Project acronym 1stProposal
Project An alternative development of analytic number theory and applications
Researcher (PI) ANDREW Granville
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), PE1, ERC-2014-ADG
Summary The traditional (Riemann) approach to analytic number theory uses the zeros of zeta functions. This requires the associated multiplicative function, say f(n), to have special enough properties that the associated Dirichlet series may be analytically continued. In this proposal we continue to develop an approach which requires less of the multiplicative function, linking the original question with the mean value of f. Such techniques have been around for a long time but have generally been regarded as “ad hoc”. In this project we aim to show that one can develop a coherent approach to the whole subject, not only reproving all of the old results, but also many new ones that appear inaccessible to traditional methods.
Our first goal is to complete a monograph yielding a reworking of all the classical theory using these new methods and then to push forward in new directions. The most important is to extend these techniques to GL(n) L-functions, which we hope will now be feasible having found the correct framework in which to proceed. Since we rarely know how to analytically continue such L-functions this could be of great benefit to the subject.
We are developing the large sieve so that it can be used for individual moduli, and will determine a strong form of that. Also a new method to give asymptotics for mean values, when they are not too small.
We wish to incorporate techniques of analytic number theory into our theory, for example recent advances on mean values of Dirichlet polynomials. Also the recent breakthroughs on the sieve suggest strong links that need further exploration.
Additive combinatorics yields important results in many areas. There are strong analogies between its results, and those for multiplicative functions, especially in large value spectrum theory, and its applications. We hope to develop these further.
Much of this is joint work with K Soundararajan of Stanford University.
Summary
The traditional (Riemann) approach to analytic number theory uses the zeros of zeta functions. This requires the associated multiplicative function, say f(n), to have special enough properties that the associated Dirichlet series may be analytically continued. In this proposal we continue to develop an approach which requires less of the multiplicative function, linking the original question with the mean value of f. Such techniques have been around for a long time but have generally been regarded as “ad hoc”. In this project we aim to show that one can develop a coherent approach to the whole subject, not only reproving all of the old results, but also many new ones that appear inaccessible to traditional methods.
Our first goal is to complete a monograph yielding a reworking of all the classical theory using these new methods and then to push forward in new directions. The most important is to extend these techniques to GL(n) L-functions, which we hope will now be feasible having found the correct framework in which to proceed. Since we rarely know how to analytically continue such L-functions this could be of great benefit to the subject.
We are developing the large sieve so that it can be used for individual moduli, and will determine a strong form of that. Also a new method to give asymptotics for mean values, when they are not too small.
We wish to incorporate techniques of analytic number theory into our theory, for example recent advances on mean values of Dirichlet polynomials. Also the recent breakthroughs on the sieve suggest strong links that need further exploration.
Additive combinatorics yields important results in many areas. There are strong analogies between its results, and those for multiplicative functions, especially in large value spectrum theory, and its applications. We hope to develop these further.
Much of this is joint work with K Soundararajan of Stanford University.
Max ERC Funding
2 011 742 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
Project acronym 3D-E
Project 3D Engineered Environments for Regenerative Medicine
Researcher (PI) Ruth Elizabeth Cameron
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), PE8, ERC-2012-ADG_20120216
Summary "This proposal develops a unified, underpinning technology to create novel, complex and biomimetic 3D environments for the control of tissue growth. As director of Cambridge Centre for Medical Materials, I have recently been approached by medical colleagues to help to solve important problems in the separate therapeutic areas of breast cancer, cardiac disease and blood disorders. In each case, the solution lies in complex 3D engineered environments for cell culture. These colleagues make it clear that existing 3D scaffolds fail to provide the required complex orientational and spatial anisotropy, and are limited in their ability to impart appropriate biochemical and mechanical cues.
I have a strong track record in this area. A particular success has been the use of a freeze drying technology to make collagen based porous implants for the cartilage-bone interface in the knee, which has now been commercialised. The novelty of this proposal lies in the broadening of the established scientific base of this technology to enable biomacromolecular structures with:
(A) controlled and complex pore orientation to mimic many normal multi-oriented tissue structures
(B) compositional and positional control to match varying local biochemical environments,
(C) the attachment of novel peptides designed to control cell behaviour, and
(D) mechanical control at both a local and macroscopic level to provide mechanical cues for cells.
These will be complemented by the development of
(E) robust characterisation methodologies for the structures created.
These advances will then be employed in each of the medical areas above.
This approach is highly interdisciplinary. Existing working relationships with experts in each medical field will guarantee expertise and licensed facilities in the required biological disciplines. Funds for this proposal would therefore establish a rich hub of mutually beneficial research and opportunities for cross-disciplinary sharing of expertise."
Summary
"This proposal develops a unified, underpinning technology to create novel, complex and biomimetic 3D environments for the control of tissue growth. As director of Cambridge Centre for Medical Materials, I have recently been approached by medical colleagues to help to solve important problems in the separate therapeutic areas of breast cancer, cardiac disease and blood disorders. In each case, the solution lies in complex 3D engineered environments for cell culture. These colleagues make it clear that existing 3D scaffolds fail to provide the required complex orientational and spatial anisotropy, and are limited in their ability to impart appropriate biochemical and mechanical cues.
I have a strong track record in this area. A particular success has been the use of a freeze drying technology to make collagen based porous implants for the cartilage-bone interface in the knee, which has now been commercialised. The novelty of this proposal lies in the broadening of the established scientific base of this technology to enable biomacromolecular structures with:
(A) controlled and complex pore orientation to mimic many normal multi-oriented tissue structures
(B) compositional and positional control to match varying local biochemical environments,
(C) the attachment of novel peptides designed to control cell behaviour, and
(D) mechanical control at both a local and macroscopic level to provide mechanical cues for cells.
These will be complemented by the development of
(E) robust characterisation methodologies for the structures created.
These advances will then be employed in each of the medical areas above.
This approach is highly interdisciplinary. Existing working relationships with experts in each medical field will guarantee expertise and licensed facilities in the required biological disciplines. Funds for this proposal would therefore establish a rich hub of mutually beneficial research and opportunities for cross-disciplinary sharing of expertise."
Max ERC Funding
2 486 267 €
Duration
Start date: 2013-04-01, End date: 2018-03-31
Project acronym ABEL
Project "Alpha-helical Barrels: Exploring, Understanding and Exploiting a New Class of Protein Structure"
Researcher (PI) Derek Neil Woolfson
Host Institution (HI) UNIVERSITY OF BRISTOL
Call Details Advanced Grant (AdG), LS9, ERC-2013-ADG
Summary "Recently through de novo peptide design, we have discovered and presented a new protein structure. This is an all-parallel, 6-helix bundle with a continuous central channel of 0.5 – 0.6 nm diameter. We posit that this is one of a broader class of protein structures that we call the alpha-helical barrels. Here, in three Work Packages, we propose to explore these structures and to develop protein functions within them. First, through a combination of computer-aided design, peptide synthesis and thorough biophysical characterization, we will examine the extents and limits of the alpha-helical-barrel structures. Whilst this is curiosity driven research, it also has practical consequences for the studies that will follow; that is, alpha-helical barrels made from increasing numbers of helices have channels or pores that increase in a predictable way. Second, we will use rational and empirical design approaches to engineer a range of functions within these cavities, including binding capabilities and enzyme-like activities. Finally, and taking the programme into another ambitious area, we will use the alpha-helical barrels to template other folds that are otherwise difficult to design and engineer, notably beta-barrels that insert into membranes to render ion-channel and sensor functions."
Summary
"Recently through de novo peptide design, we have discovered and presented a new protein structure. This is an all-parallel, 6-helix bundle with a continuous central channel of 0.5 – 0.6 nm diameter. We posit that this is one of a broader class of protein structures that we call the alpha-helical barrels. Here, in three Work Packages, we propose to explore these structures and to develop protein functions within them. First, through a combination of computer-aided design, peptide synthesis and thorough biophysical characterization, we will examine the extents and limits of the alpha-helical-barrel structures. Whilst this is curiosity driven research, it also has practical consequences for the studies that will follow; that is, alpha-helical barrels made from increasing numbers of helices have channels or pores that increase in a predictable way. Second, we will use rational and empirical design approaches to engineer a range of functions within these cavities, including binding capabilities and enzyme-like activities. Finally, and taking the programme into another ambitious area, we will use the alpha-helical barrels to template other folds that are otherwise difficult to design and engineer, notably beta-barrels that insert into membranes to render ion-channel and sensor functions."
Max ERC Funding
2 467 844 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym ACTINONSRF
Project MAL: an actin-regulated SRF transcriptional coactivator
Researcher (PI) Richard Treisman
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Advanced Grant (AdG), LS1, ERC-2010-AdG_20100317
Summary MAL: an actin-regulated SRF transcriptional coactivator
Recent years have seen a revitalised interest in the role of actin in nuclear processes, but the molecular mechanisms involved remain largely unexplored. We will elucidate the molecular basis for the actin-based control of the SRF transcriptional coactivator, MAL. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MAL, Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). MAL subcellular localisation and transcriptional activity responds to signal-induced changes in G-actin concentration, which are sensed by its actin-binding N-terminal RPEL domain. Members of a second family of RPEL proteins, the Phactrs, also exhibit actin-regulated nucleocytoplasmic shuttling. The proposal addresses the following novel features of actin biology:
¿ Actin as a transcriptional regulator
¿ Actin as a signalling molecule
¿ Actin-binding proteins as targets for regulation by actin, rather than regulators of actin function
We will analyse the sequences and proteins involved in actin-regulated nucleocytoplasmic shuttling, using structural biology and biochemistry to analyse its control by changes in actin-RPEL domain interactions. We will characterise the dynamics of shuttling, and develop reporters for changes in actin-MAL interaction for analysis of pathway activation in vivo. We will identify genes controlling MAL itself, and the balance between the nuclear and cytoplasmic actin pools. The mechanism by which actin represses transcriptional activation by MAL in the nucleus, and its relation to MAL phosphorylation, will be elucidated. Finally, we will map MRTF and TCF cofactor recruitment to SRF targets on a genome-wide scale, and identify the steps in transcription controlled by actin-MAL interaction.
Summary
MAL: an actin-regulated SRF transcriptional coactivator
Recent years have seen a revitalised interest in the role of actin in nuclear processes, but the molecular mechanisms involved remain largely unexplored. We will elucidate the molecular basis for the actin-based control of the SRF transcriptional coactivator, MAL. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MAL, Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). MAL subcellular localisation and transcriptional activity responds to signal-induced changes in G-actin concentration, which are sensed by its actin-binding N-terminal RPEL domain. Members of a second family of RPEL proteins, the Phactrs, also exhibit actin-regulated nucleocytoplasmic shuttling. The proposal addresses the following novel features of actin biology:
¿ Actin as a transcriptional regulator
¿ Actin as a signalling molecule
¿ Actin-binding proteins as targets for regulation by actin, rather than regulators of actin function
We will analyse the sequences and proteins involved in actin-regulated nucleocytoplasmic shuttling, using structural biology and biochemistry to analyse its control by changes in actin-RPEL domain interactions. We will characterise the dynamics of shuttling, and develop reporters for changes in actin-MAL interaction for analysis of pathway activation in vivo. We will identify genes controlling MAL itself, and the balance between the nuclear and cytoplasmic actin pools. The mechanism by which actin represses transcriptional activation by MAL in the nucleus, and its relation to MAL phosphorylation, will be elucidated. Finally, we will map MRTF and TCF cofactor recruitment to SRF targets on a genome-wide scale, and identify the steps in transcription controlled by actin-MAL interaction.
Max ERC Funding
1 889 995 €
Duration
Start date: 2011-10-01, End date: 2017-09-30
Project acronym ADREEM
Project Adding Another Dimension – Arrays of 3D Bio-Responsive Materials
Researcher (PI) Mark Bradley
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Call Details Advanced Grant (AdG), LS9, ERC-2013-ADG
Summary This proposal is focused in the areas of chemical medicine and chemical biology with the key drivers being the discovery and development of new materials that have practical functionality and application. The project will enable the fabrication of thousands of three-dimensional “smart-polymers” that will allow: (i). The precise and controlled release of drugs upon the addition of either a small molecule trigger or in response to disease, (ii). The discovery of materials that control and manipulate cells with the identification of scaffolds that provide the necessary biochemical cues for directing cell fate and drive tissue regeneration and (iii). The development of new classes of “smart-polymers” able, in real-time, to sense and report bacterial contamination. The newly discovered materials will find multiple biomedical applications in regenerative medicine and biotechnology ranging from 3D cell culture, bone repair and niche stabilisation to bacterial sensing/removal, while offering a new paradigm in drug delivery with biomarker triggered drug release.
Summary
This proposal is focused in the areas of chemical medicine and chemical biology with the key drivers being the discovery and development of new materials that have practical functionality and application. The project will enable the fabrication of thousands of three-dimensional “smart-polymers” that will allow: (i). The precise and controlled release of drugs upon the addition of either a small molecule trigger or in response to disease, (ii). The discovery of materials that control and manipulate cells with the identification of scaffolds that provide the necessary biochemical cues for directing cell fate and drive tissue regeneration and (iii). The development of new classes of “smart-polymers” able, in real-time, to sense and report bacterial contamination. The newly discovered materials will find multiple biomedical applications in regenerative medicine and biotechnology ranging from 3D cell culture, bone repair and niche stabilisation to bacterial sensing/removal, while offering a new paradigm in drug delivery with biomarker triggered drug release.
Max ERC Funding
2 310 884 €
Duration
Start date: 2014-11-01, End date: 2019-10-31
Project acronym AMSTAT
Project Problems at the Applied Mathematics-Statistics Interface
Researcher (PI) Andrew Stuart
Host Institution (HI) THE UNIVERSITY OF WARWICK
Call Details Advanced Grant (AdG), PE1, ERC-2008-AdG
Summary Applied mathematics is concerned with developing models with predictive capability, and with probing those models to obtain qualitative and quantitative insight into the phenomena being modelled. Statistics is data-driven and is aimed at the development of methodologies to optimize the information derived from data. The increasing complexity of phenomena that scientists and engineers wish to model, together with our increased ability to gather, store and interrogate data, mean that the subjects of applied mathematics and statistics are increasingly required to work in conjunction. This research proposal is concerned with a research program at the interface between these two disciplines, aimed at problems in differential equations where profusion of data and the sophisticated model combine to produce the mathematical problem of obtaining information from a probability measure on function space. Applications are far-reaching and include the atmospheric sciences, geophysics, chemistry, econometrics and signal processing. The objectives of the research are: (i) to create the systematic foundations for a range of problems at the applied mathematics and statistics interface which share the common mathematical structure underpinning the range of applications described above; (ii) to exploit this common mathematical structure to design effecient algorithms to sample probability measures on function space; (iii) to apply these algorithms to attack a range of significant problems arising in molecular dynamics and in the atmospheric sciences.
Summary
Applied mathematics is concerned with developing models with predictive capability, and with probing those models to obtain qualitative and quantitative insight into the phenomena being modelled. Statistics is data-driven and is aimed at the development of methodologies to optimize the information derived from data. The increasing complexity of phenomena that scientists and engineers wish to model, together with our increased ability to gather, store and interrogate data, mean that the subjects of applied mathematics and statistics are increasingly required to work in conjunction. This research proposal is concerned with a research program at the interface between these two disciplines, aimed at problems in differential equations where profusion of data and the sophisticated model combine to produce the mathematical problem of obtaining information from a probability measure on function space. Applications are far-reaching and include the atmospheric sciences, geophysics, chemistry, econometrics and signal processing. The objectives of the research are: (i) to create the systematic foundations for a range of problems at the applied mathematics and statistics interface which share the common mathematical structure underpinning the range of applications described above; (ii) to exploit this common mathematical structure to design effecient algorithms to sample probability measures on function space; (iii) to apply these algorithms to attack a range of significant problems arising in molecular dynamics and in the atmospheric sciences.
Max ERC Funding
1 693 501 €
Duration
Start date: 2008-12-01, End date: 2014-11-30
Project acronym AMYTOX
Project Amyloid fibril cytotoxicity: new insights from novel approaches
Researcher (PI) Sheena Radford
Host Institution (HI) UNIVERSITY OF LEEDS
Call Details Advanced Grant (AdG), LS1, ERC-2012-ADG_20120314
Summary Despite the discovery of amyloidosis more than a century ago, the molecular and cellular mechanisms of these devastating human disorders remain obscure. In addition to their involvement in disease, amyloid fibrils perform physiological functions, whilst others have potentials as biomaterials. To realise their use in nanotechnology and to enable the development of amyloid therapies, there is an urgent need to understand the molecular pathways of amyloid assembly and to determine how amyloid fibrils interact with cells and cellular components. The challenges lie in the transient nature and low population of aggregating species and the panoply of amyloid fibril structures. This molecular complexity renders identification of the culprits of amyloid disease impossible to achieve using traditional methods.
Here I propose a series of exciting experiments that aim to cast new light on the molecular and cellular mechanisms of amyloidosis by exploiting approaches capable of imaging individual protein molecules or single protein fibrils in vitro and in living cells. The proposal builds on new data from our laboratory that have shown that amyloid fibrils (disease-associated, functional and created from de novo designed sequences) kill cells by a mechanism that depends on fibril length and on cellular uptake. Specifically, I will (i) use single molecule fluorescence and non-covalent mass spectrometry and to determine why short fibril samples disrupt biological membranes more than their longer counterparts and electron tomography to determine, for the first time, the structural properties of cytotoxic fibril ends; (ii) develop single molecule force spectroscopy to probe the interactions between amyloid precursors, fibrils and cellular membranes; and (iii) develop cell biological assays to discover the biological mechanism(s) of amyloid-induced cell death and high resolution imaging and electron tomography to visualise amyloid fibrils in the act of killing living cells.
Summary
Despite the discovery of amyloidosis more than a century ago, the molecular and cellular mechanisms of these devastating human disorders remain obscure. In addition to their involvement in disease, amyloid fibrils perform physiological functions, whilst others have potentials as biomaterials. To realise their use in nanotechnology and to enable the development of amyloid therapies, there is an urgent need to understand the molecular pathways of amyloid assembly and to determine how amyloid fibrils interact with cells and cellular components. The challenges lie in the transient nature and low population of aggregating species and the panoply of amyloid fibril structures. This molecular complexity renders identification of the culprits of amyloid disease impossible to achieve using traditional methods.
Here I propose a series of exciting experiments that aim to cast new light on the molecular and cellular mechanisms of amyloidosis by exploiting approaches capable of imaging individual protein molecules or single protein fibrils in vitro and in living cells. The proposal builds on new data from our laboratory that have shown that amyloid fibrils (disease-associated, functional and created from de novo designed sequences) kill cells by a mechanism that depends on fibril length and on cellular uptake. Specifically, I will (i) use single molecule fluorescence and non-covalent mass spectrometry and to determine why short fibril samples disrupt biological membranes more than their longer counterparts and electron tomography to determine, for the first time, the structural properties of cytotoxic fibril ends; (ii) develop single molecule force spectroscopy to probe the interactions between amyloid precursors, fibrils and cellular membranes; and (iii) develop cell biological assays to discover the biological mechanism(s) of amyloid-induced cell death and high resolution imaging and electron tomography to visualise amyloid fibrils in the act of killing living cells.
Max ERC Funding
2 498 465 €
Duration
Start date: 2013-05-01, End date: 2019-04-30
Project acronym APRA
Project Active Polymers for Renewable Functional Actuators
Researcher (PI) Eugene TERENTJEV
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), PE8, ERC-2017-ADG
Summary The idea of mechanical actuator based on intrinsic material properties of liquid-crystalline elastomers (rather than complex engineering of interacting components) has been understood for 20+ years. The remarkable characteristics of LCE actuation (fully reversible action; large-amplitude, with a stroke of 5%-300%; stress-strain-speed response almost exactly matching the human muscle) make it highly attractive in biomedical engineering, robotics, smart textiles, and other fields. Yet, there is a profound difficulty (bottleneck), which remains the reason why this concept has not found its way into any practical devices & applications. LCE actuation requires alignment (monodomain structure) of the local anisotropy in the permanently crosslinked polymer network - which has been impossible to achieve in any useful large-scale configuration except the flat film, due to the unavoidable restrictions of two competing processes: orientational alignment and network crosslinking.
Recently, we made a breakthrough, developing LCE vitrimers (polymer networks covalently crosslinked by a bond-exchange reaction). Vitrimers are much more stable than other transient elastomer networks, allow easy thermal re-moulding (making the material fully renewable), and permit molding of complex shapes with intricate local alignment (which are impossible in traditional elastomers). This project will bridge from the concept to technology, tuning the material design for robust nematic LCE vitrimers, imparting photo-actuation capacity with a controlled wavelength, and finally utilising them in practical-engineering actuator applications where the reversible mechanical action is stimulated by light, solvent exposure, or more traditionally - heat. These applications include (but not limited to): continuous spinning light-driven motor, tactile dynamic Braille display, capillary pump and toggle flow switch for microfuidics, active textile fibre, and heliotracking filament that always points at the Sun.
Summary
The idea of mechanical actuator based on intrinsic material properties of liquid-crystalline elastomers (rather than complex engineering of interacting components) has been understood for 20+ years. The remarkable characteristics of LCE actuation (fully reversible action; large-amplitude, with a stroke of 5%-300%; stress-strain-speed response almost exactly matching the human muscle) make it highly attractive in biomedical engineering, robotics, smart textiles, and other fields. Yet, there is a profound difficulty (bottleneck), which remains the reason why this concept has not found its way into any practical devices & applications. LCE actuation requires alignment (monodomain structure) of the local anisotropy in the permanently crosslinked polymer network - which has been impossible to achieve in any useful large-scale configuration except the flat film, due to the unavoidable restrictions of two competing processes: orientational alignment and network crosslinking.
Recently, we made a breakthrough, developing LCE vitrimers (polymer networks covalently crosslinked by a bond-exchange reaction). Vitrimers are much more stable than other transient elastomer networks, allow easy thermal re-moulding (making the material fully renewable), and permit molding of complex shapes with intricate local alignment (which are impossible in traditional elastomers). This project will bridge from the concept to technology, tuning the material design for robust nematic LCE vitrimers, imparting photo-actuation capacity with a controlled wavelength, and finally utilising them in practical-engineering actuator applications where the reversible mechanical action is stimulated by light, solvent exposure, or more traditionally - heat. These applications include (but not limited to): continuous spinning light-driven motor, tactile dynamic Braille display, capillary pump and toggle flow switch for microfuidics, active textile fibre, and heliotracking filament that always points at the Sun.
Max ERC Funding
2 012 136 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym ATG9_SOLVES_IT
Project In vitro high resolution reconstitution of autophagosome nucleation and expansion catalyzed byATG9
Researcher (PI) Sharon TOOZE
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Advanced Grant (AdG), LS1, ERC-2017-ADG
Summary Autophagy is a conserved, lysosomal-mediated pathway required for cell homeostasis and survival. It is controlled by the master regulators of energy (AMPK) and growth (TORC1) and mediated by the ATG (autophagy) proteins. Deregulation of autophagy is implicated in cancer, immunity, infection, aging and neurodegeneration. Autophagosomes form and expand using membranes from the secretory and endocytic pathways but how this occurs is not understood. ATG9, the only transmembrane ATG protein traffics through the cell in vesicles, and is essential for rapid initiation and expansion of the membranes which form the autophagosome. Crucially, how ATG9 functions is unknown. I will determine how ATG9 initiates the formation and expansion of the autophagosome by amino acid starvation through a molecular dissection of proteins resident in ATG9 vesicles which modulate the composition and property of the initiating membrane. I will employ high resolution light and electron microscopy to characterize the nucleation of the autophagosome, proximity-specific biotinylation and quantitative Mass Spectrometry to uncover the proteome required for the function of the ATG9, and optogenetic tools to acutely regulate signaling lipids. Lastly, with our tools and knowledge I will develop an in vitro reconstitution system to define at a molecular level how ATG9 vesicle proteins, membranes that interact with ATG9 vesicles, and other accessory ATG components nucleate and form an autophagosome. In vitro reconstitution of autophagosomes will be assayed biochemically, and by correlative light and cryo-EM and cryo-EM tomography, while functional reconstitution of autophagy will be tested by selective cargo recruitment. The development of a reconstituted system and identification proteins and lipids which are key components for autophagosome formation will provide a means to identify a new generation of targets for translational work leading to manipulation of autophagy for disease related therapies.
Summary
Autophagy is a conserved, lysosomal-mediated pathway required for cell homeostasis and survival. It is controlled by the master regulators of energy (AMPK) and growth (TORC1) and mediated by the ATG (autophagy) proteins. Deregulation of autophagy is implicated in cancer, immunity, infection, aging and neurodegeneration. Autophagosomes form and expand using membranes from the secretory and endocytic pathways but how this occurs is not understood. ATG9, the only transmembrane ATG protein traffics through the cell in vesicles, and is essential for rapid initiation and expansion of the membranes which form the autophagosome. Crucially, how ATG9 functions is unknown. I will determine how ATG9 initiates the formation and expansion of the autophagosome by amino acid starvation through a molecular dissection of proteins resident in ATG9 vesicles which modulate the composition and property of the initiating membrane. I will employ high resolution light and electron microscopy to characterize the nucleation of the autophagosome, proximity-specific biotinylation and quantitative Mass Spectrometry to uncover the proteome required for the function of the ATG9, and optogenetic tools to acutely regulate signaling lipids. Lastly, with our tools and knowledge I will develop an in vitro reconstitution system to define at a molecular level how ATG9 vesicle proteins, membranes that interact with ATG9 vesicles, and other accessory ATG components nucleate and form an autophagosome. In vitro reconstitution of autophagosomes will be assayed biochemically, and by correlative light and cryo-EM and cryo-EM tomography, while functional reconstitution of autophagy will be tested by selective cargo recruitment. The development of a reconstituted system and identification proteins and lipids which are key components for autophagosome formation will provide a means to identify a new generation of targets for translational work leading to manipulation of autophagy for disease related therapies.
Max ERC Funding
2 121 055 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym BioBlood
Project Development of a Bio-Inspired Blood Factory for Personalised Healthcare
Researcher (PI) Athanasios Mantalaris
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Advanced Grant (AdG), PE8, ERC-2013-ADG
Summary Personalized medicine is a medical model that proposes the customization of healthcare, with decisions and practices being tailored to the individual patient by use of patient-specific information and/or application of patient-specific cell-based therapies. BioBlood aims to deliver personalised healthcare through a “step change” in the clinical field of haemato-oncology. BioBlood represents an engineered bio-inspired integrated experimental/modelling platform for normal and abnormal haematopoiesis that receives disease & patient input (patient primary cells & patient/disease-specific data) and will produce cellular (red blood cell product) and drug (optimal drug treatment) therapies as its output. Blood supply to meet demand is the primary challenge for Blood Banks and requires significant resources to avoid shortages and ensure safety. An alternative, practical and cost-effective solution to conventional donated blood is essential to reduce patient morbidity and mortality, stabilise and guarantee the donor supply, limit multiple donor exposures, reduce risk of infection of known or as yet unidentified pathogens, and ensure a robust and safe turn-around for blood supply management. BioBlood aims to meet this challenge by developing a novel in vitro platform for the mass production of RBCs for clinical use. More than £32b/year is spent to develop and bring new drugs to market, which takes 14 years. Most patients diagnosed with leukaemias are unable to tolerate treatment and would benefit from novel agents. There is a need to optimise current treatment schedules for cancers such as AML to limit toxicities and improve clinical trial pathways for new drugs to enable personalised healthcare. BioBlood’s in vitro & in silico platform would be a powerful tool to tailor treatments in a patient- and leukaemia-specific chemotherapy schedule by considering the level of toxicity to the specific individual and treatment efficiency for the specific leukaemia a priori.
Summary
Personalized medicine is a medical model that proposes the customization of healthcare, with decisions and practices being tailored to the individual patient by use of patient-specific information and/or application of patient-specific cell-based therapies. BioBlood aims to deliver personalised healthcare through a “step change” in the clinical field of haemato-oncology. BioBlood represents an engineered bio-inspired integrated experimental/modelling platform for normal and abnormal haematopoiesis that receives disease & patient input (patient primary cells & patient/disease-specific data) and will produce cellular (red blood cell product) and drug (optimal drug treatment) therapies as its output. Blood supply to meet demand is the primary challenge for Blood Banks and requires significant resources to avoid shortages and ensure safety. An alternative, practical and cost-effective solution to conventional donated blood is essential to reduce patient morbidity and mortality, stabilise and guarantee the donor supply, limit multiple donor exposures, reduce risk of infection of known or as yet unidentified pathogens, and ensure a robust and safe turn-around for blood supply management. BioBlood aims to meet this challenge by developing a novel in vitro platform for the mass production of RBCs for clinical use. More than £32b/year is spent to develop and bring new drugs to market, which takes 14 years. Most patients diagnosed with leukaemias are unable to tolerate treatment and would benefit from novel agents. There is a need to optimise current treatment schedules for cancers such as AML to limit toxicities and improve clinical trial pathways for new drugs to enable personalised healthcare. BioBlood’s in vitro & in silico platform would be a powerful tool to tailor treatments in a patient- and leukaemia-specific chemotherapy schedule by considering the level of toxicity to the specific individual and treatment efficiency for the specific leukaemia a priori.
Max ERC Funding
2 498 903 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
