Project acronym ANOBEST
Project Structure function and pharmacology of calcium-activated chloride channels: Anoctamins and Bestrophins
Researcher (PI) Raimund Dutzler
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Advanced Grant (AdG), LS1, ERC-2013-ADG
Summary Calcium-activated chloride channels (CaCCs) play key roles in a range of physiological processes such as the control of membrane excitability, photoreception and epithelial secretion. Although the importance of these channels has been recognized for more than 30 years their molecular identity remained obscure. The recent discovery of two protein families encoding for CaCCs, Anoctamins and Bestrophins, was a scientific breakthrough that has provided first insight into two novel ion channel architectures. Within this proposal we aim to determine the first high resolution structures of members of both families and study their functional behavior by an interdisciplinary approach combining biochemistry, X-ray crystallography and electrophysiology. The structural investigation of eukaryotic membrane proteins is extremely challenging and will require us to investigate large numbers of candidates to single out family members with superior biochemical properties. During the last year we have made large progress in this direction. By screening numerous eukaryotic Anoctamins and prokaryotic Bestrophins we have identified well-behaved proteins for both families, which were successfully scaled-up and purified. Additional family members will be identified within the course of the project. For these stable proteins we plan to grow crystals diffracting to high resolution and to proceed with structure determination. With first structural information in hand we will perform detailed functional studies using electrophysiology and complementary biophysical techniques to gain mechanistic insight into ion permeation and gating. As the pharmacology of both families is still in its infancy we will in later stages also engage in the identification and characterization of inhibitors and activators of Anoctamins and Bestrophins to open up a field that may ultimately lead to the discovery of novel therapeutic strategies targeting calcium-activated chloride channels.
Summary
Calcium-activated chloride channels (CaCCs) play key roles in a range of physiological processes such as the control of membrane excitability, photoreception and epithelial secretion. Although the importance of these channels has been recognized for more than 30 years their molecular identity remained obscure. The recent discovery of two protein families encoding for CaCCs, Anoctamins and Bestrophins, was a scientific breakthrough that has provided first insight into two novel ion channel architectures. Within this proposal we aim to determine the first high resolution structures of members of both families and study their functional behavior by an interdisciplinary approach combining biochemistry, X-ray crystallography and electrophysiology. The structural investigation of eukaryotic membrane proteins is extremely challenging and will require us to investigate large numbers of candidates to single out family members with superior biochemical properties. During the last year we have made large progress in this direction. By screening numerous eukaryotic Anoctamins and prokaryotic Bestrophins we have identified well-behaved proteins for both families, which were successfully scaled-up and purified. Additional family members will be identified within the course of the project. For these stable proteins we plan to grow crystals diffracting to high resolution and to proceed with structure determination. With first structural information in hand we will perform detailed functional studies using electrophysiology and complementary biophysical techniques to gain mechanistic insight into ion permeation and gating. As the pharmacology of both families is still in its infancy we will in later stages also engage in the identification and characterization of inhibitors and activators of Anoctamins and Bestrophins to open up a field that may ultimately lead to the discovery of novel therapeutic strategies targeting calcium-activated chloride channels.
Max ERC Funding
2 176 000 €
Duration
Start date: 2014-02-01, End date: 2020-01-31
Project acronym BRIDGES
Project Bridging Non-Equilibrium Problems: From the Fourier Law to Gene Expression
Researcher (PI) Jean-Pierre Eckmann
Host Institution (HI) UNIVERSITE DE GENEVE
Call Details Advanced Grant (AdG), PE1, ERC-2011-ADG_20110209
Summary My goal is to study several important open mathematical problems in non-equilibrium (NEQ) systems and to build a bridge between these problems and NEQ aspects of soft sciences, in particular biological questions. Traffic on this bridge is going to be two-way, the mathematics carrying a long history as a language of science towards the soft sciences, and the soft sciences fruitfully asking new questions and building new paradigms for mathematical research.
Out-of-equilibrium systems pose several fascinating problems: The Fourier law which says that resistance of a wire is proportional to its length is still presenting hard problems for research, and even the existence and the convergence to a NEQ steady state are continuously posing new puzzles, as do questions of smoothness and correlations of such states. These will be addressed with stochastic differential equations, and with particlescatterer systems, both canonical and grand-canonical. The latter are extensions of the well-known Lorentz gas and the study of hyperbolic billiards.
Another field where NEQ plays an important role is the study of glassy systems. They were studied with molecular dynamics (MD) but I have used a topological variant, which mimics astonishingly well what happens in MD simulations. The aim is to extend this to 3 dimensions, where new problems appear.
Finally, I will apply the NEQ studies to biological systems: How a system copes with the varying environment,adapting in this way to a novel type of NEQ. I will study networks of communication among neurons,which are like random graphs with the additional property of being embedded, and the arrangement of genes on chromosomes in such a way as to optimize the adaptation to the different cell types which must be produced using the same genetic information.
I will answer such questions with students and collaborators, who will specialize in the subprojects but will interact with my help across the common bridge.
Summary
My goal is to study several important open mathematical problems in non-equilibrium (NEQ) systems and to build a bridge between these problems and NEQ aspects of soft sciences, in particular biological questions. Traffic on this bridge is going to be two-way, the mathematics carrying a long history as a language of science towards the soft sciences, and the soft sciences fruitfully asking new questions and building new paradigms for mathematical research.
Out-of-equilibrium systems pose several fascinating problems: The Fourier law which says that resistance of a wire is proportional to its length is still presenting hard problems for research, and even the existence and the convergence to a NEQ steady state are continuously posing new puzzles, as do questions of smoothness and correlations of such states. These will be addressed with stochastic differential equations, and with particlescatterer systems, both canonical and grand-canonical. The latter are extensions of the well-known Lorentz gas and the study of hyperbolic billiards.
Another field where NEQ plays an important role is the study of glassy systems. They were studied with molecular dynamics (MD) but I have used a topological variant, which mimics astonishingly well what happens in MD simulations. The aim is to extend this to 3 dimensions, where new problems appear.
Finally, I will apply the NEQ studies to biological systems: How a system copes with the varying environment,adapting in this way to a novel type of NEQ. I will study networks of communication among neurons,which are like random graphs with the additional property of being embedded, and the arrangement of genes on chromosomes in such a way as to optimize the adaptation to the different cell types which must be produced using the same genetic information.
I will answer such questions with students and collaborators, who will specialize in the subprojects but will interact with my help across the common bridge.
Max ERC Funding
2 135 385 €
Duration
Start date: 2012-04-01, End date: 2017-07-31
Project acronym CausalStats
Project Statistics, Prediction and Causality for Large-Scale Data
Researcher (PI) Peter Lukas Bühlmann
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Advanced Grant (AdG), PE1, ERC-2017-ADG
Summary Understanding cause-effect relationships between variables is of great interest in many fields of science. However, causal inference from data is much more ambitious and difficult than inferring (undirected) measures of association such as correlations, partial correlations or multivariate regression coefficients, mainly because of fundamental identifiability
problems. A main objective of the proposal is to exploit advantages from large-scale heterogeneous data for causal inference where heterogeneity arises from different experimental conditions or different unknown sub-populations. A key idea is to consider invariance or stability across different experimental conditions of certain conditional probability distributions: the invariants correspond on the one hand to (properly defined) causal variables which are of main interest in causality; andon the other hand, they correspond to the features for constructing powerful predictions for new scenarios which are unobserved in the data (new probability distributions). This opens novel perspectives: causal inference
can be phrased as a prediction problem of a certain kind, and vice versa, new prediction methods which work well across different scenarios (unobserved in the data) should be based on or regularized towards causal variables. Fundamental identifiability limits will become weaker with increased degree of heterogeneity, as we expect in large-scale data. The topic is essentially unexplored, yet it opens new avenues for causal inference, structural equation and graphical modeling, and robust prediction based on large-scale complex data. We will develop mathematical theory, statistical methodology and efficient algorithms; and we will also work and collaborate on major application problems such as inferring causal effects (i.e., total intervention effects) from gene knock-out or RNA interference perturbation experiments, genome-wide association studies and novel prediction tasks in economics.
Summary
Understanding cause-effect relationships between variables is of great interest in many fields of science. However, causal inference from data is much more ambitious and difficult than inferring (undirected) measures of association such as correlations, partial correlations or multivariate regression coefficients, mainly because of fundamental identifiability
problems. A main objective of the proposal is to exploit advantages from large-scale heterogeneous data for causal inference where heterogeneity arises from different experimental conditions or different unknown sub-populations. A key idea is to consider invariance or stability across different experimental conditions of certain conditional probability distributions: the invariants correspond on the one hand to (properly defined) causal variables which are of main interest in causality; andon the other hand, they correspond to the features for constructing powerful predictions for new scenarios which are unobserved in the data (new probability distributions). This opens novel perspectives: causal inference
can be phrased as a prediction problem of a certain kind, and vice versa, new prediction methods which work well across different scenarios (unobserved in the data) should be based on or regularized towards causal variables. Fundamental identifiability limits will become weaker with increased degree of heterogeneity, as we expect in large-scale data. The topic is essentially unexplored, yet it opens new avenues for causal inference, structural equation and graphical modeling, and robust prediction based on large-scale complex data. We will develop mathematical theory, statistical methodology and efficient algorithms; and we will also work and collaborate on major application problems such as inferring causal effects (i.e., total intervention effects) from gene knock-out or RNA interference perturbation experiments, genome-wide association studies and novel prediction tasks in economics.
Max ERC Funding
2 184 375 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym CFRFSS
Project Chromatin Fiber and Remodeling Factor Structural Studies
Researcher (PI) Timothy John Richmond
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Advanced Grant (AdG), LS1, ERC-2012-ADG_20120314
Summary "DNA in higher organisms is organized in a nucleoprotein complex called chromatin. The structure of chromatin is responsible for compacting DNA to fit within the nucleus and for governing its access in nuclear processes. Epigenetic information is encoded chiefly via chromatin modifications. Readout of the genetic code depends on chromatin remodeling, a process actively altering chromatin structure. An understanding of the hierarchical structure of chromatin and of structurally based, remodeling mechanisms will have enormous impact for developments in medicine.
Following our high resolution structure of the nucleosome core particle, the fundamental repeating unit of chromatin, we have endeavored to determine the structure of the chromatin fiber. We showed with our X-ray structure of a tetranucleosome how nucleosomes could be organized in the fiber. Further progress has been limited by structural polymorphism and crystal disorder, but new evidence on the in vivo spacing of nucleosomes in chromatin should stimulate more advances. Part A of this application describes how we would apply these new findings to our cryo-electron microscopy study of the chromatin fiber and to our crystallographic study of a tetranucleosome containing linker histone.
Recently, my laboratory succeeded in providing the first structurally based mechanism for nucleosome spacing by a chromatin remodeling factor. We combined the X-ray structure of ISW1a(ATPase) bound to DNA with cryo-EM structures of the factor bound to two different nucleosomes to build a model showing how this remodeler uses a dinucleosome, not a mononucleosome, as its substrate. Our results from a functional assay using ISW1a further justified this model. Part B of this application describes how we would proceed to the relevant cryo-EM and X-ray structures incorporating dinucleosomes. Our recombinant ISW1a allows us to study in addition the interaction of the ATPase domain with nucleosome substrates."
Summary
"DNA in higher organisms is organized in a nucleoprotein complex called chromatin. The structure of chromatin is responsible for compacting DNA to fit within the nucleus and for governing its access in nuclear processes. Epigenetic information is encoded chiefly via chromatin modifications. Readout of the genetic code depends on chromatin remodeling, a process actively altering chromatin structure. An understanding of the hierarchical structure of chromatin and of structurally based, remodeling mechanisms will have enormous impact for developments in medicine.
Following our high resolution structure of the nucleosome core particle, the fundamental repeating unit of chromatin, we have endeavored to determine the structure of the chromatin fiber. We showed with our X-ray structure of a tetranucleosome how nucleosomes could be organized in the fiber. Further progress has been limited by structural polymorphism and crystal disorder, but new evidence on the in vivo spacing of nucleosomes in chromatin should stimulate more advances. Part A of this application describes how we would apply these new findings to our cryo-electron microscopy study of the chromatin fiber and to our crystallographic study of a tetranucleosome containing linker histone.
Recently, my laboratory succeeded in providing the first structurally based mechanism for nucleosome spacing by a chromatin remodeling factor. We combined the X-ray structure of ISW1a(ATPase) bound to DNA with cryo-EM structures of the factor bound to two different nucleosomes to build a model showing how this remodeler uses a dinucleosome, not a mononucleosome, as its substrate. Our results from a functional assay using ISW1a further justified this model. Part B of this application describes how we would proceed to the relevant cryo-EM and X-ray structures incorporating dinucleosomes. Our recombinant ISW1a allows us to study in addition the interaction of the ATPase domain with nucleosome substrates."
Max ERC Funding
2 500 000 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym CHANGE
Project New CHallenges for (adaptive) PDE solvers: the interplay of ANalysis and GEometry
Researcher (PI) Annalisa BUFFA
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Advanced Grant (AdG), PE1, ERC-2015-AdG
Summary The simulation of Partial Differential Equations (PDEs) is an indispensable tool for innovation in science and technology.
Computer-based simulation of PDEs approximates unknowns defined on a geometrical entity such as the computational domain with all of its properties. Mainly due to historical reasons, geometric design and numerical methods for PDEs have been developed independently, resulting in tools that rely on different representations of the same objects.
CHANGE aims at developing innovative mathematical tools for numerically solving PDEs and for geometric modeling and processing, the final goal being the definition of a common framework where geometrical entities and simulation are coherently integrated and where adaptive methods can be used to guarantee optimal use of computer resources, from the geometric description to the simulation.
We will concentrate on two classes of methods for the discretisation of PDEs that are having growing impact:
isogeometric methods and variational methods on polyhedral partitions. They are both extensions of standard finite elements enjoying exciting features, but both lack of an ad-hoc geometric modelling counterpart.
We will extend numerical methods to ensure robustness on the most general geometric models, and we will develop geometric tools to construct, manipulate and refine such models. Based on our tools, we will design an innovative adaptive framework, that jointly exploits multilevel representation of geometric entities and PDE unknowns.
Moreover, efficient algorithms call for efficient implementation: the issue of the optimisation of our algorithms on modern computer architecture will be addressed.
Our research (and the team involved in the project) will combine competencies in computer science, numerical analysis, high performance computing, and computational mechanics. Leveraging our innovative tools, we will also tackle challenging numerical problems deriving from bio-mechanical applications.
Summary
The simulation of Partial Differential Equations (PDEs) is an indispensable tool for innovation in science and technology.
Computer-based simulation of PDEs approximates unknowns defined on a geometrical entity such as the computational domain with all of its properties. Mainly due to historical reasons, geometric design and numerical methods for PDEs have been developed independently, resulting in tools that rely on different representations of the same objects.
CHANGE aims at developing innovative mathematical tools for numerically solving PDEs and for geometric modeling and processing, the final goal being the definition of a common framework where geometrical entities and simulation are coherently integrated and where adaptive methods can be used to guarantee optimal use of computer resources, from the geometric description to the simulation.
We will concentrate on two classes of methods for the discretisation of PDEs that are having growing impact:
isogeometric methods and variational methods on polyhedral partitions. They are both extensions of standard finite elements enjoying exciting features, but both lack of an ad-hoc geometric modelling counterpart.
We will extend numerical methods to ensure robustness on the most general geometric models, and we will develop geometric tools to construct, manipulate and refine such models. Based on our tools, we will design an innovative adaptive framework, that jointly exploits multilevel representation of geometric entities and PDE unknowns.
Moreover, efficient algorithms call for efficient implementation: the issue of the optimisation of our algorithms on modern computer architecture will be addressed.
Our research (and the team involved in the project) will combine competencies in computer science, numerical analysis, high performance computing, and computational mechanics. Leveraging our innovative tools, we will also tackle challenging numerical problems deriving from bio-mechanical applications.
Max ERC Funding
2 199 219 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym CHLIP
Project "Understanding Halogenated Lipids: Synthesis, Mode of Action, Structural Studies, and Applications"
Researcher (PI) Erick Moran Carreira
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Advanced Grant (AdG), PE5, ERC-2012-ADG_20120216
Summary "Among the various toxins isolated, the chlorosulfolipids are particularly intriguing because of their structural and stereochemical complexity. The mechanism of biological activity remains unknown. The lack of availability of the natural products has impaired more in-depth studies aimed at pharmacological, biological, and chemical characterization for proper evaluation of the risk for human health and their role in nature. The proposal takes as its basis this unusual class of natural products and delineates a multifaceted program of inquiry involving: (1) structural characterization of the most complex chlorosulfolipid isolated to date, (2) conformational studies in solution of chlorinated lipids, (3) synthesis and study of brominated lipid analogs, (4) development of analytical methods for detection of these toxins in the environment, (5) the discovery and development of reagents and catalysts for asymmetric chlorination of olefins, (6) examination of lipid conformation in constrained media, (7) examination of the mechanism of anchimeric assistance by chlorides, and (8) applications to drug discovery."
Summary
"Among the various toxins isolated, the chlorosulfolipids are particularly intriguing because of their structural and stereochemical complexity. The mechanism of biological activity remains unknown. The lack of availability of the natural products has impaired more in-depth studies aimed at pharmacological, biological, and chemical characterization for proper evaluation of the risk for human health and their role in nature. The proposal takes as its basis this unusual class of natural products and delineates a multifaceted program of inquiry involving: (1) structural characterization of the most complex chlorosulfolipid isolated to date, (2) conformational studies in solution of chlorinated lipids, (3) synthesis and study of brominated lipid analogs, (4) development of analytical methods for detection of these toxins in the environment, (5) the discovery and development of reagents and catalysts for asymmetric chlorination of olefins, (6) examination of lipid conformation in constrained media, (7) examination of the mechanism of anchimeric assistance by chlorides, and (8) applications to drug discovery."
Max ERC Funding
2 233 240 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym CLaQS
Project Correlations in Large Quantum Systems
Researcher (PI) Benjamin Schlein
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Advanced Grant (AdG), PE1, ERC-2018-ADG
Summary This project is devoted to the mathematical analysis of important physical properties of many-body quantum systems. We will be interested in properties of the ground state and low-energy excitations but also of non-equilibrium dynamics. We are going to consider systems with different statistics and in different regimes. The questions we are going to address have a common aspect: correlations among particles play a crucial role. Our main goal consists in developing new tools that allow us to correctly describe many-body correlations and to understand their effects. The starting point of our proposal are ideas and techniques that have been introduced in a series of papers establishing the validity of Bogoliubov theory for Bose gases in the Gross-Pitaevskii regime, and in a recent preprint showing how (bosonic) Bogoliubov theory can also be used to study the correlation energy of Fermi gases. In this project, we plan to develop these techniques further and to apply them to new contexts. We believe they have the potential to approach some fundamental open problem in mathematical physics. Among our most ambitious objectives, we include the proof of the Lee-Huang-Yang formula for the energy of dilute Bose gases and of the corresponding Huang-Yang formula for dilute Fermi gases, as well as the derivation of the Gell-Mann--Brueckner expression for the correlation energy of a high density Fermi system. Furthermore, we propose to work on long-term projects (going beyond the duration of the grant) aiming at a rigorous justification of the quantum Boltzmann equation for fermions in the weak coupling limit and at a proof of Bose-Einstein condensation in the thermodynamic limit, two very challenging and important questions in the field.
Summary
This project is devoted to the mathematical analysis of important physical properties of many-body quantum systems. We will be interested in properties of the ground state and low-energy excitations but also of non-equilibrium dynamics. We are going to consider systems with different statistics and in different regimes. The questions we are going to address have a common aspect: correlations among particles play a crucial role. Our main goal consists in developing new tools that allow us to correctly describe many-body correlations and to understand their effects. The starting point of our proposal are ideas and techniques that have been introduced in a series of papers establishing the validity of Bogoliubov theory for Bose gases in the Gross-Pitaevskii regime, and in a recent preprint showing how (bosonic) Bogoliubov theory can also be used to study the correlation energy of Fermi gases. In this project, we plan to develop these techniques further and to apply them to new contexts. We believe they have the potential to approach some fundamental open problem in mathematical physics. Among our most ambitious objectives, we include the proof of the Lee-Huang-Yang formula for the energy of dilute Bose gases and of the corresponding Huang-Yang formula for dilute Fermi gases, as well as the derivation of the Gell-Mann--Brueckner expression for the correlation energy of a high density Fermi system. Furthermore, we propose to work on long-term projects (going beyond the duration of the grant) aiming at a rigorous justification of the quantum Boltzmann equation for fermions in the weak coupling limit and at a proof of Bose-Einstein condensation in the thermodynamic limit, two very challenging and important questions in the field.
Max ERC Funding
1 876 050 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym COMPASP
Project Complex analysis and statistical physics
Researcher (PI) Stanislav Smirnov
Host Institution (HI) UNIVERSITE DE GENEVE
Call Details Advanced Grant (AdG), PE1, ERC-2013-ADG
Summary "The goal of this project is to achieve breakthroughs in a few fundamental questions in 2D statistical physics, using techniques from complex analysis, probability, dynamical systems, geometric measure theory and theoretical physics.
Over the last decade, we significantly expanded our understanding of 2D lattice models of statistical physics, their conformally invariant scaling limits and related random geometries. However, there seem to be serious obstacles, preventing further development and requiring novel ideas. We plan to attack those, in particular we intend to:
(A) Describe new scaling limits by Schramm’s SLE curves and their generalizations,
(B) Study discrete complex structures and use them to describe more 2D models,
(C) Describe the scaling limits of random planar graphs by the Liouville Quantum Gravity,
(D) Understand universality and lay framework for the Renormalization Group Formalism,
(E) Go beyond the current setup of spin models and SLEs.
These problems are known to be very difficult, but fundamental questions, which have the potential to lead to significant breakthroughs in our understanding of phase transitions, allowing for further progresses. In resolving them, we plan to exploit interactions of different subjects, and recent advances are encouraging."
Summary
"The goal of this project is to achieve breakthroughs in a few fundamental questions in 2D statistical physics, using techniques from complex analysis, probability, dynamical systems, geometric measure theory and theoretical physics.
Over the last decade, we significantly expanded our understanding of 2D lattice models of statistical physics, their conformally invariant scaling limits and related random geometries. However, there seem to be serious obstacles, preventing further development and requiring novel ideas. We plan to attack those, in particular we intend to:
(A) Describe new scaling limits by Schramm’s SLE curves and their generalizations,
(B) Study discrete complex structures and use them to describe more 2D models,
(C) Describe the scaling limits of random planar graphs by the Liouville Quantum Gravity,
(D) Understand universality and lay framework for the Renormalization Group Formalism,
(E) Go beyond the current setup of spin models and SLEs.
These problems are known to be very difficult, but fundamental questions, which have the potential to lead to significant breakthroughs in our understanding of phase transitions, allowing for further progresses. In resolving them, we plan to exploit interactions of different subjects, and recent advances are encouraging."
Max ERC Funding
1 995 900 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym CONFRA
Project Conformal fractals in analysis, dynamics, physics
Researcher (PI) Stanislav Smirnov
Host Institution (HI) UNIVERSITE DE GENEVE
Call Details Advanced Grant (AdG), PE1, ERC-2008-AdG
Summary The goal of this project is to study conformally invariant fractal structures from the perspectives of analysis, dynamics, probability, geometry and physics, emphasizing interrelations of these fields. In the last two decades such structures emerged in several areas: continuum scaling limits of 2D critical models in statistical physics (percolation, Ising model); extremal configurations for various problems in complex analysis (multifractal harmonic measures, coefficient growth of univalent maps, Brennan's conjecture); chaotic sets for complex dynamical systems (Julia sets, Kleinian groups). Capitalizing on recent successes, I plan to continue my work in these areas, exploiting their interactions and connections to physics. I intend to achieve at least some of the following goals: * To establish that several critical lattice models have conformally invariant scaling limits, by building upon results on percolation and Ising models and finding discrete holomorphic observables. * To study geometric properties of arising fractal curves and random fields by connecting them to Schramm's SLE curves and Gaussian Free Fields. * To investigate massive scaling limits by describing them geometrically with generalizations of SLEs. * To lay mathematical framework behind relevant physical notions, such as Coulomb Gas (by relating height functions to GFFs) and Quantum Gravity (by identifying limits of random planar graphs with Liouville QGs). * To improve known bounds in several old questions in complex analysis by studying multifractal spectra of harmonic measures. * To estimate extremal behavior of such spectra by using holomorphic motions of (quasi) conformal maps and thermodynamic formalism. * To understand nature of extremal multifractals for harmonic measure by studying random and dynamical fractals. The topics involved range from century old to very young ones. Recently connections between them started to emerge, opening exciting possibilities for new developments in some long standing open problems.
Summary
The goal of this project is to study conformally invariant fractal structures from the perspectives of analysis, dynamics, probability, geometry and physics, emphasizing interrelations of these fields. In the last two decades such structures emerged in several areas: continuum scaling limits of 2D critical models in statistical physics (percolation, Ising model); extremal configurations for various problems in complex analysis (multifractal harmonic measures, coefficient growth of univalent maps, Brennan's conjecture); chaotic sets for complex dynamical systems (Julia sets, Kleinian groups). Capitalizing on recent successes, I plan to continue my work in these areas, exploiting their interactions and connections to physics. I intend to achieve at least some of the following goals: * To establish that several critical lattice models have conformally invariant scaling limits, by building upon results on percolation and Ising models and finding discrete holomorphic observables. * To study geometric properties of arising fractal curves and random fields by connecting them to Schramm's SLE curves and Gaussian Free Fields. * To investigate massive scaling limits by describing them geometrically with generalizations of SLEs. * To lay mathematical framework behind relevant physical notions, such as Coulomb Gas (by relating height functions to GFFs) and Quantum Gravity (by identifying limits of random planar graphs with Liouville QGs). * To improve known bounds in several old questions in complex analysis by studying multifractal spectra of harmonic measures. * To estimate extremal behavior of such spectra by using holomorphic motions of (quasi) conformal maps and thermodynamic formalism. * To understand nature of extremal multifractals for harmonic measure by studying random and dynamical fractals. The topics involved range from century old to very young ones. Recently connections between them started to emerge, opening exciting possibilities for new developments in some long standing open problems.
Max ERC Funding
1 278 000 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym CsnCRL
Project The molecular basis of CULLIN E3 ligase regulation by the COP9 signalosome
Researcher (PI) Nicolas Thoma
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Advanced Grant (AdG), LS1, ERC-2014-ADG
Summary Specificity in the ubiquitin-proteasome system is largely conferred by ubiquitin E3 ligases (E3s). Cullin-RING ligases (CRLs), constituting ~30% of all E3s in humans, mediate the ubiquitination of ~20% of the proteins degraded by the proteasome. CRLs are divided into seven families based on their cullin constituent. Each cullin binds a RING domain protein, and a vast repertoire of adaptor/substrate receptor modules, collectively creating more than 200 distinct CRLs. All CRLs are regulated by the COP9 signalosome (CSN), an eight-protein isopeptidase that removes the covalently attached activator, NEDD8, from the cullin. Independent of NEDD8 cleavage, CSN forms protective complexes with CRLs, which prevents destructive auto-ubiquitination.
The integrity of the CSN-CRL system is crucially important for the normal cell physiology. Based on our previous work on CRL structures (Fischer, et al., Nature 2014; Fischer, et al., Cell 2011) and that of isolated CSN (Lingaraju et al., Nature 2014), We now intend to provide the underlying molecular mechanism of CRL regulation by CSN. Structural insights at atomic resolution, combined with in vitro and in vivo functional studies are designed to reveal (i) how the signalosome deneddylates and maintains the bound ligases in an inactive state, (ii) how the multiple CSN subunits bind to structurally diverse CRLs, and (iii) how CSN is itself subject to regulation by post-translational modifications or additional further factors.
The ERC funding would allow my lab to pursue an ambitious interdisciplinary approach combining X-ray crystallography, cryo-electron microscopy, biochemistry and cell biology. This is expected to provide a unique molecular understanding of CSN action. Beyond ubiquitination, insight into this >13- subunit CSN-CRL assembly will allow examining general principles of multi-subunit complex action and reveal how the numerous, often essential, subunits contribute to complex function.
Summary
Specificity in the ubiquitin-proteasome system is largely conferred by ubiquitin E3 ligases (E3s). Cullin-RING ligases (CRLs), constituting ~30% of all E3s in humans, mediate the ubiquitination of ~20% of the proteins degraded by the proteasome. CRLs are divided into seven families based on their cullin constituent. Each cullin binds a RING domain protein, and a vast repertoire of adaptor/substrate receptor modules, collectively creating more than 200 distinct CRLs. All CRLs are regulated by the COP9 signalosome (CSN), an eight-protein isopeptidase that removes the covalently attached activator, NEDD8, from the cullin. Independent of NEDD8 cleavage, CSN forms protective complexes with CRLs, which prevents destructive auto-ubiquitination.
The integrity of the CSN-CRL system is crucially important for the normal cell physiology. Based on our previous work on CRL structures (Fischer, et al., Nature 2014; Fischer, et al., Cell 2011) and that of isolated CSN (Lingaraju et al., Nature 2014), We now intend to provide the underlying molecular mechanism of CRL regulation by CSN. Structural insights at atomic resolution, combined with in vitro and in vivo functional studies are designed to reveal (i) how the signalosome deneddylates and maintains the bound ligases in an inactive state, (ii) how the multiple CSN subunits bind to structurally diverse CRLs, and (iii) how CSN is itself subject to regulation by post-translational modifications or additional further factors.
The ERC funding would allow my lab to pursue an ambitious interdisciplinary approach combining X-ray crystallography, cryo-electron microscopy, biochemistry and cell biology. This is expected to provide a unique molecular understanding of CSN action. Beyond ubiquitination, insight into this >13- subunit CSN-CRL assembly will allow examining general principles of multi-subunit complex action and reveal how the numerous, often essential, subunits contribute to complex function.
Max ERC Funding
2 200 677 €
Duration
Start date: 2016-01-01, End date: 2020-12-31