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 2-3-AUT
Project Surfaces, 3-manifolds and automorphism groups
Researcher (PI) Nathalie Wahl
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Starting Grant (StG), PE1, ERC-2009-StG
Summary The scientific goal of the proposal is to answer central questions related to diffeomorphism groups of manifolds of dimension 2 and 3, and to their deformation invariant analogs, the mapping class groups. While the classification of surfaces has been known for more than a century, their automorphism groups have yet to be fully understood. Even less is known about diffeomorphisms of 3-manifolds despite much interest, and the objects here have only been classified recently, by the breakthrough work of Perelman on the Poincar\'e and geometrization conjectures. In dimension 2, I will focus on the relationship between mapping class groups and topological conformal field theories, with applications to Hochschild homology. In dimension 3, I propose to compute the stable homology of classifying spaces of diffeomorphism groups and mapping class groups, as well as study the homotopy type of the space of diffeomorphisms. I propose moreover to establish homological stability theorems in the wider context of automorphism groups and more general families of groups. The project combines breakthrough methods from homotopy theory with methods from differential and geometric topology. The research team will consist of 3 PhD students, and 4 postdocs, which I will lead.
Summary
The scientific goal of the proposal is to answer central questions related to diffeomorphism groups of manifolds of dimension 2 and 3, and to their deformation invariant analogs, the mapping class groups. While the classification of surfaces has been known for more than a century, their automorphism groups have yet to be fully understood. Even less is known about diffeomorphisms of 3-manifolds despite much interest, and the objects here have only been classified recently, by the breakthrough work of Perelman on the Poincar\'e and geometrization conjectures. In dimension 2, I will focus on the relationship between mapping class groups and topological conformal field theories, with applications to Hochschild homology. In dimension 3, I propose to compute the stable homology of classifying spaces of diffeomorphism groups and mapping class groups, as well as study the homotopy type of the space of diffeomorphisms. I propose moreover to establish homological stability theorems in the wider context of automorphism groups and more general families of groups. The project combines breakthrough methods from homotopy theory with methods from differential and geometric topology. The research team will consist of 3 PhD students, and 4 postdocs, which I will lead.
Max ERC Funding
724 992 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym 3D_Tryps
Project The role of three-dimensional genome architecture in antigenic variation
Researcher (PI) Tim Nicolai SIEGEL
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), LS6, ERC-2016-STG
Summary Antigenic variation is a widely employed strategy to evade the host immune response. It has similar functional requirements even in evolutionarily divergent pathogens. These include the mutually exclusive expression of antigens and the periodic, nonrandom switching in the expression of different antigens during the course of an infection. Despite decades of research the mechanisms of antigenic variation are not fully understood in any organism.
The recent development of high-throughput sequencing-based assays to probe the 3D genome architecture (Hi-C) has revealed the importance of the spatial organization of DNA inside the nucleus. 3D genome architecture plays a critical role in the regulation of mutually exclusive gene expression and the frequency of translocation between different genomic loci in many eukaryotes. Thus, genome architecture may also be a key regulator of antigenic variation, yet the causal links between genome architecture and the expression of antigens have not been studied systematically. In addition, the development of CRISPR-Cas9-based approaches to perform nucleotide-specific genome editing has opened unprecedented opportunities to study the influence of DNA sequence elements on the spatial organization of DNA and how this impacts antigen expression.
I have adapted both Hi-C and CRISPR-Cas9 technology to the protozoan parasite Trypanosoma brucei, one of the most important model organisms to study antigenic variation. These techniques will enable me to bridge the field of antigenic variation research with that of genome architecture. I will perform the first systematic analysis of the role of genome architecture in the mutually exclusive and hierarchical expression of antigens in any pathogen.
The experiments outlined in this proposal will provide new insight, facilitating a new view of antigenic variation and may eventually help medical intervention in T. brucei and in other pathogens relying on antigenic variation for their survival.
Summary
Antigenic variation is a widely employed strategy to evade the host immune response. It has similar functional requirements even in evolutionarily divergent pathogens. These include the mutually exclusive expression of antigens and the periodic, nonrandom switching in the expression of different antigens during the course of an infection. Despite decades of research the mechanisms of antigenic variation are not fully understood in any organism.
The recent development of high-throughput sequencing-based assays to probe the 3D genome architecture (Hi-C) has revealed the importance of the spatial organization of DNA inside the nucleus. 3D genome architecture plays a critical role in the regulation of mutually exclusive gene expression and the frequency of translocation between different genomic loci in many eukaryotes. Thus, genome architecture may also be a key regulator of antigenic variation, yet the causal links between genome architecture and the expression of antigens have not been studied systematically. In addition, the development of CRISPR-Cas9-based approaches to perform nucleotide-specific genome editing has opened unprecedented opportunities to study the influence of DNA sequence elements on the spatial organization of DNA and how this impacts antigen expression.
I have adapted both Hi-C and CRISPR-Cas9 technology to the protozoan parasite Trypanosoma brucei, one of the most important model organisms to study antigenic variation. These techniques will enable me to bridge the field of antigenic variation research with that of genome architecture. I will perform the first systematic analysis of the role of genome architecture in the mutually exclusive and hierarchical expression of antigens in any pathogen.
The experiments outlined in this proposal will provide new insight, facilitating a new view of antigenic variation and may eventually help medical intervention in T. brucei and in other pathogens relying on antigenic variation for their survival.
Max ERC Funding
1 498 175 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym 3DWATERWAVES
Project Mathematical aspects of three-dimensional water waves with vorticity
Researcher (PI) Erik Torsten Wahlén
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), PE1, ERC-2015-STG
Summary The goal of this project is to develop a mathematical theory for steady three-dimensional water waves with vorticity. The mathematical model consists of the incompressible Euler equations with a free surface, and vorticity is important for modelling the interaction of surface waves with non-uniform currents. In the two-dimensional case, there has been a lot of progress on water waves with vorticity in the last decade. This progress has mainly been based on the stream function formulation, in which the problem is reformulated as a nonlinear elliptic free boundary problem. An analogue of this formulation is not available in three dimensions, and the theory has therefore so far been restricted to irrotational flow. In this project we seek to go beyond this restriction using two different approaches. In the first approach we will adapt methods which have been used to construct three-dimensional ideal flows with vorticity in domains with a fixed boundary to the free boundary context (for example Beltrami flows). In the second approach we will develop methods which are new even in the case of a fixed boundary, by performing a detailed study of the structure of the equations close to a given shear flow using ideas from infinite-dimensional bifurcation theory. This involves handling infinitely many resonances.
Summary
The goal of this project is to develop a mathematical theory for steady three-dimensional water waves with vorticity. The mathematical model consists of the incompressible Euler equations with a free surface, and vorticity is important for modelling the interaction of surface waves with non-uniform currents. In the two-dimensional case, there has been a lot of progress on water waves with vorticity in the last decade. This progress has mainly been based on the stream function formulation, in which the problem is reformulated as a nonlinear elliptic free boundary problem. An analogue of this formulation is not available in three dimensions, and the theory has therefore so far been restricted to irrotational flow. In this project we seek to go beyond this restriction using two different approaches. In the first approach we will adapt methods which have been used to construct three-dimensional ideal flows with vorticity in domains with a fixed boundary to the free boundary context (for example Beltrami flows). In the second approach we will develop methods which are new even in the case of a fixed boundary, by performing a detailed study of the structure of the equations close to a given shear flow using ideas from infinite-dimensional bifurcation theory. This involves handling infinitely many resonances.
Max ERC Funding
1 203 627 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym AAMOT
Project Arithmetic of automorphic motives
Researcher (PI) Michael Harris
Host Institution (HI) INSTITUT DES HAUTES ETUDES SCIENTIFIQUES
Call Details Advanced Grant (AdG), PE1, ERC-2011-ADG_20110209
Summary The primary purpose of this project is to build on recent spectacular progress in the Langlands program to study the arithmetic properties of automorphic motives constructed in the cohomology of Shimura varieties. Because automorphic methods are available to study the L-functions of these motives, which include elliptic curves and certain families of Calabi-Yau varieties over totally real fields (possibly after base change), they represent the most accessible class of varieties for which one can hope to verify fundamental conjectures on special values of L-functions, including Deligne's conjecture and the Main Conjecture of Iwasawa theory. Immediate goals include the proof of irreducibility of automorphic Galois representations; the establishment of period relations for automorphic and potentially automorphic realizations of motives in the cohomology of distinct Shimura varieties; the construction of p-adic L-functions for these and related motives, notably adjoint and tensor product L-functions in p-adic families; and the geometrization of the p-adic and mod p Langlands program. All four goals, as well as the others mentioned in the body of the proposal, are interconnected; the final goal provides a bridge to related work in geometric representation theory, algebraic geometry, and mathematical physics.
Summary
The primary purpose of this project is to build on recent spectacular progress in the Langlands program to study the arithmetic properties of automorphic motives constructed in the cohomology of Shimura varieties. Because automorphic methods are available to study the L-functions of these motives, which include elliptic curves and certain families of Calabi-Yau varieties over totally real fields (possibly after base change), they represent the most accessible class of varieties for which one can hope to verify fundamental conjectures on special values of L-functions, including Deligne's conjecture and the Main Conjecture of Iwasawa theory. Immediate goals include the proof of irreducibility of automorphic Galois representations; the establishment of period relations for automorphic and potentially automorphic realizations of motives in the cohomology of distinct Shimura varieties; the construction of p-adic L-functions for these and related motives, notably adjoint and tensor product L-functions in p-adic families; and the geometrization of the p-adic and mod p Langlands program. All four goals, as well as the others mentioned in the body of the proposal, are interconnected; the final goal provides a bridge to related work in geometric representation theory, algebraic geometry, and mathematical physics.
Max ERC Funding
1 491 348 €
Duration
Start date: 2012-06-01, End date: 2018-05-31
Project acronym AAS
Project Approximate algebraic structure and applications
Researcher (PI) Ben Green
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Starting Grant (StG), PE1, ERC-2011-StG_20101014
Summary This project studies several mathematical topics with a related theme, all of them part of the relatively new discipline known as additive combinatorics.
We look at approximate, or rough, variants of familiar mathematical notions such as group, polynomial or homomorphism. In each case we seek to describe the structure of these approximate objects, and then to give applications of the resulting theorems. This endeavour has already lead to groundbreaking results in the theory of prime numbers, group theory and combinatorial number theory.
Summary
This project studies several mathematical topics with a related theme, all of them part of the relatively new discipline known as additive combinatorics.
We look at approximate, or rough, variants of familiar mathematical notions such as group, polynomial or homomorphism. In each case we seek to describe the structure of these approximate objects, and then to give applications of the resulting theorems. This endeavour has already lead to groundbreaking results in the theory of prime numbers, group theory and combinatorial number theory.
Max ERC Funding
1 000 000 €
Duration
Start date: 2011-10-01, End date: 2016-09-30
Project acronym ACCOPT
Project ACelerated COnvex OPTimization
Researcher (PI) Yurii NESTEROV
Host Institution (HI) UNIVERSITE CATHOLIQUE DE LOUVAIN
Call Details Advanced Grant (AdG), PE1, ERC-2017-ADG
Summary The amazing rate of progress in the computer technologies and telecommunications presents many new challenges for Optimization Theory. New problems are usually very big in size, very special in structure and possibly have a distributed data support. This makes them unsolvable by the standard optimization methods. In these situations, old theoretical models, based on the hidden Black-Box information, cannot work. New theoretical and algorithmic solutions are urgently needed. In this project we will concentrate on development of fast optimization methods for problems of big and very big size. All the new methods will be endowed with provable efficiency guarantees for large classes of optimization problems, arising in practical applications. Our main tool is the acceleration technique developed for the standard Black-Box methods as applied to smooth convex functions. However, we will have to adapt it to deal with different situations.
The first line of development will be based on the smoothing technique as applied to a non-smooth functions. We propose to substantially extend this approach to generate approximate solutions in relative scale. The second line of research will be related to applying acceleration techniques to the second-order methods minimizing functions with sparse Hessians. Finally, we aim to develop fast gradient methods for huge-scale problems. The size of these problems is so big that even the usual vector operations are extremely expensive. Thus, we propose to develop new methods with sublinear iteration costs. In our approach, the main source for achieving improvements will be the proper use of problem structure.
Our overall aim is to be able to solve in a routine way many important problems, which currently look unsolvable. Moreover, the theoretical development of Convex Optimization will reach the state, when there is no gap between theory and practice: the theoretically most efficient methods will definitely outperform any homebred heuristics.
Summary
The amazing rate of progress in the computer technologies and telecommunications presents many new challenges for Optimization Theory. New problems are usually very big in size, very special in structure and possibly have a distributed data support. This makes them unsolvable by the standard optimization methods. In these situations, old theoretical models, based on the hidden Black-Box information, cannot work. New theoretical and algorithmic solutions are urgently needed. In this project we will concentrate on development of fast optimization methods for problems of big and very big size. All the new methods will be endowed with provable efficiency guarantees for large classes of optimization problems, arising in practical applications. Our main tool is the acceleration technique developed for the standard Black-Box methods as applied to smooth convex functions. However, we will have to adapt it to deal with different situations.
The first line of development will be based on the smoothing technique as applied to a non-smooth functions. We propose to substantially extend this approach to generate approximate solutions in relative scale. The second line of research will be related to applying acceleration techniques to the second-order methods minimizing functions with sparse Hessians. Finally, we aim to develop fast gradient methods for huge-scale problems. The size of these problems is so big that even the usual vector operations are extremely expensive. Thus, we propose to develop new methods with sublinear iteration costs. In our approach, the main source for achieving improvements will be the proper use of problem structure.
Our overall aim is to be able to solve in a routine way many important problems, which currently look unsolvable. Moreover, the theoretical development of Convex Optimization will reach the state, when there is no gap between theory and practice: the theoretically most efficient methods will definitely outperform any homebred heuristics.
Max ERC Funding
2 090 038 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym ADAPTIVES
Project Algorithmic Development and Analysis of Pioneer Techniques for Imaging with waVES
Researcher (PI) Chrysoula Tsogka
Host Institution (HI) IDRYMA TECHNOLOGIAS KAI EREVNAS
Call Details Starting Grant (StG), PE1, ERC-2009-StG
Summary The proposed work concerns the theoretical and numerical development of robust and adaptive methodologies for broadband imaging in clutter. The word clutter expresses our uncertainty on the wave speed of the propagation medium. Our results are expected to have a strong impact in a wide range of applications, including underwater acoustics, exploration geophysics and ultrasound non-destructive testing. Our machinery is coherent interferometry (CINT), a state-of-the-art statistically stable imaging methodology, highly suitable for the development of imaging methods in clutter. We aim to extend CINT along two complementary directions: novel types of applications, and further mathematical and numerical development so as to assess and extend its range of applicability. CINT is designed for imaging with partially coherent array data recorded in richly scattering media. It uses statistical smoothing techniques to obtain results that are independent of the clutter realization. Quantifying the amount of smoothing needed is difficult, especially when there is no a priori knowledge about the propagation medium. We intend to address this question by coupling the imaging process with the estimation of the medium's large scale features. Our algorithms rely on the residual coherence in the data. When the coherent signal is too weak, the CINT results are unsatisfactory. We propose two ways for enhancing the resolution of CINT: filter the data prior to imaging (noise reduction) and waveform design (optimize the source distribution). Finally, we propose to extend the applicability of our imaging-in-clutter methodologies by investigating the possibility of utilizing ambient noise sources to perform passive sensor imaging, as well as by studying the imaging problem in random waveguides.
Summary
The proposed work concerns the theoretical and numerical development of robust and adaptive methodologies for broadband imaging in clutter. The word clutter expresses our uncertainty on the wave speed of the propagation medium. Our results are expected to have a strong impact in a wide range of applications, including underwater acoustics, exploration geophysics and ultrasound non-destructive testing. Our machinery is coherent interferometry (CINT), a state-of-the-art statistically stable imaging methodology, highly suitable for the development of imaging methods in clutter. We aim to extend CINT along two complementary directions: novel types of applications, and further mathematical and numerical development so as to assess and extend its range of applicability. CINT is designed for imaging with partially coherent array data recorded in richly scattering media. It uses statistical smoothing techniques to obtain results that are independent of the clutter realization. Quantifying the amount of smoothing needed is difficult, especially when there is no a priori knowledge about the propagation medium. We intend to address this question by coupling the imaging process with the estimation of the medium's large scale features. Our algorithms rely on the residual coherence in the data. When the coherent signal is too weak, the CINT results are unsatisfactory. We propose two ways for enhancing the resolution of CINT: filter the data prior to imaging (noise reduction) and waveform design (optimize the source distribution). Finally, we propose to extend the applicability of our imaging-in-clutter methodologies by investigating the possibility of utilizing ambient noise sources to perform passive sensor imaging, as well as by studying the imaging problem in random waveguides.
Max ERC Funding
690 000 €
Duration
Start date: 2010-06-01, End date: 2015-11-30
Project acronym ADDECCO
Project Adaptive Schemes for Deterministic and Stochastic Flow Problems
Researcher (PI) Remi Abgrall
Host Institution (HI) INSTITUT NATIONAL DE RECHERCHE ENINFORMATIQUE ET AUTOMATIQUE
Call Details Advanced Grant (AdG), PE1, ERC-2008-AdG
Summary The numerical simulation of complex compressible flow problem is still a challenge nowaday even for simple models. In our opinion, the most important hard points that need currently to be tackled and solved is how to obtain stable, scalable, very accurate, easy to code and to maintain schemes on complex geometries. The method should easily handle mesh refinement, even near the boundary where the most interesting engineering quantities have to be evaluated. Unsteady uncertainties in the model, for example in the geometry or the boundary conditions should represented efficiently.This proposal goal is to design, develop and evaluate solutions to each of the above problems. Our work program will lead to significant breakthroughs for flow simulations. More specifically, we propose to work on 3 connected problems: 1-A class of very high order numerical schemes able to easily deal with the geometry of boundaries and still can solve steep problems. The geometry is generally defined by CAD tools. The output is used to generate a mesh which is then used by the scheme. Hence, any mesh refinement process is disconnected from the CAD, a situation that prevents the spread of mesh adaptation techniques in industry! 2-A class of very high order numerical schemes which can utilize possibly solution dependant basis functions in order to lower the number of degrees of freedom, for example to compute accurately boundary layers with low resolutions. 3-A general non intrusive technique for handling uncertainties in order to deal with irregular probability density functions (pdf) and also to handle pdf that may evolve in time, for example thanks to an optimisation loop. The curse of dimensionality will be dealt thanks Harten's multiresolution method combined with sparse grid methods. Currently, and up to our knowledge, no scheme has each of these properties. This research program will have an impact on numerical schemes and industrial applications.
Summary
The numerical simulation of complex compressible flow problem is still a challenge nowaday even for simple models. In our opinion, the most important hard points that need currently to be tackled and solved is how to obtain stable, scalable, very accurate, easy to code and to maintain schemes on complex geometries. The method should easily handle mesh refinement, even near the boundary where the most interesting engineering quantities have to be evaluated. Unsteady uncertainties in the model, for example in the geometry or the boundary conditions should represented efficiently.This proposal goal is to design, develop and evaluate solutions to each of the above problems. Our work program will lead to significant breakthroughs for flow simulations. More specifically, we propose to work on 3 connected problems: 1-A class of very high order numerical schemes able to easily deal with the geometry of boundaries and still can solve steep problems. The geometry is generally defined by CAD tools. The output is used to generate a mesh which is then used by the scheme. Hence, any mesh refinement process is disconnected from the CAD, a situation that prevents the spread of mesh adaptation techniques in industry! 2-A class of very high order numerical schemes which can utilize possibly solution dependant basis functions in order to lower the number of degrees of freedom, for example to compute accurately boundary layers with low resolutions. 3-A general non intrusive technique for handling uncertainties in order to deal with irregular probability density functions (pdf) and also to handle pdf that may evolve in time, for example thanks to an optimisation loop. The curse of dimensionality will be dealt thanks Harten's multiresolution method combined with sparse grid methods. Currently, and up to our knowledge, no scheme has each of these properties. This research program will have an impact on numerical schemes and industrial applications.
Max ERC Funding
1 432 769 €
Duration
Start date: 2008-12-01, End date: 2013-11-30
Project acronym ADIMMUNE
Project Decoding interactions between adipose tissue immune cells, metabolic function, and the intestinal microbiome in obesity
Researcher (PI) Eran Elinav
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Consolidator Grant (CoG), LS6, ERC-2018-COG
Summary Obesity and its metabolic co-morbidities have given rise to a rapidly expanding ‘metabolic syndrome’ pandemic affecting
hundreds of millions of individuals worldwide. The integrative genetic and environmental causes of the obesity pandemic
remain elusive. White adipose tissue (WAT)-resident immune cells have recently been highlighted as important factors
contributing to metabolic complications. However, a comprehensive understanding of the regulatory circuits governing their
function and the cell type-specific mechanisms by which they contribute to the development of metabolic syndrome is
lacking. Likewise, the gut microbiome has been suggested as a critical regulator of obesity, but the bacterial species and
metabolites that influence WAT inflammation are entirely unknown.
We propose to use our recently developed high-throughput genomic and gnotobiotic tools, integrated with CRISPR-mediated interrogation of gene function, microbial culturomics, and in-vivo metabolic analysis in newly generated mouse models, in order to achieve a new level of molecular understanding of how WAT immune cells integrate environmental cues into their crosstalk with organismal metabolism, and to explore the microbial contributions to the molecular etiology of WAT inflammation in the pathogenesis of diet-induced obesity. Specifically, we aim to (a) decipher the global regulatory landscape and interaction networks of WAT hematopoietic cells at the single-cell level, (b) identify new mediators of WAT immune cell contributions to metabolic homeostasis, and (c) decode how host-microbiome communication shapes the development of WAT inflammation and obesity.
Unraveling the principles of WAT immune cell regulation and their amenability to change by host-microbiota interactions
may lead to a conceptual leap forward in our understanding of metabolic physiology and disease. Concomitantly, it may
generate a platform for microbiome-based personalized therapy against obesity and its complications.
Summary
Obesity and its metabolic co-morbidities have given rise to a rapidly expanding ‘metabolic syndrome’ pandemic affecting
hundreds of millions of individuals worldwide. The integrative genetic and environmental causes of the obesity pandemic
remain elusive. White adipose tissue (WAT)-resident immune cells have recently been highlighted as important factors
contributing to metabolic complications. However, a comprehensive understanding of the regulatory circuits governing their
function and the cell type-specific mechanisms by which they contribute to the development of metabolic syndrome is
lacking. Likewise, the gut microbiome has been suggested as a critical regulator of obesity, but the bacterial species and
metabolites that influence WAT inflammation are entirely unknown.
We propose to use our recently developed high-throughput genomic and gnotobiotic tools, integrated with CRISPR-mediated interrogation of gene function, microbial culturomics, and in-vivo metabolic analysis in newly generated mouse models, in order to achieve a new level of molecular understanding of how WAT immune cells integrate environmental cues into their crosstalk with organismal metabolism, and to explore the microbial contributions to the molecular etiology of WAT inflammation in the pathogenesis of diet-induced obesity. Specifically, we aim to (a) decipher the global regulatory landscape and interaction networks of WAT hematopoietic cells at the single-cell level, (b) identify new mediators of WAT immune cell contributions to metabolic homeostasis, and (c) decode how host-microbiome communication shapes the development of WAT inflammation and obesity.
Unraveling the principles of WAT immune cell regulation and their amenability to change by host-microbiota interactions
may lead to a conceptual leap forward in our understanding of metabolic physiology and disease. Concomitantly, it may
generate a platform for microbiome-based personalized therapy against obesity and its complications.
Max ERC Funding
2 000 000 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
