Project acronym 2DHIBSA
Project Nanoscopic and Hierachical Materials via Living Crystallization-Driven Self-Assembly
Researcher (PI) Ian MANNERS
Host Institution (HI) UNIVERSITY OF BRISTOL
Country United Kingdom
Call Details Advanced Grant (AdG), PE5, ERC-2017-ADG
Summary A key synthetic challenge of widespread interest in chemical science involves the creation of well-defined 2D functional materials that exist on a length-scale of nanometers to microns. In this ambitious 5 year proposal we aim to tackle this issue by exploiting the unique opportunities made possible by recent developments with the living crystallization-driven self-assembly (CDSA) platform. Using this solution processing approach, amphiphilic block copolymers (BCPs) with crystallizable blocks, related amphiphiles, and polymers with charged end groups will be used to predictably construct monodisperse samples of tailored, functional soft matter-based 2D nanostructures with controlled shape, size, and spatially-defined chemistries. Many of the resulting nanostructures will also offer unprecedented opportunities as precursors to materials with hierarchical structures through further solution-based “bottom-up” assembly methods. In addition to fundamental studies, the proposed work also aims to make important impact in the cutting-edge fields of liquid crystals, interface stabilization, catalysis, supramolecular polymers, and hierarchical materials.
Summary
A key synthetic challenge of widespread interest in chemical science involves the creation of well-defined 2D functional materials that exist on a length-scale of nanometers to microns. In this ambitious 5 year proposal we aim to tackle this issue by exploiting the unique opportunities made possible by recent developments with the living crystallization-driven self-assembly (CDSA) platform. Using this solution processing approach, amphiphilic block copolymers (BCPs) with crystallizable blocks, related amphiphiles, and polymers with charged end groups will be used to predictably construct monodisperse samples of tailored, functional soft matter-based 2D nanostructures with controlled shape, size, and spatially-defined chemistries. Many of the resulting nanostructures will also offer unprecedented opportunities as precursors to materials with hierarchical structures through further solution-based “bottom-up” assembly methods. In addition to fundamental studies, the proposed work also aims to make important impact in the cutting-edge fields of liquid crystals, interface stabilization, catalysis, supramolecular polymers, and hierarchical materials.
Max ERC Funding
2 499 597 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym 2DNanoSpec
Project Nanoscale Vibrational Spectroscopy of Sensitive 2D Molecular Materials
Researcher (PI) Renato ZENOBI
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Advanced Grant (AdG), PE4, ERC-2016-ADG
Summary I propose to investigate the nanometer scale organization of delicate 2-dimensional molecular materials using nanoscale vibrational spectroscopy. 2D structures are of great scientific and technological importance, for example as novel materials (graphene, MoS2, WS2, etc.), and in the form of biological membranes and synthetic 2D-polymers. Powerful methods for their analysis and imaging with molecular selectivity and sufficient spatial resolution, however, are lacking. Tip-enhanced Raman spectroscopy (TERS) allows label-free spectroscopic identification of molecular species, with ≈10 nm spatial resolution, and with single molecule sensitivity for strong Raman scatterers. So far, however, TERS is not being carried out in liquids, which is the natural environment for membranes, and its application to poor Raman scatterers such as components of 2D polymers, lipids, or other membrane compounds (proteins, sugars) is difficult. TERS has the potential to overcome the restrictions of other optical/spectroscopic methods to study 2D materials, namely (i) insufficient spatial resolution of diffraction-limited optical methods; (ii) the need for labelling for all methods relying on fluorescence; and (iii) the inability of some methods to work in liquids. I propose to address a number of scientific questions associated with the spatial organization, and the occurrence of defects in sensitive 2D molecular materials. The success of these studies will also rely critically on technical innovations of TERS that notably address the problem of energy dissipation. This will for the first time allow its application to study of complex, delicate 2D molecular systems without photochemical damage.
Summary
I propose to investigate the nanometer scale organization of delicate 2-dimensional molecular materials using nanoscale vibrational spectroscopy. 2D structures are of great scientific and technological importance, for example as novel materials (graphene, MoS2, WS2, etc.), and in the form of biological membranes and synthetic 2D-polymers. Powerful methods for their analysis and imaging with molecular selectivity and sufficient spatial resolution, however, are lacking. Tip-enhanced Raman spectroscopy (TERS) allows label-free spectroscopic identification of molecular species, with ≈10 nm spatial resolution, and with single molecule sensitivity for strong Raman scatterers. So far, however, TERS is not being carried out in liquids, which is the natural environment for membranes, and its application to poor Raman scatterers such as components of 2D polymers, lipids, or other membrane compounds (proteins, sugars) is difficult. TERS has the potential to overcome the restrictions of other optical/spectroscopic methods to study 2D materials, namely (i) insufficient spatial resolution of diffraction-limited optical methods; (ii) the need for labelling for all methods relying on fluorescence; and (iii) the inability of some methods to work in liquids. I propose to address a number of scientific questions associated with the spatial organization, and the occurrence of defects in sensitive 2D molecular materials. The success of these studies will also rely critically on technical innovations of TERS that notably address the problem of energy dissipation. This will for the first time allow its application to study of complex, delicate 2D molecular systems without photochemical damage.
Max ERC Funding
2 311 696 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym 3DBrainStrom
Project Brain metastases: Deciphering tumor-stroma interactions in three dimensions for the rational design of nanomedicines
Researcher (PI) Ronit Satchi Fainaro
Host Institution (HI) TEL AVIV UNIVERSITY
Country Israel
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary Brain metastases represent a major therapeutic challenge. Despite significant breakthroughs in targeted therapies, survival rates of patients with brain metastases remain poor. Nowadays, discovery, development and evaluation of new therapies are performed on human cancer cells grown in 2D on rigid plastic plates followed by in vivo testing in immunodeficient mice. These experimental settings are lacking and constitute a fundamental hurdle for the translation of preclinical discoveries into clinical practice. We propose to establish 3D-printed models of brain metastases (Aim 1), which include brain extracellular matrix, stroma and serum containing immune cells flowing in functional tumor vessels. Our unique models better capture the clinical physio-mechanical tissue properties, signaling pathways, hemodynamics and drug responsiveness. Using our 3D-printed models, we aim to develop two new fronts for identifying novel clinically-relevant molecular drivers (Aim 2) followed by the development of precision nanomedicines (Aim 3). We will exploit our vast experience in anticancer nanomedicines to design three therapeutic approaches that target various cellular compartments involved in brain metastases: 1) Prevention of brain metastatic colonization using targeted nano-vaccines, which elicit antitumor immune response; 2) Intervention of tumor-brain stroma cells crosstalk when brain micrometastases establish; 3) Regression of macrometastatic disease by selectively targeting tumor cells. These approaches will materialize using our libraries of polymeric nanocarriers that selectively accumulate in tumors.
This project will result in a paradigm shift by generating new preclinical cancer models that will bridge the translational gap in cancer therapeutics. The insights and tumor-stroma-targeted nanomedicines developed here will pave the way for prediction of patient outcome, revolutionizing our perception of tumor modelling and consequently the way we prevent and treat cancer.
Summary
Brain metastases represent a major therapeutic challenge. Despite significant breakthroughs in targeted therapies, survival rates of patients with brain metastases remain poor. Nowadays, discovery, development and evaluation of new therapies are performed on human cancer cells grown in 2D on rigid plastic plates followed by in vivo testing in immunodeficient mice. These experimental settings are lacking and constitute a fundamental hurdle for the translation of preclinical discoveries into clinical practice. We propose to establish 3D-printed models of brain metastases (Aim 1), which include brain extracellular matrix, stroma and serum containing immune cells flowing in functional tumor vessels. Our unique models better capture the clinical physio-mechanical tissue properties, signaling pathways, hemodynamics and drug responsiveness. Using our 3D-printed models, we aim to develop two new fronts for identifying novel clinically-relevant molecular drivers (Aim 2) followed by the development of precision nanomedicines (Aim 3). We will exploit our vast experience in anticancer nanomedicines to design three therapeutic approaches that target various cellular compartments involved in brain metastases: 1) Prevention of brain metastatic colonization using targeted nano-vaccines, which elicit antitumor immune response; 2) Intervention of tumor-brain stroma cells crosstalk when brain micrometastases establish; 3) Regression of macrometastatic disease by selectively targeting tumor cells. These approaches will materialize using our libraries of polymeric nanocarriers that selectively accumulate in tumors.
This project will result in a paradigm shift by generating new preclinical cancer models that will bridge the translational gap in cancer therapeutics. The insights and tumor-stroma-targeted nanomedicines developed here will pave the way for prediction of patient outcome, revolutionizing our perception of tumor modelling and consequently the way we prevent and treat cancer.
Max ERC Funding
2 353 125 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym 3DIMAGE
Project 3D Imaging Across Lengthscales: From Atoms to Grains
Researcher (PI) Paul Anthony Midgley
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Advanced Grant (AdG), PE4, ERC-2011-ADG_20110209
Summary "Understanding structure-property relationships across lengthscales is key to the design of functional and structural materials and devices. Moreover, the complexity of modern devices extends to three dimensions and as such 3D characterization is required across those lengthscales to provide a complete understanding and enable improvement in the material’s physical and chemical behaviour. 3D imaging and analysis from the atomic scale through to granular microstructure is proposed through the development of electron tomography using (S)TEM, and ‘dual beam’ SEM-FIB, techniques offering complementary approaches to 3D imaging across lengthscales stretching over 5 orders of magnitude.
We propose to extend tomography to include novel methods to determine atom positions in 3D with approaches incorporating new reconstruction algorithms, image processing and complementary nano-diffraction techniques. At the nanoscale, true 3D nano-metrology of morphology and composition is a key objective of the project, minimizing reconstruction and visualization artefacts. Mapping strain and optical properties in 3D are ambitious and exciting challenges that will yield new information at the nanoscale. Using the SEM-FIB, 3D ‘mesoscale’ structures will be revealed: morphology, crystallography and composition can be mapped simultaneously, with ~5nm resolution and over volumes too large to tackle by (S)TEM and too small for most x-ray techniques. In parallel, we will apply 3D imaging to a wide variety of key materials including heterogeneous catalysts, aerospace alloys, biomaterials, photovoltaic materials, and novel semiconductors.
We will collaborate with many departments in Cambridge and institutes worldwide. The personnel on the proposal will cover all aspects of the tomography proposed using high-end TEMs, including an aberration-corrected Titan, and a Helios dual beam. Importantly, a postdoc is dedicated to developing new algorithms for reconstruction, image and spectral processing."
Summary
"Understanding structure-property relationships across lengthscales is key to the design of functional and structural materials and devices. Moreover, the complexity of modern devices extends to three dimensions and as such 3D characterization is required across those lengthscales to provide a complete understanding and enable improvement in the material’s physical and chemical behaviour. 3D imaging and analysis from the atomic scale through to granular microstructure is proposed through the development of electron tomography using (S)TEM, and ‘dual beam’ SEM-FIB, techniques offering complementary approaches to 3D imaging across lengthscales stretching over 5 orders of magnitude.
We propose to extend tomography to include novel methods to determine atom positions in 3D with approaches incorporating new reconstruction algorithms, image processing and complementary nano-diffraction techniques. At the nanoscale, true 3D nano-metrology of morphology and composition is a key objective of the project, minimizing reconstruction and visualization artefacts. Mapping strain and optical properties in 3D are ambitious and exciting challenges that will yield new information at the nanoscale. Using the SEM-FIB, 3D ‘mesoscale’ structures will be revealed: morphology, crystallography and composition can be mapped simultaneously, with ~5nm resolution and over volumes too large to tackle by (S)TEM and too small for most x-ray techniques. In parallel, we will apply 3D imaging to a wide variety of key materials including heterogeneous catalysts, aerospace alloys, biomaterials, photovoltaic materials, and novel semiconductors.
We will collaborate with many departments in Cambridge and institutes worldwide. The personnel on the proposal will cover all aspects of the tomography proposed using high-end TEMs, including an aberration-corrected Titan, and a Helios dual beam. Importantly, a postdoc is dedicated to developing new algorithms for reconstruction, image and spectral processing."
Max ERC Funding
2 337 330 €
Duration
Start date: 2012-01-01, End date: 2017-12-31
Project acronym 3DNANOMECH
Project Three-dimensional molecular resolution mapping of soft matter-liquid interfaces
Researcher (PI) Ricardo Garcia
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Country Spain
Call Details Advanced Grant (AdG), PE4, ERC-2013-ADG
Summary Optical, electron and probe microscopes are enabling tools for discoveries and knowledge generation in nanoscale sicence and technology. High resolution –nanoscale or molecular-, noninvasive and label-free imaging of three-dimensional soft matter-liquid interfaces has not been achieved by any microscopy method.
Force microscopy (AFM) is considered the second most relevant advance in materials science since 1960. Despite its impressive range of applications, the technique has some key limitations. Force microscopy has not three dimensional depth. What lies above or in the subsurface is not readily characterized.
3DNanoMech proposes to design, build and operate a high speed force-based method for the three-dimensional characterization soft matter-liquid interfaces (3D AFM). The microscope will combine a detection method based on force perturbations, adaptive algorithms, high speed piezo actuators and quantitative-oriented multifrequency approaches. The development of the microscope cannot be separated from its applications: imaging the error-free DNA repair and to understand the relationship existing between the nanomechanical properties and the malignancy of cancer cells. Those problems encompass the different spatial –molecular-nano-mesoscopic- and time –milli to seconds- scales of the instrument.
In short, 3DNanoMech aims to image, map and measure with picoNewton, millisecond and angstrom resolution soft matter surfaces and interfaces in liquid. The long-term vision of 3DNanoMech is to replace models or computer animations of bimolecular-liquid interfaces by real time, molecular resolution maps of properties and processes.
Summary
Optical, electron and probe microscopes are enabling tools for discoveries and knowledge generation in nanoscale sicence and technology. High resolution –nanoscale or molecular-, noninvasive and label-free imaging of three-dimensional soft matter-liquid interfaces has not been achieved by any microscopy method.
Force microscopy (AFM) is considered the second most relevant advance in materials science since 1960. Despite its impressive range of applications, the technique has some key limitations. Force microscopy has not three dimensional depth. What lies above or in the subsurface is not readily characterized.
3DNanoMech proposes to design, build and operate a high speed force-based method for the three-dimensional characterization soft matter-liquid interfaces (3D AFM). The microscope will combine a detection method based on force perturbations, adaptive algorithms, high speed piezo actuators and quantitative-oriented multifrequency approaches. The development of the microscope cannot be separated from its applications: imaging the error-free DNA repair and to understand the relationship existing between the nanomechanical properties and the malignancy of cancer cells. Those problems encompass the different spatial –molecular-nano-mesoscopic- and time –milli to seconds- scales of the instrument.
In short, 3DNanoMech aims to image, map and measure with picoNewton, millisecond and angstrom resolution soft matter surfaces and interfaces in liquid. The long-term vision of 3DNanoMech is to replace models or computer animations of bimolecular-liquid interfaces by real time, molecular resolution maps of properties and processes.
Max ERC Funding
2 499 928 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym 4D IMAGING
Project Towards 4D Imaging of Fundamental Processes on the Atomic and Sub-Atomic Scale
Researcher (PI) Ferenc Krausz
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Country Germany
Call Details Advanced Grant (AdG), PE2, ERC-2009-AdG
Summary State-of-the-art microscopy and diffraction imaging provides insight into the atomic and sub-atomic structure of matter. They permit determination of the positions of atoms in a crystal lattice or in a molecule as well as the distribution of electrons inside atoms. State-of-the-art time-resolved spectroscopy with femtosecond and attosecond resolution provides access to dynamic changes in the atomic and electronic structure of matter. Our proposal aims at combining these two frontier techniques of XXI century science to make a long-standing dream of scientist come true: the direct observation of atoms and electrons in their natural state: in motion. Shifts in the atoms positions by tens to hundreds of picometers can make chemical bonds break apart or newly form, changing the structure and/or chemical composition of matter. Electronic motion on similar scales may result in the emission of light, or the initiation of processes that lead to a change in physical or chemical properties, or biological function. These motions happen within femtoseconds and attoseconds, respectively. To make them observable, we need a 4-dimensional (4D) imaging technique capable of recording freeze-frame snapshots of microscopic systems with picometer spatial resolution and femtosecond to attosecond exposure time. The motion can then be visualized by slow-motion replay of the freeze-frame shots. The goal of this project is to develop a 4D imaging technique that will ultimately offer picometer resolution is space and attosecond resolution in time.
Summary
State-of-the-art microscopy and diffraction imaging provides insight into the atomic and sub-atomic structure of matter. They permit determination of the positions of atoms in a crystal lattice or in a molecule as well as the distribution of electrons inside atoms. State-of-the-art time-resolved spectroscopy with femtosecond and attosecond resolution provides access to dynamic changes in the atomic and electronic structure of matter. Our proposal aims at combining these two frontier techniques of XXI century science to make a long-standing dream of scientist come true: the direct observation of atoms and electrons in their natural state: in motion. Shifts in the atoms positions by tens to hundreds of picometers can make chemical bonds break apart or newly form, changing the structure and/or chemical composition of matter. Electronic motion on similar scales may result in the emission of light, or the initiation of processes that lead to a change in physical or chemical properties, or biological function. These motions happen within femtoseconds and attoseconds, respectively. To make them observable, we need a 4-dimensional (4D) imaging technique capable of recording freeze-frame snapshots of microscopic systems with picometer spatial resolution and femtosecond to attosecond exposure time. The motion can then be visualized by slow-motion replay of the freeze-frame shots. The goal of this project is to develop a 4D imaging technique that will ultimately offer picometer resolution is space and attosecond resolution in time.
Max ERC Funding
2 500 000 €
Duration
Start date: 2010-03-01, End date: 2015-02-28
Project acronym 4D-PET
Project Innovative PET scanner for dynamic imaging
Researcher (PI) Jose MarIa BENLLOCH BAVIERA
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Country Spain
Call Details Advanced Grant (AdG), LS7, ERC-2015-AdG
Summary The main objective of 4D-PET is to develop an innovative whole-body PET scanner based in a new detector concept that stores 3D position and time of every single gamma interaction with unprecedented resolution. The combination of scanner geometrical design and high timing resolution will enable developing a full sequence of all gamma-ray interactions inside the scanner, including Compton interactions, like in a 3D movie. 4D-PET fully exploits Time Of Flight (TOF) information to obtain a better image quality and to increase scanner sensitivity, through the inclusion in the image formation of all Compton events occurring inside the detector, which are always rejected in state-of-the-art PET scanners. The new PET design will radically improve state-of-the-art PET performance features, overcoming limitations of current PET technology and opening up new diagnostic venues and very valuable physiological information
Summary
The main objective of 4D-PET is to develop an innovative whole-body PET scanner based in a new detector concept that stores 3D position and time of every single gamma interaction with unprecedented resolution. The combination of scanner geometrical design and high timing resolution will enable developing a full sequence of all gamma-ray interactions inside the scanner, including Compton interactions, like in a 3D movie. 4D-PET fully exploits Time Of Flight (TOF) information to obtain a better image quality and to increase scanner sensitivity, through the inclusion in the image formation of all Compton events occurring inside the detector, which are always rejected in state-of-the-art PET scanners. The new PET design will radically improve state-of-the-art PET performance features, overcoming limitations of current PET technology and opening up new diagnostic venues and very valuable physiological information
Max ERC Funding
2 048 386 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym 4DBIOSERS
Project Four-Dimensional Monitoring of Tumour Growth by Surface Enhanced Raman Scattering
Researcher (PI) Luis LIZ-MARZAN
Host Institution (HI) ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOMATERIALES- CIC biomaGUNE
Country Spain
Call Details Advanced Grant (AdG), PE5, ERC-2017-ADG
Summary Optical bioimaging is limited by visible light penetration depth and stability of fluorescent dyes over extended periods of time. Surface enhanced Raman scattering (SERS) offers the possibility to overcome these drawbacks, through SERS-encoded nanoparticle tags, which can be excited with near-IR light (within the biological transparency window), providing high intensity, stable, multiplexed signals. SERS can also be used to monitor relevant bioanalytes within cells and tissues, during the development of diseases, such as tumours. In 4DBIOSERS we shall combine both capabilities of SERS, to go well beyond the current state of the art, by building three-dimensional scaffolds that support tissue (tumour) growth within a controlled environment, so that not only the fate of each (SERS-labelled) cell within the tumour can be monitored in real time (thus adding a fourth dimension to SERS bioimaging), but also recording the release of tumour metabolites and other indicators of cellular activity. Although 4DBIOSERS can be applied to a variety of diseases, we shall focus on cancer, melanoma and breast cancer in particular, as these are readily accessible by optical methods. We aim at acquiring a better understanding of tumour growth and dynamics, while avoiding animal experimentation. 3D printing will be used to generate hybrid scaffolds where tumour and healthy cells will be co-incubated to simulate a more realistic environment, thus going well beyond the potential of 2D cell cultures. Each cell type will be encoded with ultra-bright SERS tags, so that real-time monitoring can be achieved by confocal SERS microscopy. Tumour development will be correlated with simultaneous detection of various cancer biomarkers, during standard conditions and upon addition of selected drugs. The scope of 4DBIOSERS is multidisciplinary, as it involves the design of high-end nanocomposites, development of 3D cell culture models and optimization of emerging SERS tomography methods.
Summary
Optical bioimaging is limited by visible light penetration depth and stability of fluorescent dyes over extended periods of time. Surface enhanced Raman scattering (SERS) offers the possibility to overcome these drawbacks, through SERS-encoded nanoparticle tags, which can be excited with near-IR light (within the biological transparency window), providing high intensity, stable, multiplexed signals. SERS can also be used to monitor relevant bioanalytes within cells and tissues, during the development of diseases, such as tumours. In 4DBIOSERS we shall combine both capabilities of SERS, to go well beyond the current state of the art, by building three-dimensional scaffolds that support tissue (tumour) growth within a controlled environment, so that not only the fate of each (SERS-labelled) cell within the tumour can be monitored in real time (thus adding a fourth dimension to SERS bioimaging), but also recording the release of tumour metabolites and other indicators of cellular activity. Although 4DBIOSERS can be applied to a variety of diseases, we shall focus on cancer, melanoma and breast cancer in particular, as these are readily accessible by optical methods. We aim at acquiring a better understanding of tumour growth and dynamics, while avoiding animal experimentation. 3D printing will be used to generate hybrid scaffolds where tumour and healthy cells will be co-incubated to simulate a more realistic environment, thus going well beyond the potential of 2D cell cultures. Each cell type will be encoded with ultra-bright SERS tags, so that real-time monitoring can be achieved by confocal SERS microscopy. Tumour development will be correlated with simultaneous detection of various cancer biomarkers, during standard conditions and upon addition of selected drugs. The scope of 4DBIOSERS is multidisciplinary, as it involves the design of high-end nanocomposites, development of 3D cell culture models and optimization of emerging SERS tomography methods.
Max ERC Funding
2 410 771 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym 5D Heart Patch
Project A Functional, Mature In vivo Human Ventricular Muscle Patch for Cardiomyopathy
Researcher (PI) Kenneth Randall Chien
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy
Summary
Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy
Max ERC Funding
2 149 228 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
Project acronym 5HT-OPTOGENETICS
Project Optogenetic Analysis of Serotonin Function in the Mammalian Brain
Researcher (PI) Zachary Mainen
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Country Portugal
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary Serotonin (5-HT) is implicated in a wide spectrum of brain functions and disorders. However, its functions remain controversial and enigmatic. We suggest that past work on the 5-HT system have been significantly hampered by technical limitations in the selectivity and temporal resolution of the conventional pharmacological and electrophysiological methods that have been applied. We therefore propose to apply novel optogenetic methods that will allow us to overcome these limitations and thereby gain new insight into the biological functions of this important molecule. In preliminary studies, we have demonstrated that we can deliver exogenous proteins specifically to 5-HT neurons using viral vectors. Our objectives are to (1) record, (2) stimulate and (3) silence the activity of 5-HT neurons with high molecular selectivity and temporal precision by using genetically-encoded sensors, activators and inhibitors of neural function. These tools will allow us to monitor and control the 5-HT system in real-time in freely-behaving animals and thereby to establish causal links between information processing in 5-HT neurons and specific behaviors. In combination with quantitative behavioral assays, we will use this approach to define the role of 5-HT in sensory, motor and cognitive functions. The significance of the work is three-fold. First, we will establish a new arsenal of tools for probing the physiological and behavioral functions of 5-HT neurons. Second, we will make definitive tests of major hypotheses of 5-HT function. Third, we will have possible therapeutic applications. In this way, the proposed work has the potential for a major impact in research on the role of 5-HT in brain function and dysfunction.
Summary
Serotonin (5-HT) is implicated in a wide spectrum of brain functions and disorders. However, its functions remain controversial and enigmatic. We suggest that past work on the 5-HT system have been significantly hampered by technical limitations in the selectivity and temporal resolution of the conventional pharmacological and electrophysiological methods that have been applied. We therefore propose to apply novel optogenetic methods that will allow us to overcome these limitations and thereby gain new insight into the biological functions of this important molecule. In preliminary studies, we have demonstrated that we can deliver exogenous proteins specifically to 5-HT neurons using viral vectors. Our objectives are to (1) record, (2) stimulate and (3) silence the activity of 5-HT neurons with high molecular selectivity and temporal precision by using genetically-encoded sensors, activators and inhibitors of neural function. These tools will allow us to monitor and control the 5-HT system in real-time in freely-behaving animals and thereby to establish causal links between information processing in 5-HT neurons and specific behaviors. In combination with quantitative behavioral assays, we will use this approach to define the role of 5-HT in sensory, motor and cognitive functions. The significance of the work is three-fold. First, we will establish a new arsenal of tools for probing the physiological and behavioral functions of 5-HT neurons. Second, we will make definitive tests of major hypotheses of 5-HT function. Third, we will have possible therapeutic applications. In this way, the proposed work has the potential for a major impact in research on the role of 5-HT in brain function and dysfunction.
Max ERC Funding
2 318 636 €
Duration
Start date: 2010-07-01, End date: 2015-12-31