
Max ERC Funding
1 271 138 €
Duration
Start date: 2015-11-01, End date: 2020-10-31
Project acronym INTHERM
Project Design, manufacturing and control of INterfaces in THERMally conductive polymer nanocomposites
Researcher (PI) Alberto Fina
Host Institution (HI) POLITECNICO DI TORINO
Call Details Starting Grant (StG), PE8, ERC-2014-STG
Summary This proposal addresses the design, manufacturing and control of interfaces in thermally conductive polymer/graphene nanocomposites.
In particular, the strong reduction of thermal resistance associated to the contacts between conductive particles in a percolating network throughout the polymer matrix is targeted, to overcome the present bottleneck for heat transfer in nanocomposites.
The project includes the investigation of novel chemical modifications of nanoparticles to behave as thermal bridges between adjacent particles, advanced characterization methods for particle/particle interfaces and controlled processing methods for the preparations of nanocomposites with superior thermal conductivity.
The results of this project will contribute to the fundamental understanding of heat transfer in complex solids, while success in mastering interfacial properties would open the way to a new generation of advanced materials coupling high thermal conductivity with low density, ease of processing, toughness and corrosion resistance.
Summary
This proposal addresses the design, manufacturing and control of interfaces in thermally conductive polymer/graphene nanocomposites.
In particular, the strong reduction of thermal resistance associated to the contacts between conductive particles in a percolating network throughout the polymer matrix is targeted, to overcome the present bottleneck for heat transfer in nanocomposites.
The project includes the investigation of novel chemical modifications of nanoparticles to behave as thermal bridges between adjacent particles, advanced characterization methods for particle/particle interfaces and controlled processing methods for the preparations of nanocomposites with superior thermal conductivity.
The results of this project will contribute to the fundamental understanding of heat transfer in complex solids, while success in mastering interfacial properties would open the way to a new generation of advanced materials coupling high thermal conductivity with low density, ease of processing, toughness and corrosion resistance.
Max ERC Funding
1 404 132 €
Duration
Start date: 2015-03-01, End date: 2020-02-29
Project acronym iTPX
Project In-cavity thermophotonic cooling
Researcher (PI) Jani Erkki Oksanen
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Starting Grant (StG), PE8, ERC-2014-STG
Summary Thermophotonic (TPX) coolers and generators based on electroluminescent (EL) cooling have the potential to enable a high efficiency replacement for thermoelectric devices. Highly optimized TPX devices can even outperform modern compressor based household refrigerators and heat pumps, enabling a significant reduction in the global energy consumption of cooling and heating. While the EL cooling phenomenon is theoretically well understood, it was only very recently demonstrated for the first time under very small power conditions. Enabling high power EL cooling, however, will require a breakthrough in reducing the losses present in conventional light emitting diodes (LED).
iTPX aims to enable this breakthrough by developing an alternative approach to enhance the efficiency of light emission. The approach is based on enclosing the emitter-absorber pair used in TPX in a single semiconductor structure forming an optical cavity. This enhances the light emission rate by an order of magnitude and provides a substantial increase in the efficiency as well as several other technical and fundamental benefits. The main goal of iTPX is to demonstrate high power EL cooling for the first time and to provide quantitative insight on the limitations and possibilities of the cavity-based approach. Recent studies have shown extremely high – over 99 % – internal and external quantum efficiencies of light emission from optically pumped semiconductor structures. This suggests that the material quality of common III-V compound semiconductors is perfectly sufficient for EL cooling if similarly performing electrically injected structures can be fabricated in the single cavity configuration.
Summary
Thermophotonic (TPX) coolers and generators based on electroluminescent (EL) cooling have the potential to enable a high efficiency replacement for thermoelectric devices. Highly optimized TPX devices can even outperform modern compressor based household refrigerators and heat pumps, enabling a significant reduction in the global energy consumption of cooling and heating. While the EL cooling phenomenon is theoretically well understood, it was only very recently demonstrated for the first time under very small power conditions. Enabling high power EL cooling, however, will require a breakthrough in reducing the losses present in conventional light emitting diodes (LED).
iTPX aims to enable this breakthrough by developing an alternative approach to enhance the efficiency of light emission. The approach is based on enclosing the emitter-absorber pair used in TPX in a single semiconductor structure forming an optical cavity. This enhances the light emission rate by an order of magnitude and provides a substantial increase in the efficiency as well as several other technical and fundamental benefits. The main goal of iTPX is to demonstrate high power EL cooling for the first time and to provide quantitative insight on the limitations and possibilities of the cavity-based approach. Recent studies have shown extremely high – over 99 % – internal and external quantum efficiencies of light emission from optically pumped semiconductor structures. This suggests that the material quality of common III-V compound semiconductors is perfectly sufficient for EL cooling if similarly performing electrically injected structures can be fabricated in the single cavity configuration.
Max ERC Funding
1 981 250 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym LUNELY
Project ALK as a common target for the pathogenesis and therapy in lymphoma, lung carcinoma and neuroblastoma
Researcher (PI) Roberto Chiarle
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TORINO
Call Details Starting Grant (StG), LS4, ERC-2009-StG
Summary The Anaplastic Lymphoma Kinase (ALK) has been discovered as the result of chromosomal translocations in Anaplastic Large Cell Lymphomas (ALCL) (Chiarle et al Nat Rev Cancer. 2008, 8:11). In ALCL, the role of the ALK oncogenic translocations has been established in vitro and in transgenic mouse models. Recent findings have shown ALK translocations, mutations or amplifications in other types of solid cancers, such as lung carcinoma (Soda et al. Nature. 2007, 448:561) and neuroblastoma (Mossè et al. Nature 2008, 455: 930). However, the role of ALK gene mutations in these solid tumours remains largely undetermined. This lack of knowledge is even worse given the fact that a therapy that targets ALK in these tumours could be feasible. Aim 1. Targeting of ALK in ALCL lymphomas. ALCL ALK positive lymphomas will be tested for small molecule inhibitors of the activity of ALK. In addition, a combination of gene silencing, such as small interfering RNA (siRNA), and vaccination against ALK will be validated as selective ALK therapies. Aim 2. Characterization of the role of ALK in lung cancer through the generation of mouse models. We propose to characterize the pathogenetic role of ALK in lung cancer by in vitro studies and by generating mouse models for ALK positive lung cancers. These mouse models will be fundamental to validate the innovative therapies against ALK positive lung carcinoma. Aim 3. Validation of ALK as an oncogene and a therapeutic target in neuroblastoma. We plan to develop mouse models of neuroblastoma to investigate the pathogenetic role of ALK in the onset and maintenance of neuroblastoma in vivo. These mouse model of neuroblastoma will be used for the validation of ALK specific therapies. Overall, the proposed project will define the role of ALK in lymphoma, neuroblastoma and lungcancer and validate its potential use as a a target for therapy in those tumours. The impact of these novel therapies will be of great value in these deadly tumours.
Summary
The Anaplastic Lymphoma Kinase (ALK) has been discovered as the result of chromosomal translocations in Anaplastic Large Cell Lymphomas (ALCL) (Chiarle et al Nat Rev Cancer. 2008, 8:11). In ALCL, the role of the ALK oncogenic translocations has been established in vitro and in transgenic mouse models. Recent findings have shown ALK translocations, mutations or amplifications in other types of solid cancers, such as lung carcinoma (Soda et al. Nature. 2007, 448:561) and neuroblastoma (Mossè et al. Nature 2008, 455: 930). However, the role of ALK gene mutations in these solid tumours remains largely undetermined. This lack of knowledge is even worse given the fact that a therapy that targets ALK in these tumours could be feasible. Aim 1. Targeting of ALK in ALCL lymphomas. ALCL ALK positive lymphomas will be tested for small molecule inhibitors of the activity of ALK. In addition, a combination of gene silencing, such as small interfering RNA (siRNA), and vaccination against ALK will be validated as selective ALK therapies. Aim 2. Characterization of the role of ALK in lung cancer through the generation of mouse models. We propose to characterize the pathogenetic role of ALK in lung cancer by in vitro studies and by generating mouse models for ALK positive lung cancers. These mouse models will be fundamental to validate the innovative therapies against ALK positive lung carcinoma. Aim 3. Validation of ALK as an oncogene and a therapeutic target in neuroblastoma. We plan to develop mouse models of neuroblastoma to investigate the pathogenetic role of ALK in the onset and maintenance of neuroblastoma in vivo. These mouse model of neuroblastoma will be used for the validation of ALK specific therapies. Overall, the proposed project will define the role of ALK in lymphoma, neuroblastoma and lungcancer and validate its potential use as a a target for therapy in those tumours. The impact of these novel therapies will be of great value in these deadly tumours.
Max ERC Funding
1 010 000 €
Duration
Start date: 2009-11-01, End date: 2014-04-30
Project acronym MISTRANSMITO
Project Tissue-specific mitochondrial signaling and adaptations to mistranslation
Researcher (PI) Henna Riikka Susanna Tyynismaa
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary Mitochondria play a central role in the energy metabolism of our bodies and their defects give rise to a large variety of clinical phenotypes that can affect practically any tissue. The mechanisms for the tissue-specific outcomes of mitochondrial diseases are poorly understood. Mitochondrial energy production relies on two separate protein synthesis machineries, cytoplasmic and mitochondrial, but the mechanisms regulating the concerted actions between the two are largely to be discovered. Defects in either protein synthesis system that lead to accumulation of mistranslated mitochondrial proteins, intrinsic or imported from the cytoplasm, result in stress signals from mitochondria and in adaptive responses within the organelle and the entire cell. My hypothesis is that some of these signals and adaptive mechanisms are tissue-specific. My group will test the hypothesis by 1) generating and characterizing mouse models of cytoplasmic and mitochondrial mistranslation to be able to address our questions in different tissues. 2) We will develop methods for detection of ribosome stalling in mouse tissues to identify the consequences of mistranslation for individual proteins. 3) We will use systems biology approaches to identify stress signal responses to mitochondrial and/or cytoplasmic mistranslation using different tissues of our models, to identify those that are unique or global. 4) Our previous study has identified an interesting candidate responder to mistranslation stress and we will test the role of this factor in knockout animal models and by crossing with the mistranslation mice. I expect to gain important new knowledge of in vivo responses to mistranslation and execution of quality control. This proposal investigates key questions in understanding differential tissue involvement in metabolic defects, and will provide new directions for utilization of tissue-specific adaptations in finding interventions for mitochondrial diseases.
Summary
Mitochondria play a central role in the energy metabolism of our bodies and their defects give rise to a large variety of clinical phenotypes that can affect practically any tissue. The mechanisms for the tissue-specific outcomes of mitochondrial diseases are poorly understood. Mitochondrial energy production relies on two separate protein synthesis machineries, cytoplasmic and mitochondrial, but the mechanisms regulating the concerted actions between the two are largely to be discovered. Defects in either protein synthesis system that lead to accumulation of mistranslated mitochondrial proteins, intrinsic or imported from the cytoplasm, result in stress signals from mitochondria and in adaptive responses within the organelle and the entire cell. My hypothesis is that some of these signals and adaptive mechanisms are tissue-specific. My group will test the hypothesis by 1) generating and characterizing mouse models of cytoplasmic and mitochondrial mistranslation to be able to address our questions in different tissues. 2) We will develop methods for detection of ribosome stalling in mouse tissues to identify the consequences of mistranslation for individual proteins. 3) We will use systems biology approaches to identify stress signal responses to mitochondrial and/or cytoplasmic mistranslation using different tissues of our models, to identify those that are unique or global. 4) Our previous study has identified an interesting candidate responder to mistranslation stress and we will test the role of this factor in knockout animal models and by crossing with the mistranslation mice. I expect to gain important new knowledge of in vivo responses to mistranslation and execution of quality control. This proposal investigates key questions in understanding differential tissue involvement in metabolic defects, and will provide new directions for utilization of tissue-specific adaptations in finding interventions for mitochondrial diseases.
Max ERC Funding
1 354 508 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym NICHOID
Project Mechanobiology of nuclear import of transcription factors modeled within a bioengineered stem cell niche.
Researcher (PI) Manuela Teresa Raimondi
Host Institution (HI) POLITECNICO DI MILANO
Call Details Consolidator Grant (CoG), PE8, ERC-2014-CoG
Summary Many therapeutic applications of stem cells require accurate control of their differentiation. To this purpose there is a major ongoing effort in the development of advanced culture substrates to be used as “synthetic niches” for the cells, mimicking the native ones. The goal of this project is to use a synthetic niche cell culture model to test my revolutionary hypothesis that in stem cell differentiation, nuclear import of gene-regulating transcription factors is controlled by the stretch of the nuclear pore complexes. If verified, this idea could lead to a breakthrough in biomimetic approaches to engineering stem cell differentiation.
I investigate this question specifically in mesenchymal stem cells (MSC), because they are adherent and highly mechano-sensitive to architectural cues of the microenvironment. To verify my hypothesis I will use a combined experimental-computational model of mechanotransduction. I will a) scale-up an existing three-dimensional synthetic niche culture substrate, fabricated by two-photon laser polymerization, b) characterize the effect of tridimensionality on the differentiation fate of MSC cultured in the niches, c) develop a multiphysics/multiscale computational model of nuclear import of transcription factors within differentially-spread cultured cells, and d) integrate the numerical predictions with experimentally-measured import of fluorescently-labelled transcription factors.
This project requires the synergic combination of several advanced bioengineering technologies, including micro/nano fabrication and biomimetics. The use of two-photon laser polymerization for controlling the geometry of the synthetic cell niches is very innovative and will highly impact the fields of bioengineering and biomaterial technology. A successful outcome will lead to a deeper understanding of bioengineering methods to direct stem cell fate and have therefore a significant impact in tissue repair technologies and regenerative medicine.
Summary
Many therapeutic applications of stem cells require accurate control of their differentiation. To this purpose there is a major ongoing effort in the development of advanced culture substrates to be used as “synthetic niches” for the cells, mimicking the native ones. The goal of this project is to use a synthetic niche cell culture model to test my revolutionary hypothesis that in stem cell differentiation, nuclear import of gene-regulating transcription factors is controlled by the stretch of the nuclear pore complexes. If verified, this idea could lead to a breakthrough in biomimetic approaches to engineering stem cell differentiation.
I investigate this question specifically in mesenchymal stem cells (MSC), because they are adherent and highly mechano-sensitive to architectural cues of the microenvironment. To verify my hypothesis I will use a combined experimental-computational model of mechanotransduction. I will a) scale-up an existing three-dimensional synthetic niche culture substrate, fabricated by two-photon laser polymerization, b) characterize the effect of tridimensionality on the differentiation fate of MSC cultured in the niches, c) develop a multiphysics/multiscale computational model of nuclear import of transcription factors within differentially-spread cultured cells, and d) integrate the numerical predictions with experimentally-measured import of fluorescently-labelled transcription factors.
This project requires the synergic combination of several advanced bioengineering technologies, including micro/nano fabrication and biomimetics. The use of two-photon laser polymerization for controlling the geometry of the synthetic cell niches is very innovative and will highly impact the fields of bioengineering and biomaterial technology. A successful outcome will lead to a deeper understanding of bioengineering methods to direct stem cell fate and have therefore a significant impact in tissue repair technologies and regenerative medicine.
Max ERC Funding
1 903 330 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym rEnDOx
Project REDOX SIGNALING AND METABOLIC STATES IN ANGIOGENESIS IN HEALTH AND DISEASE
Researcher (PI) Massimo Santoro
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PADOVA
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Endothelial cells (ECs) exhibit a remarkable and unique plasticity in terms of redox biology and metabolism. They can quickly adapt to oxygen, nitric oxide and metabolic variations. Therefore, EC must be equipped with a selective and unique repertoire of redox and metabolic mechanisms, that play a crucial role to preserve redox balance, and adjust metabolic conditions in both normal and pathological angiogenesis. The identification of such redox signaling and metabolic pathways is crucial to the gaining of better insights in endothelial biology and dysfunction. More importantly, these insights could be used to establish innovative therapeutic approaches for the treatment of those conditions where aberrant or excessive angiogenesis is the underlying cause of the disease itself. However, the formation, actions, key molecular interactions, and physiological and pathological relevance of redox signals in ECs remain unclear. Here, by using cutting-edge real-time redox imaging platforms, and innovative molecular and genetic approaches in different in vivo animal models, we will (1) reveal the working of redox signaling in EC in health and disease, (2) shed light on the novel role for the mevalonate metabolic pathway in angiogenesis and (3) provide solid evidence, that manipulation of endothelial redox and metabolic state by genetic alteration of the redox rheostat UBIAD1, is a valuable strategy by which to block pathological angiogenesis in vivo.
The ultimate objective is to open the way for the development of innovative (cancer) therapeutic strategies and complement the existing ones based on genetic or pharmacological manipulation of redox rheostats to balance oxidative or reductive stress in angiogenic processes. The success of this project is built upon our major expertise in the field of angiogenesis in small vertebrate animal models as well as on the collaborations with leading laboratories that are active in research on the pre-clinical stages for angiogenesis-rel
Summary
Endothelial cells (ECs) exhibit a remarkable and unique plasticity in terms of redox biology and metabolism. They can quickly adapt to oxygen, nitric oxide and metabolic variations. Therefore, EC must be equipped with a selective and unique repertoire of redox and metabolic mechanisms, that play a crucial role to preserve redox balance, and adjust metabolic conditions in both normal and pathological angiogenesis. The identification of such redox signaling and metabolic pathways is crucial to the gaining of better insights in endothelial biology and dysfunction. More importantly, these insights could be used to establish innovative therapeutic approaches for the treatment of those conditions where aberrant or excessive angiogenesis is the underlying cause of the disease itself. However, the formation, actions, key molecular interactions, and physiological and pathological relevance of redox signals in ECs remain unclear. Here, by using cutting-edge real-time redox imaging platforms, and innovative molecular and genetic approaches in different in vivo animal models, we will (1) reveal the working of redox signaling in EC in health and disease, (2) shed light on the novel role for the mevalonate metabolic pathway in angiogenesis and (3) provide solid evidence, that manipulation of endothelial redox and metabolic state by genetic alteration of the redox rheostat UBIAD1, is a valuable strategy by which to block pathological angiogenesis in vivo.
The ultimate objective is to open the way for the development of innovative (cancer) therapeutic strategies and complement the existing ones based on genetic or pharmacological manipulation of redox rheostats to balance oxidative or reductive stress in angiogenic processes. The success of this project is built upon our major expertise in the field of angiogenesis in small vertebrate animal models as well as on the collaborations with leading laboratories that are active in research on the pre-clinical stages for angiogenesis-rel
Max ERC Funding
1 999 827 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
