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 ANDLICA
Project Anderson Localization of Light by Cold Atoms
Researcher (PI) Robin KAISER
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Advanced Grant (AdG), PE2, ERC-2018-ADG
Summary I propose to use large clouds of cold Ytterbium atoms to observe Anderson localization of light in three dimensions, which has challenged theoreticians and experimentalists for many decades.
After the prediction by Anderson of a disorder-induced conductor to insulator transition for electrons, light has been proposed as ideal non interacting waves to explore coherent transport properties in the absence of interactions. The development in experiments and theory over the past several years have shown a route towards the experimental realization of this phase transition.
Previous studies on Anderson localization of light using semiconductor powders or dielectric particles have shown that intrinsic material properties, such as absorption or inelastic scattering of light, need to be taken into account in the interpretation of experimental signatures of Anderson localization. Laser-cooled clouds of atoms avoid the problems of samples used so far to study Anderson localization of light. Ab initio theoretical models, available for cold Ytterbium atoms, have shown that the mere high spatial density of the scattering sample is not sufficient to allow for Anderson localization of photons in three dimensions, but that an additional magnetic field or additional disorder on the level shifts can induce a phase transition in three dimensions.
The role of disorder in atom-light interactions has important consequences for the next generation of high precision atomic clocks and quantum memories. By connecting the mesoscopic physics approach to quantum optics and cooperative scattering, this project will allow better control of cold atoms as building blocks of future quantum technologies. Time-resolved transport experiments will connect super- and subradiant assisted transmission with the extended and localized eigenstates of the system.
Having pioneered studies on weak localization and cooperative scattering enables me to diagnostic strong localization of light by cold atoms.
Summary
I propose to use large clouds of cold Ytterbium atoms to observe Anderson localization of light in three dimensions, which has challenged theoreticians and experimentalists for many decades.
After the prediction by Anderson of a disorder-induced conductor to insulator transition for electrons, light has been proposed as ideal non interacting waves to explore coherent transport properties in the absence of interactions. The development in experiments and theory over the past several years have shown a route towards the experimental realization of this phase transition.
Previous studies on Anderson localization of light using semiconductor powders or dielectric particles have shown that intrinsic material properties, such as absorption or inelastic scattering of light, need to be taken into account in the interpretation of experimental signatures of Anderson localization. Laser-cooled clouds of atoms avoid the problems of samples used so far to study Anderson localization of light. Ab initio theoretical models, available for cold Ytterbium atoms, have shown that the mere high spatial density of the scattering sample is not sufficient to allow for Anderson localization of photons in three dimensions, but that an additional magnetic field or additional disorder on the level shifts can induce a phase transition in three dimensions.
The role of disorder in atom-light interactions has important consequences for the next generation of high precision atomic clocks and quantum memories. By connecting the mesoscopic physics approach to quantum optics and cooperative scattering, this project will allow better control of cold atoms as building blocks of future quantum technologies. Time-resolved transport experiments will connect super- and subradiant assisted transmission with the extended and localized eigenstates of the system.
Having pioneered studies on weak localization and cooperative scattering enables me to diagnostic strong localization of light by cold atoms.
Max ERC Funding
2 490 717 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym ARTimmune
Project Programmable ARTificial immune systems to fight cancer
Researcher (PI) Carl FIGDOR
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Country Netherlands
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary Immunotherapy has entered centre stage as a novel treatment modality for cancer. Notwithstanding this major step forward, toxicity and immunosuppression remain major obstacles, and illustrate the pressing need for more powerful and specific immunotherapies against cancer. To overcome these roadblocks, in ARTimmune, I propose to follow a radically different approach by developing local rather than systemic immunotherapies. Taking advantage of the architecture of a lymph node (LN), I aim to design fully synthetic immune niches to locally instruct immune cell function. I hypothesize that programmable synthetic immune niches, when injected next to a tumour, will act as local powerhouses to generate bursts of cytotoxic T cells for tumour destruction, without toxic side effects. Single cell transcriptomics on LN, obtained from patients that are vaccinated against cancer, will provide unique insight in communication within immune cell clusters and provide a blueprint for the intelligent design of synthetic immune niches. Chemical tools will be used to build branched polymeric structures decorated with immunomodulating molecules to mimic LN architecture. These will be injected, mixed with sponge-like scaffolds to provide porosity needed for immune cell infiltration. Programming of immune cell function will be accomplished by in vivo targeting- and proteolytic activation- of immunomodulators for fine-tuning, and to extend the life span of these local powerhouses. The innovative character of ARTimmune comes from: 1) novel fundamental immunological insight in complex communication within LN cell clusters, 2) a revolutionary new approach in immunotherapy, by the development of 3) injectable- and 4) programmable- synthetic immune niches by state-of-the-art chemical technology. When successful, it will revolutionize cancer immunotherapy, moving from maximal tolerable dose systemic treatment with significant toxicity to local low dose treatment in the direct vicinity of a tumour
Summary
Immunotherapy has entered centre stage as a novel treatment modality for cancer. Notwithstanding this major step forward, toxicity and immunosuppression remain major obstacles, and illustrate the pressing need for more powerful and specific immunotherapies against cancer. To overcome these roadblocks, in ARTimmune, I propose to follow a radically different approach by developing local rather than systemic immunotherapies. Taking advantage of the architecture of a lymph node (LN), I aim to design fully synthetic immune niches to locally instruct immune cell function. I hypothesize that programmable synthetic immune niches, when injected next to a tumour, will act as local powerhouses to generate bursts of cytotoxic T cells for tumour destruction, without toxic side effects. Single cell transcriptomics on LN, obtained from patients that are vaccinated against cancer, will provide unique insight in communication within immune cell clusters and provide a blueprint for the intelligent design of synthetic immune niches. Chemical tools will be used to build branched polymeric structures decorated with immunomodulating molecules to mimic LN architecture. These will be injected, mixed with sponge-like scaffolds to provide porosity needed for immune cell infiltration. Programming of immune cell function will be accomplished by in vivo targeting- and proteolytic activation- of immunomodulators for fine-tuning, and to extend the life span of these local powerhouses. The innovative character of ARTimmune comes from: 1) novel fundamental immunological insight in complex communication within LN cell clusters, 2) a revolutionary new approach in immunotherapy, by the development of 3) injectable- and 4) programmable- synthetic immune niches by state-of-the-art chemical technology. When successful, it will revolutionize cancer immunotherapy, moving from maximal tolerable dose systemic treatment with significant toxicity to local low dose treatment in the direct vicinity of a tumour
Max ERC Funding
2 500 000 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
Project acronym AsthmaVir
Project The roles of innate lymphoid cells and rhinovirus in asthma exacerbations
Researcher (PI) Hergen Spits
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Country Netherlands
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.
Summary
Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.
Max ERC Funding
2 499 593 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym AtomicGaugeSimulator
Project Classical and Atomic Quantum Simulation of Gauge Theories in Particle and Condensed Matter Physics
Researcher (PI) Uwe-Jens Richard Christian Wiese
Host Institution (HI) UNIVERSITAET BERN
Country Switzerland
Call Details Advanced Grant (AdG), PE2, ERC-2013-ADG
Summary Gauge theories play a central role in particle and condensed matter physics. Heavy-ion collisions explore the strong dynamics of quarks and gluons, which also governs the deep interior of neutron stars, while strongly correlated electrons determine the physics of high-temperature superconductors and spin liquids. Numerical simulations of such systems are often hindered by sign problems. In quantum link models - an alternative formulation of gauge theories developed by the applicant - gauge fields emerge from discrete quantum variables. In the past year, in close collaboration with atomic physicists, we have established quantum link models as a framework for the atomic quantum simulation of dynamical gauge fields. Abelian gauge theories can be realized with Bose-Fermi mixtures of ultracold atoms in an optical lattice, while non-Abelian gauge fields arise from fermionic constituents embodied by alkaline-earth atoms. Quantum simulators, which do not suffer from the sign problem, shall be constructed to address non-trivial dynamics, including quantum phase transitions in spin liquids, the real-time dynamics of confining strings as well as of chiral symmetry restoration at finite temperature and baryon density, baryon superfluidity, or color-flavor locking. New classical simulation algorithms shall be developed in order to solve severe sign problems, to investigate confining gauge theories, and to validate the proposed quantum simulators. Starting from U(1) and SU(2) gauge theories, an atomic physics tool box shall be developed for quantum simulation of gauge theories of increasing complexity, ultimately aiming at 4-d Quantum Chromodynamics (QCD). This project is based on innovative ideas from particle, condensed matter, and computational physics, and requires an interdisciplinary team of researchers. It has the potential to drastically increase the power of simulations and to address very challenging problems that cannot be solved with classical simulation methods.
Summary
Gauge theories play a central role in particle and condensed matter physics. Heavy-ion collisions explore the strong dynamics of quarks and gluons, which also governs the deep interior of neutron stars, while strongly correlated electrons determine the physics of high-temperature superconductors and spin liquids. Numerical simulations of such systems are often hindered by sign problems. In quantum link models - an alternative formulation of gauge theories developed by the applicant - gauge fields emerge from discrete quantum variables. In the past year, in close collaboration with atomic physicists, we have established quantum link models as a framework for the atomic quantum simulation of dynamical gauge fields. Abelian gauge theories can be realized with Bose-Fermi mixtures of ultracold atoms in an optical lattice, while non-Abelian gauge fields arise from fermionic constituents embodied by alkaline-earth atoms. Quantum simulators, which do not suffer from the sign problem, shall be constructed to address non-trivial dynamics, including quantum phase transitions in spin liquids, the real-time dynamics of confining strings as well as of chiral symmetry restoration at finite temperature and baryon density, baryon superfluidity, or color-flavor locking. New classical simulation algorithms shall be developed in order to solve severe sign problems, to investigate confining gauge theories, and to validate the proposed quantum simulators. Starting from U(1) and SU(2) gauge theories, an atomic physics tool box shall be developed for quantum simulation of gauge theories of increasing complexity, ultimately aiming at 4-d Quantum Chromodynamics (QCD). This project is based on innovative ideas from particle, condensed matter, and computational physics, and requires an interdisciplinary team of researchers. It has the potential to drastically increase the power of simulations and to address very challenging problems that cannot be solved with classical simulation methods.
Max ERC Funding
1 975 242 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym BACTERIAL RESPONSE
Project New Concepts in Bacterial Response to their Surroundings
Researcher (PI) Sigal Ben-Yehuda
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary Bacteria in nature exhibit remarkable capacity to sense their surroundings and rapidly adapt to diverse conditions by gaining new beneficial traits. This extraordinary feature facilitates their survival when facing extreme environments. Utilizing Bacillus subtilis as our primary model organism, we propose to study two facets of this vital bacterial attribute: communication via extracellular nanotubes, and persistence as resilient spores while maintaining the potential to revive. Exploring these fascinating aspects of bacterial physiology is likely to change our view as to how bacteria sense, respond, endure and communicate with their extracellular environment.
We have recently discovered a previously uncharacterized mode of bacterial communication, mediated by tubular extensions (nanotubes) that bridge neighboring cells, providing a route for exchange of intracellular molecules. Nanotube-mediated molecular sharing may represent a key form of bacterial communication in nature, allowing for the emergence of new phenotypes and increasing survival in fluctuating environments. Here we propose to develop strategies for observing nanotube formation and molecular exchange in living bacterial cells, and to characterize the molecular composition of nanotubes. We will explore the premise that nanotubes serve as a strategy to expand the cell surface, and will determine whether nanotubes provide a conduit for phage infection and spreading. Furthermore, the formation and functionality of interspecies nanotubes will be explored. An additional mode employed by bacteria to achieve extreme robustness is the ability to reside as long lasting spores. Previously held views considered the spore to be dormant and metabolically inert. However, we have recently shown that at least one week following spore formation, during an adaptive period, the spore senses and responds to environmental cues and undergoes corresponding molecular changes, influencing subsequent emergence from quiescence.
Summary
Bacteria in nature exhibit remarkable capacity to sense their surroundings and rapidly adapt to diverse conditions by gaining new beneficial traits. This extraordinary feature facilitates their survival when facing extreme environments. Utilizing Bacillus subtilis as our primary model organism, we propose to study two facets of this vital bacterial attribute: communication via extracellular nanotubes, and persistence as resilient spores while maintaining the potential to revive. Exploring these fascinating aspects of bacterial physiology is likely to change our view as to how bacteria sense, respond, endure and communicate with their extracellular environment.
We have recently discovered a previously uncharacterized mode of bacterial communication, mediated by tubular extensions (nanotubes) that bridge neighboring cells, providing a route for exchange of intracellular molecules. Nanotube-mediated molecular sharing may represent a key form of bacterial communication in nature, allowing for the emergence of new phenotypes and increasing survival in fluctuating environments. Here we propose to develop strategies for observing nanotube formation and molecular exchange in living bacterial cells, and to characterize the molecular composition of nanotubes. We will explore the premise that nanotubes serve as a strategy to expand the cell surface, and will determine whether nanotubes provide a conduit for phage infection and spreading. Furthermore, the formation and functionality of interspecies nanotubes will be explored. An additional mode employed by bacteria to achieve extreme robustness is the ability to reside as long lasting spores. Previously held views considered the spore to be dormant and metabolically inert. However, we have recently shown that at least one week following spore formation, during an adaptive period, the spore senses and responds to environmental cues and undergoes corresponding molecular changes, influencing subsequent emergence from quiescence.
Max ERC Funding
1 497 800 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym BARCODE
Project The use of genetic profiling to guide prostate cancer targeted screening and cancer care
Researcher (PI) Rosalind Anne Eeles
Host Institution (HI) THE INSTITUTE OF CANCER RESEARCH: ROYAL CANCER HOSPITAL
Country United Kingdom
Call Details Advanced Grant (AdG), LS7, ERC-2013-ADG
Summary "Prostate cancer is the commonest solid cancer in men in the European Community. There is evidence for genetic predisposition to the development of prostate cancer and our group has found the largest number of such genetic variants described to date worldwide. The next challenge is to harness these discoveries to advance the clinical care of populations and prostate cancer patients to improve screening and target treatments. This proposal, BARCODE, aims to be ground-breaking in this area. BARCODE has two components (1) to profile a population in England using the current 77 genetic variant profile and compare screening outcomes with those from population based screening studies to determine if genetics can target screening more effectively in this disease by identifying prostate cancer that more often needs treatment and (2) genetically profiling men with prostate cancer in the uro-oncology clinic for a panel of genes which predict for worse outcome so that these men can be offered more intensive staging and treatment within clinical trials. This will use next generation sequencing technology using a barcoding system which we have developed to speed up throughput and reduce costs. The PI will spend 35% of her time on this project and she will not charge for her time spent on this grant as she is funded by The University of London UK. The research team at The Institute Of Cancer Research, London, UK is a multidisciplinary team which leads the field of genetic predisposition to prostate cancer and its clinical application and so is well placed to deliver on this research. This application will have a dramatic impact on other researchers as it is ground –breaking and state of the art in its application of genetic findings to public health and cancer care. It will therefore influence the work being undertaken in both these areas to integrate genetic profiling and gene panel analysis into population screening and cancer care respectively."
Summary
"Prostate cancer is the commonest solid cancer in men in the European Community. There is evidence for genetic predisposition to the development of prostate cancer and our group has found the largest number of such genetic variants described to date worldwide. The next challenge is to harness these discoveries to advance the clinical care of populations and prostate cancer patients to improve screening and target treatments. This proposal, BARCODE, aims to be ground-breaking in this area. BARCODE has two components (1) to profile a population in England using the current 77 genetic variant profile and compare screening outcomes with those from population based screening studies to determine if genetics can target screening more effectively in this disease by identifying prostate cancer that more often needs treatment and (2) genetically profiling men with prostate cancer in the uro-oncology clinic for a panel of genes which predict for worse outcome so that these men can be offered more intensive staging and treatment within clinical trials. This will use next generation sequencing technology using a barcoding system which we have developed to speed up throughput and reduce costs. The PI will spend 35% of her time on this project and she will not charge for her time spent on this grant as she is funded by The University of London UK. The research team at The Institute Of Cancer Research, London, UK is a multidisciplinary team which leads the field of genetic predisposition to prostate cancer and its clinical application and so is well placed to deliver on this research. This application will have a dramatic impact on other researchers as it is ground –breaking and state of the art in its application of genetic findings to public health and cancer care. It will therefore influence the work being undertaken in both these areas to integrate genetic profiling and gene panel analysis into population screening and cancer care respectively."
Max ERC Funding
2 499 123 €
Duration
Start date: 2014-10-01, End date: 2019-09-30
Project acronym BEEHIVE
Project Bridging the Evolution and Epidemiology of HIV in Europe
Researcher (PI) Christopher Fraser
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Advanced Grant (AdG), LS2, ERC-2013-ADG
Summary The aim of the BEEHIVE project is to generate novel insight into HIV biology, evolution and epidemiology, leveraging next-generation high-throughput sequencing and bioinformatics to produce and analyse whole-genomes of viruses from approximately 3,000 European HIV-1 infected patients. These patients have known dates of infection spread over the last 25 years, good clinical follow up, and a wide range of clinical prognostic indicators and outcomes. The primary objective is to discover the viral genetic determinants of severity of infection and set-point viral load. This primary objective is high-risk & blue-skies: there is ample indirect evidence of polymorphisms that alter virulence, but they have never been identified, and it is not known how easy they are to discover. However, the project is also high-reward: it could lead to a substantial shift in the understanding of HIV disease.
Technologically, the BEEHIVE project will deliver new approaches for undertaking whole genome association studies on RNA viruses, including delivering an innovative high-throughput bioinformatics pipeline for handling genetically diverse viral quasi-species data (with viral diversity both within and between infected patients).
The project also includes secondary and tertiary objectives that address critical open questions in HIV epidemiology and evolution. The secondary objective is to use viral genetic sequences allied to mathematical epidemic models to better understand the resurgent European epidemic amongst high-risk groups, especially men who have sex with men. The aim will not just be to establish who is at risk of infection, which is known from conventional epidemiological approaches, but also to characterise the risk factors for onwards transmission of the virus. Tertiary objectives involve understanding the relationship between the genetic diversity within viral samples, indicative of on-going evolution or dual infections, to clinical outcomes.
Summary
The aim of the BEEHIVE project is to generate novel insight into HIV biology, evolution and epidemiology, leveraging next-generation high-throughput sequencing and bioinformatics to produce and analyse whole-genomes of viruses from approximately 3,000 European HIV-1 infected patients. These patients have known dates of infection spread over the last 25 years, good clinical follow up, and a wide range of clinical prognostic indicators and outcomes. The primary objective is to discover the viral genetic determinants of severity of infection and set-point viral load. This primary objective is high-risk & blue-skies: there is ample indirect evidence of polymorphisms that alter virulence, but they have never been identified, and it is not known how easy they are to discover. However, the project is also high-reward: it could lead to a substantial shift in the understanding of HIV disease.
Technologically, the BEEHIVE project will deliver new approaches for undertaking whole genome association studies on RNA viruses, including delivering an innovative high-throughput bioinformatics pipeline for handling genetically diverse viral quasi-species data (with viral diversity both within and between infected patients).
The project also includes secondary and tertiary objectives that address critical open questions in HIV epidemiology and evolution. The secondary objective is to use viral genetic sequences allied to mathematical epidemic models to better understand the resurgent European epidemic amongst high-risk groups, especially men who have sex with men. The aim will not just be to establish who is at risk of infection, which is known from conventional epidemiological approaches, but also to characterise the risk factors for onwards transmission of the virus. Tertiary objectives involve understanding the relationship between the genetic diversity within viral samples, indicative of on-going evolution or dual infections, to clinical outcomes.
Max ERC Funding
2 499 739 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym Bio-Phononics
Project Advanced Microfluidics & Diagnostics using Acoustic Holograms – Bio-Phononics
Researcher (PI) Jonathan Cooper
Host Institution (HI) UNIVERSITY OF GLASGOW
Country United Kingdom
Call Details Advanced Grant (AdG), LS7, ERC-2013-ADG
Summary This proposal seeks to develop a novel technique for fluid and particle manipulations, based upon exploiting the mechanical interactions between acoustic waves and phononic. The new platform involves generating surface acoustic waves (SAWs) on piezoelectric chips, but, unlike previous work, the ultrasonic waves are first coupled into a phononic lattice, which is placed in the path of the ultrasonic wave. The phononic lattice comprises a miniaturised array of mechanical elements which modulates the sound in a manner analogous to how light is “patterned” using a hologram. However, whilst in an optical hologram, the pattern is created by exploiting the differences in refractive indices of the elements of the structure, here the ultrasonic field is modulated both by the elastic contrast between the elements in the array, as well as by the dimensions of the array and its surrounding matrix (including the size and pitch of the features within the array). The result of passing the acoustic wave through a phononic crystal is the formation of new and complex ultrasonic landscapes.
As part of the proposed work we aim to understand the physics of this technology and to exploit its development in a range of medical devices. We will show that by using phononic crystals it is possible to create highly controllable patterns of acoustic field intensities, which propagate into the fluid, creating pressure differences that result in unique flow patterns to enable a new platform for including biological sample processing, medical diagnostics, drug delivery and blood clotting devices – all on low cost disposable devices. Different frequencies of ultrasound will interact with different phononic structures to give different functions, providing a toolbox of different functions. Just as in electronics, where discrete components are combined to create circuits, so we propose to combine different phononic lattices to create fluidic microcircuits with important new applications.
Summary
This proposal seeks to develop a novel technique for fluid and particle manipulations, based upon exploiting the mechanical interactions between acoustic waves and phononic. The new platform involves generating surface acoustic waves (SAWs) on piezoelectric chips, but, unlike previous work, the ultrasonic waves are first coupled into a phononic lattice, which is placed in the path of the ultrasonic wave. The phononic lattice comprises a miniaturised array of mechanical elements which modulates the sound in a manner analogous to how light is “patterned” using a hologram. However, whilst in an optical hologram, the pattern is created by exploiting the differences in refractive indices of the elements of the structure, here the ultrasonic field is modulated both by the elastic contrast between the elements in the array, as well as by the dimensions of the array and its surrounding matrix (including the size and pitch of the features within the array). The result of passing the acoustic wave through a phononic crystal is the formation of new and complex ultrasonic landscapes.
As part of the proposed work we aim to understand the physics of this technology and to exploit its development in a range of medical devices. We will show that by using phononic crystals it is possible to create highly controllable patterns of acoustic field intensities, which propagate into the fluid, creating pressure differences that result in unique flow patterns to enable a new platform for including biological sample processing, medical diagnostics, drug delivery and blood clotting devices – all on low cost disposable devices. Different frequencies of ultrasound will interact with different phononic structures to give different functions, providing a toolbox of different functions. Just as in electronics, where discrete components are combined to create circuits, so we propose to combine different phononic lattices to create fluidic microcircuits with important new applications.
Max ERC Funding
2 208 594 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym CAN-IT-BARRIERS
Project Disruption of systemic and microenvironmental barriers to immunotherapy of antigenic tumors
Researcher (PI) Douglas HANAHAN
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary The frontier in cancer therapy of orchestrating the immune system to attack tumors is producing unprecedented survival benefit in some patients. The corollary is lack of efficacy both in ostensibly responsive tumor types as well as others that are mostly non-responsive. The basis lies in pre-existing and adaptive resistance mechanisms that circumvent induction of tumor-reactive cytotoxic T cells (CTLs) capable of infiltrating solid tumors and eliminating cancer cells. A priori, cancers induced by expression of human papillomavirus oncogenes should be responsive to immunotherapy: these cancers encode immunogenic neo-antigens – the oncoproteins E6/7 – necessary for their manifestation. Rather, such tumors are poorly responsive to immunotherapies. Results from my lab and others using mouse models of HPV-induced cancer have established an actionable hypothesis: during tumorigenesis, such tumors erect multiple barriers to the induction, infiltration, and killing of cancer cells by tumor antigen-reactive CTLs. These include overarching systemic antigen-nonspecific immunosuppression mediated by expanded populations of myeloid cells in spleen and lymph nodes, complemented by immune response-impairing barriers operative in the tumor microenvironment. A spectrum of models will probe these barriers, genetically and pharmacologically, establishing their functional importance, alone and in concert. A major focus will be on how oncogene-expressing keratinocytes elicit a marked expansion of immunosuppressive myeloid cells in spleen and lymph nodes, and how these myeloid cells in turn inhibit development and activation of CD8 T cells and antigen-presenting dendritic cells. Then we’ll assess the therapeutic potential of barrier-breaking strategies combined with immuno-stimulatory modalities. This project will deliver new knowledge about multi-faceted barriers to immunotherapy in these refractory cancers, helping lay the groundwork for efficacious immunotherapy.
Summary
The frontier in cancer therapy of orchestrating the immune system to attack tumors is producing unprecedented survival benefit in some patients. The corollary is lack of efficacy both in ostensibly responsive tumor types as well as others that are mostly non-responsive. The basis lies in pre-existing and adaptive resistance mechanisms that circumvent induction of tumor-reactive cytotoxic T cells (CTLs) capable of infiltrating solid tumors and eliminating cancer cells. A priori, cancers induced by expression of human papillomavirus oncogenes should be responsive to immunotherapy: these cancers encode immunogenic neo-antigens – the oncoproteins E6/7 – necessary for their manifestation. Rather, such tumors are poorly responsive to immunotherapies. Results from my lab and others using mouse models of HPV-induced cancer have established an actionable hypothesis: during tumorigenesis, such tumors erect multiple barriers to the induction, infiltration, and killing of cancer cells by tumor antigen-reactive CTLs. These include overarching systemic antigen-nonspecific immunosuppression mediated by expanded populations of myeloid cells in spleen and lymph nodes, complemented by immune response-impairing barriers operative in the tumor microenvironment. A spectrum of models will probe these barriers, genetically and pharmacologically, establishing their functional importance, alone and in concert. A major focus will be on how oncogene-expressing keratinocytes elicit a marked expansion of immunosuppressive myeloid cells in spleen and lymph nodes, and how these myeloid cells in turn inhibit development and activation of CD8 T cells and antigen-presenting dendritic cells. Then we’ll assess the therapeutic potential of barrier-breaking strategies combined with immuno-stimulatory modalities. This project will deliver new knowledge about multi-faceted barriers to immunotherapy in these refractory cancers, helping lay the groundwork for efficacious immunotherapy.
Max ERC Funding
2 500 000 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
