Project acronym 20SComplexity
Project An integrative approach to uncover the multilevel regulation of 20S proteasome degradation
Researcher (PI) Michal Sharon
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS1, ERC-2014-STG
Summary For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route.
To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation:
Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome.
Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function.
Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach.
Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
Summary
For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route.
To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation:
Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome.
Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function.
Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach.
Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym ABDESIGN
Project Computational design of novel protein function in antibodies
Researcher (PI) Sarel-Jacob Fleishman
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS1, ERC-2013-StG
Summary We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.
Summary
We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.
Max ERC Funding
1 499 930 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
Project acronym AGALT
Project Asymptotic Geometric Analysis and Learning Theory
Researcher (PI) Shahar Mendelson
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), PE1, ERC-2007-StG
Summary In a typical learning problem one tries to approximate an unknown function by a function from a given class using random data, sampled according to an unknown measure. In this project we will be interested in parameters that govern the complexity of a learning problem. It turns out that this complexity is determined by the geometry of certain sets in high dimension that are connected to the given class (random coordinate projections of the class). Thus, one has to understand the structure of these sets as a function of the dimension - which is given by the cardinality of the random sample. The resulting analysis leads to many theoretical questions in Asymptotic Geometric Analysis, Probability (most notably, Empirical Processes Theory) and Combinatorics, which are of independent interest beyond the application to Learning Theory. Our main goal is to describe the role of various complexity parameters involved in a learning problem, to analyze the connections between them and to investigate the way they determine the geometry of the relevant high dimensional sets. Some of the questions we intend to tackle are well known open problems and making progress towards their solution will have a significant theoretical impact. Moreover, this project should lead to a more complete theory of learning and is likely to have some practical impact, for example, in the design of more efficient learning algorithms.
Summary
In a typical learning problem one tries to approximate an unknown function by a function from a given class using random data, sampled according to an unknown measure. In this project we will be interested in parameters that govern the complexity of a learning problem. It turns out that this complexity is determined by the geometry of certain sets in high dimension that are connected to the given class (random coordinate projections of the class). Thus, one has to understand the structure of these sets as a function of the dimension - which is given by the cardinality of the random sample. The resulting analysis leads to many theoretical questions in Asymptotic Geometric Analysis, Probability (most notably, Empirical Processes Theory) and Combinatorics, which are of independent interest beyond the application to Learning Theory. Our main goal is to describe the role of various complexity parameters involved in a learning problem, to analyze the connections between them and to investigate the way they determine the geometry of the relevant high dimensional sets. Some of the questions we intend to tackle are well known open problems and making progress towards their solution will have a significant theoretical impact. Moreover, this project should lead to a more complete theory of learning and is likely to have some practical impact, for example, in the design of more efficient learning algorithms.
Max ERC Funding
750 000 €
Duration
Start date: 2009-03-01, End date: 2014-02-28
Project acronym ARITHQUANTUMCHAOS
Project Arithmetic and Quantum Chaos
Researcher (PI) Zeev Rudnick
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Advanced Grant (AdG), PE1, ERC-2012-ADG_20120216
Summary Quantum Chaos is an emerging discipline which is crossing over from Physics into Pure Mathematics. The recent crossover is driven in part by a connection with Number Theory. This project explores several aspects of this interrelationship and is composed of a number of sub-projects. The sub-projects deal with: statistics of energy levels and wave functions of pseudo-integrable systems, a hitherto unexplored subject in the mathematical community which is not well understood in the physics community; with statistics of zeros of zeta functions over function fields, a purely number theoretic topic which is linked to the subproject on Quantum Chaos through the mysterious connections to Random Matrix Theory and an analogy between energy levels and zeta zeros; and with spatial statistics in arithmetic.
Summary
Quantum Chaos is an emerging discipline which is crossing over from Physics into Pure Mathematics. The recent crossover is driven in part by a connection with Number Theory. This project explores several aspects of this interrelationship and is composed of a number of sub-projects. The sub-projects deal with: statistics of energy levels and wave functions of pseudo-integrable systems, a hitherto unexplored subject in the mathematical community which is not well understood in the physics community; with statistics of zeros of zeta functions over function fields, a purely number theoretic topic which is linked to the subproject on Quantum Chaos through the mysterious connections to Random Matrix Theory and an analogy between energy levels and zeta zeros; and with spatial statistics in arithmetic.
Max ERC Funding
1 714 000 €
Duration
Start date: 2013-02-01, End date: 2019-01-31
Project acronym BACTERIAL SPORES
Project Investigating the Nature of Bacterial Spores
Researcher (PI) Sigal Ben-Yehuda
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.
Summary
When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.
Max ERC Funding
1 630 000 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym BeyondA1
Project Set theory beyond the first uncountable cardinal
Researcher (PI) Assaf Shmuel Rinot
Host Institution (HI) BAR ILAN UNIVERSITY
Call Details Starting Grant (StG), PE1, ERC-2018-STG
Summary We propose to establish a research group that will unveil the combinatorial nature of the second uncountable cardinal. This includes its Ramsey-theoretic, order-theoretic, graph-theoretic and topological features. Among others, we will be directly addressing fundamental problems due to Erdos, Rado, Galvin, and Shelah.
While some of these problems are old and well-known, an unexpected series of breakthroughs from the last three years suggest that now is a promising point in time to carry out such a project. Indeed, through a short period, four previously unattainable problems concerning the second uncountable cardinal were successfully tackled: Aspero on a club-guessing problem of Shelah, Krueger on the club-isomorphism problem for Aronszajn trees, Neeman on the isomorphism problem for dense sets of reals, and the PI on the Souslin problem. Each of these results was obtained through the development of a completely new technical framework, and these frameworks could now pave the way for the solution of some major open questions.
A goal of the highest risk in this project is the discovery of a consistent (possibly, parameterized) forcing axiom that will (preferably, simultaneously) provide structure theorems for stationary sets, linearly ordered sets, trees, graphs, and partition relations, as well as the refutation of various forms of club-guessing principles, all at the level of the second uncountable cardinal. In comparison, at the level of the first uncountable cardinal, a forcing axiom due to Foreman, Magidor and Shelah achieves exactly that.
To approach our goals, the proposed project is divided into four core areas: Uncountable trees, Ramsey theory on ordinals, Club-guessing principles, and Forcing Axioms. There is a rich bilateral interaction between any pair of the four different cores, but the proposed division will allow an efficient allocation of manpower, and will increase the chances of parallel success.
Summary
We propose to establish a research group that will unveil the combinatorial nature of the second uncountable cardinal. This includes its Ramsey-theoretic, order-theoretic, graph-theoretic and topological features. Among others, we will be directly addressing fundamental problems due to Erdos, Rado, Galvin, and Shelah.
While some of these problems are old and well-known, an unexpected series of breakthroughs from the last three years suggest that now is a promising point in time to carry out such a project. Indeed, through a short period, four previously unattainable problems concerning the second uncountable cardinal were successfully tackled: Aspero on a club-guessing problem of Shelah, Krueger on the club-isomorphism problem for Aronszajn trees, Neeman on the isomorphism problem for dense sets of reals, and the PI on the Souslin problem. Each of these results was obtained through the development of a completely new technical framework, and these frameworks could now pave the way for the solution of some major open questions.
A goal of the highest risk in this project is the discovery of a consistent (possibly, parameterized) forcing axiom that will (preferably, simultaneously) provide structure theorems for stationary sets, linearly ordered sets, trees, graphs, and partition relations, as well as the refutation of various forms of club-guessing principles, all at the level of the second uncountable cardinal. In comparison, at the level of the first uncountable cardinal, a forcing axiom due to Foreman, Magidor and Shelah achieves exactly that.
To approach our goals, the proposed project is divided into four core areas: Uncountable trees, Ramsey theory on ordinals, Club-guessing principles, and Forcing Axioms. There is a rich bilateral interaction between any pair of the four different cores, but the proposed division will allow an efficient allocation of manpower, and will increase the chances of parallel success.
Max ERC Funding
1 362 500 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym BirNonArchGeom
Project Birational and non-archimedean geometries
Researcher (PI) Michael TEMKIN
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Consolidator Grant (CoG), PE1, ERC-2017-COG
Summary Resolution of singularities is one of classical, central and difficult areas of algebraic geometry, with a centennial history of intensive research and contributions of such great names as Zariski, Hironaka and Abhyankar. Nowadays, desingularization of schemes of characteristic zero is very well understood, while semistable reduction of morphisms and desingularization in positive characteristic are still waiting for major breakthroughs. In addition to the classical techniques with their triumph in characteristic zero, modern resolution of singularities includes de Jong's method of alterations, toroidal methods, formal analytic and non-archimedean methods, etc.
The aim of the proposed research is to study nearly all directions in resolution of singularities and semistable reduction, as well as the wild ramification phenomena, which are probably the main obstacle to transfer methods from characteristic zero to positive characteristic.
The methods of algebraic and non-archimedean geometries are intertwined in the proposal, though algebraic geometry is somewhat dominating, especially due to the new stack-theoretic techniques. It seems very probable that increasing the symbiosis between birational and non-archimedean geometries will be one of by-products of this research.
Summary
Resolution of singularities is one of classical, central and difficult areas of algebraic geometry, with a centennial history of intensive research and contributions of such great names as Zariski, Hironaka and Abhyankar. Nowadays, desingularization of schemes of characteristic zero is very well understood, while semistable reduction of morphisms and desingularization in positive characteristic are still waiting for major breakthroughs. In addition to the classical techniques with their triumph in characteristic zero, modern resolution of singularities includes de Jong's method of alterations, toroidal methods, formal analytic and non-archimedean methods, etc.
The aim of the proposed research is to study nearly all directions in resolution of singularities and semistable reduction, as well as the wild ramification phenomena, which are probably the main obstacle to transfer methods from characteristic zero to positive characteristic.
The methods of algebraic and non-archimedean geometries are intertwined in the proposal, though algebraic geometry is somewhat dominating, especially due to the new stack-theoretic techniques. It seems very probable that increasing the symbiosis between birational and non-archimedean geometries will be one of by-products of this research.
Max ERC Funding
1 365 600 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym CASe
Project Combinatorics with an analytic structure
Researcher (PI) Karim ADIPRASITO
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), PE1, ERC-2016-STG
Summary "Combinatorics, and its interplay with geometry, has fascinated our ancestors as shown by early stone carvings in the Neolithic period. Modern combinatorics is motivated by the ubiquity of its structures in both pure and applied mathematics.
The work of Hochster and Stanley, who realized the relation of enumerative questions to commutative algebra and toric geometry made a vital contribution to the development of this subject. Their work was a central contribution to the classification of face numbers of simple polytopes, and the initial success lead to a wealth of research in which combinatorial problems were translated to algebra and geometry and then solved using deep results such as Saito's hard Lefschetz theorem. As a caveat, this also made branches of combinatorics reliant on algebra and geometry to provide new ideas.
In this proposal, I want to reverse this approach and extend our understanding of geometry and algebra guided by combinatorial methods. In this spirit I propose new combinatorial approaches to the interplay of curvature and topology, to isoperimetry, geometric analysis, and intersection theory, to name a few. In addition, while these subjects are interesting by themselves, they are also designed to advance classical topics, for example, the diameter of polyhedra (as in the Hirsch conjecture), arrangement theory (and the study of arrangement complements), Hodge theory (as in Grothendieck's standard conjectures), and realization problems of discrete objects (as in Connes embedding problem for type II factors).
This proposal is supported by the review of some already developed tools, such as relative Stanley--Reisner theory (which is equipped to deal with combinatorial isoperimetries), combinatorial Hodge theory (which extends the ``K\""ahler package'' to purely combinatorial settings), and discrete PDEs (which were used to construct counterexamples to old problems in discrete geometry)."
Summary
"Combinatorics, and its interplay with geometry, has fascinated our ancestors as shown by early stone carvings in the Neolithic period. Modern combinatorics is motivated by the ubiquity of its structures in both pure and applied mathematics.
The work of Hochster and Stanley, who realized the relation of enumerative questions to commutative algebra and toric geometry made a vital contribution to the development of this subject. Their work was a central contribution to the classification of face numbers of simple polytopes, and the initial success lead to a wealth of research in which combinatorial problems were translated to algebra and geometry and then solved using deep results such as Saito's hard Lefschetz theorem. As a caveat, this also made branches of combinatorics reliant on algebra and geometry to provide new ideas.
In this proposal, I want to reverse this approach and extend our understanding of geometry and algebra guided by combinatorial methods. In this spirit I propose new combinatorial approaches to the interplay of curvature and topology, to isoperimetry, geometric analysis, and intersection theory, to name a few. In addition, while these subjects are interesting by themselves, they are also designed to advance classical topics, for example, the diameter of polyhedra (as in the Hirsch conjecture), arrangement theory (and the study of arrangement complements), Hodge theory (as in Grothendieck's standard conjectures), and realization problems of discrete objects (as in Connes embedding problem for type II factors).
This proposal is supported by the review of some already developed tools, such as relative Stanley--Reisner theory (which is equipped to deal with combinatorial isoperimetries), combinatorial Hodge theory (which extends the ``K\""ahler package'' to purely combinatorial settings), and discrete PDEs (which were used to construct counterexamples to old problems in discrete geometry)."
Max ERC Funding
1 337 200 €
Duration
Start date: 2016-12-01, End date: 2021-11-30
Project acronym CELLREPROGRAMMING
Project Uncovering the Mechanisms of Epigenetic Reprogramming of Pluripotent and Somatic Cell States
Researcher (PI) Yaqub Hanna
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary The generation of animals by nuclear transfer demonstrated that the epigenetic state of somatic cells could be reset to an embryonic state, capable of directing the development of a new organism. The nuclear cloning technology is of interest for transplantation medicine, but any application is hampered by the inefficiency and ethical problems. A breakthrough solving these issues has been the in vitro derivation of reprogrammed Induced Pluripotent Stem “iPS” cells by the ectopic expression of defined transcription factors in somatic cells. iPS cells recapitulate all defining features of embryo-derived pluripotent stem cells, including the ability to differentiate into all somatic cell types. Further, recent publications have demonstrated the ability to directly trans-differentiate somatic cell types by ectopic expression of lineage specification factors. Thus, it is becoming increasingly clear that an ultimate goal in the stem cell field is to enable scientists to have the power to safely manipulate somatic cells by “reprogramming” their behavior at will. However, to frame this challenge, we must understand the basic mechanisms underlying the generation of reprogrammed cells in parallel to designing strategies for their medical application and their use in human disease specific research. In this ERC Starting Grant proposal, I describe comprehensive lines of experimentation that I plan to conduct in my new lab scheduled to open in April 2011 at the Weizmann Institute of Science. We will utilize exacting transgenic mammalian models and high throughput sequencing and genomic screening tools for in depth characterization of the molecular “rules” of rewiring the epigenome of somatic and pluripotent cell states. The proposed research endeavors will not only contribute to the development of safer strategies for cell reprogramming, but will also help decipher how diverse gene expression programs lead to cellular specification during normal development.
Summary
The generation of animals by nuclear transfer demonstrated that the epigenetic state of somatic cells could be reset to an embryonic state, capable of directing the development of a new organism. The nuclear cloning technology is of interest for transplantation medicine, but any application is hampered by the inefficiency and ethical problems. A breakthrough solving these issues has been the in vitro derivation of reprogrammed Induced Pluripotent Stem “iPS” cells by the ectopic expression of defined transcription factors in somatic cells. iPS cells recapitulate all defining features of embryo-derived pluripotent stem cells, including the ability to differentiate into all somatic cell types. Further, recent publications have demonstrated the ability to directly trans-differentiate somatic cell types by ectopic expression of lineage specification factors. Thus, it is becoming increasingly clear that an ultimate goal in the stem cell field is to enable scientists to have the power to safely manipulate somatic cells by “reprogramming” their behavior at will. However, to frame this challenge, we must understand the basic mechanisms underlying the generation of reprogrammed cells in parallel to designing strategies for their medical application and their use in human disease specific research. In this ERC Starting Grant proposal, I describe comprehensive lines of experimentation that I plan to conduct in my new lab scheduled to open in April 2011 at the Weizmann Institute of Science. We will utilize exacting transgenic mammalian models and high throughput sequencing and genomic screening tools for in depth characterization of the molecular “rules” of rewiring the epigenome of somatic and pluripotent cell states. The proposed research endeavors will not only contribute to the development of safer strategies for cell reprogramming, but will also help decipher how diverse gene expression programs lead to cellular specification during normal development.
Max ERC Funding
1 960 000 €
Duration
Start date: 2011-11-01, End date: 2016-10-31
Project acronym CIRCOMMUNICATION
Project Deciphering molecular pathways of circadian clock communication
Researcher (PI) gad ASHER
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Consolidator Grant (CoG), LS1, ERC-2017-COG
Summary The overarching objective of this interdisciplinary project is to elucidate mechanisms through which billions of individual clocks in the body communicate with each other and tick in harmony. The mammalian circadian timing system consists of a master clock in the brain and subsidiary oscillators in almost every cell of the body. Since these clocks anticipate environmental changes and function together to orchestrate daily physiology and behavior their temporal synchronization is critical.
Our recent finding that oxygen serves as a resetting cue for circadian clocks points towards the unprecedented involvement of blood gases as time signals. We will apply cutting edge continuous physiological measurements in freely moving animals, alongside biochemical/molecular biology approaches and advanced cell culture setup to determine the molecular role of oxygen, carbon dioxide and pH in circadian clock communication and function.
The intricate nature of the mammalian circadian system demands the presence of communication mechanisms between clocks throughout the body at multiple levels. While previous studies primarily addressed the role of the master clock in resetting peripheral clocks, our knowledge regarding the communication among clocks between and within peripheral organs is rudimentary. We will reconstruct the mammalian circadian system from the bottom up, sequentially restoring clocks in peripheral tissues of a non-rhythmic animal to (i) obtain a system-view of the peripheral circadian communication network; and (ii) study novel tissue-derived circadian communication mechanisms.
This integrative proposal addresses fundamental aspects of circadian biology. It is expected to unravel the circadian communication network and shed light on how billions of clocks in the body function in unison. Its impact extends beyond circadian rhythms and bears great potential for research on communication between cells/tissues in various fields of biology.
Summary
The overarching objective of this interdisciplinary project is to elucidate mechanisms through which billions of individual clocks in the body communicate with each other and tick in harmony. The mammalian circadian timing system consists of a master clock in the brain and subsidiary oscillators in almost every cell of the body. Since these clocks anticipate environmental changes and function together to orchestrate daily physiology and behavior their temporal synchronization is critical.
Our recent finding that oxygen serves as a resetting cue for circadian clocks points towards the unprecedented involvement of blood gases as time signals. We will apply cutting edge continuous physiological measurements in freely moving animals, alongside biochemical/molecular biology approaches and advanced cell culture setup to determine the molecular role of oxygen, carbon dioxide and pH in circadian clock communication and function.
The intricate nature of the mammalian circadian system demands the presence of communication mechanisms between clocks throughout the body at multiple levels. While previous studies primarily addressed the role of the master clock in resetting peripheral clocks, our knowledge regarding the communication among clocks between and within peripheral organs is rudimentary. We will reconstruct the mammalian circadian system from the bottom up, sequentially restoring clocks in peripheral tissues of a non-rhythmic animal to (i) obtain a system-view of the peripheral circadian communication network; and (ii) study novel tissue-derived circadian communication mechanisms.
This integrative proposal addresses fundamental aspects of circadian biology. It is expected to unravel the circadian communication network and shed light on how billions of clocks in the body function in unison. Its impact extends beyond circadian rhythms and bears great potential for research on communication between cells/tissues in various fields of biology.
Max ERC Funding
1 999 945 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym CONC-VIA-RIEMANN
Project High-Dimensional Convexity, Isoperimetry and Concentration via a Riemannian Vantage Point
Researcher (PI) Emanuel Milman
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), PE1, ERC-2014-STG
Summary "In recent years, the importance of superimposing the contribution of the measure to that of the metric, in determining the underlying space's (generalized Ricci) curvature, has been clarified in the works of Lott, Sturm, Villani and others, following the definition of Curvature-Dimension introduced by Bakry and Emery. We wish to systematically incorporate
this important idea of considering the measure and metric in tandem, in the study of questions pertaining to isoperimetric and concentration properties of convex domains in high-dimensional Euclidean space, where a-priori there is only a trivial metric (Euclidean) and trivial measure (Lebesgue).
The first step of enriching the class of uniform measures on convex domains to that of non-negatively curved (""log-concave"") measures in Euclidean space has been very successfully implemented in the last decades, leading to substantial progress in our understanding of volumetric properties of convex domains, mostly regarding concentration of linear functionals. However, the potential advantages of altering the Euclidean metric into a more general Riemannian one or exploiting related Riemannian structures have not been systematically explored. Our main paradigm is that in order to progress in non-linear questions pertaining to concentration in Euclidean space, it is imperative to cast and study these problems in the more general Riemannian context.
As witnessed by our own work over the last years, we expect that broadening the scope and incorporating tools from the Riemannian world will lead to significant progress in our understanding of the qualitative and quantitative structure of isoperimetric minimizers in the purely Euclidean setting. Such progress would have dramatic impact on long-standing fundamental conjectures regarding concentration of measure on high-dimensional convex domains, as well as other closely related fields such as Probability Theory, Learning Theory, Random Matrix Theory and Algorithmic Geometry."
Summary
"In recent years, the importance of superimposing the contribution of the measure to that of the metric, in determining the underlying space's (generalized Ricci) curvature, has been clarified in the works of Lott, Sturm, Villani and others, following the definition of Curvature-Dimension introduced by Bakry and Emery. We wish to systematically incorporate
this important idea of considering the measure and metric in tandem, in the study of questions pertaining to isoperimetric and concentration properties of convex domains in high-dimensional Euclidean space, where a-priori there is only a trivial metric (Euclidean) and trivial measure (Lebesgue).
The first step of enriching the class of uniform measures on convex domains to that of non-negatively curved (""log-concave"") measures in Euclidean space has been very successfully implemented in the last decades, leading to substantial progress in our understanding of volumetric properties of convex domains, mostly regarding concentration of linear functionals. However, the potential advantages of altering the Euclidean metric into a more general Riemannian one or exploiting related Riemannian structures have not been systematically explored. Our main paradigm is that in order to progress in non-linear questions pertaining to concentration in Euclidean space, it is imperative to cast and study these problems in the more general Riemannian context.
As witnessed by our own work over the last years, we expect that broadening the scope and incorporating tools from the Riemannian world will lead to significant progress in our understanding of the qualitative and quantitative structure of isoperimetric minimizers in the purely Euclidean setting. Such progress would have dramatic impact on long-standing fundamental conjectures regarding concentration of measure on high-dimensional convex domains, as well as other closely related fields such as Probability Theory, Learning Theory, Random Matrix Theory and Algorithmic Geometry."
Max ERC Funding
1 194 190 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym CRYOMATH
Project Cryo-electron microscopy: mathematical foundations and algorithms
Researcher (PI) Yoel SHKOLNISKY
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Consolidator Grant (CoG), PE1, ERC-2016-COG
Summary The importance of understanding the functions of the basic building blocks of life, such as proteins, cannot be overstated (as asserted by two recent Nobel prizes in Chemistry), as this understanding unravels the mechanisms that control all organisms. The critical step towards such an understanding is to reveal the structures of these building blocks. A leading method for resolving such structures is cryo-electron microscopy (cryo-EM), in which the structure of a molecule is recovered from its images taken by an electron microscope, by using sophisticated mathematical algorithms (to which my group has made several key mathematical and algorithmic contributions). Due to hardware breakthroughs in the past three years, cryo-EM has made a giant leap forward, introducing capabilities that until recently were unimaginable, opening an opportunity to revolutionize our biological understanding. As extracting information from cryo-EM experiments completely relies on mathematical algorithms, the method’s deep mathematical challenges that have emerged must be solved as soon as possible. Only then cryo-EM could realize its nearly inconceivable potential. These challenges, for which no adequate solutions exist (or none at all), focus on integrating information from huge sets of extremely noisy images reliability and efficiently. Based on the experience of my research group in developing algorithms for cryo-EM data processing, gained during the past eight years, we will address the three key open challenges of the field – a) deriving reliable and robust reconstruction algorithms from cryo-EM data, b) developing tools to process heterogeneous cryo-EM data sets, and c) devising validation and quality measures for structures determined from cryo-EM data. The fourth goal of the project, which ties all goals together and promotes the broad interdisciplinary impact of the project, is to merge all our algorithms into a software platform for state-of-the-art processing of cryo-EM data.
Summary
The importance of understanding the functions of the basic building blocks of life, such as proteins, cannot be overstated (as asserted by two recent Nobel prizes in Chemistry), as this understanding unravels the mechanisms that control all organisms. The critical step towards such an understanding is to reveal the structures of these building blocks. A leading method for resolving such structures is cryo-electron microscopy (cryo-EM), in which the structure of a molecule is recovered from its images taken by an electron microscope, by using sophisticated mathematical algorithms (to which my group has made several key mathematical and algorithmic contributions). Due to hardware breakthroughs in the past three years, cryo-EM has made a giant leap forward, introducing capabilities that until recently were unimaginable, opening an opportunity to revolutionize our biological understanding. As extracting information from cryo-EM experiments completely relies on mathematical algorithms, the method’s deep mathematical challenges that have emerged must be solved as soon as possible. Only then cryo-EM could realize its nearly inconceivable potential. These challenges, for which no adequate solutions exist (or none at all), focus on integrating information from huge sets of extremely noisy images reliability and efficiently. Based on the experience of my research group in developing algorithms for cryo-EM data processing, gained during the past eight years, we will address the three key open challenges of the field – a) deriving reliable and robust reconstruction algorithms from cryo-EM data, b) developing tools to process heterogeneous cryo-EM data sets, and c) devising validation and quality measures for structures determined from cryo-EM data. The fourth goal of the project, which ties all goals together and promotes the broad interdisciplinary impact of the project, is to merge all our algorithms into a software platform for state-of-the-art processing of cryo-EM data.
Max ERC Funding
1 751 250 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym CSG
Project C° symplectic geometry
Researcher (PI) Lev Buhovski
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Starting Grant (StG), PE1, ERC-2017-STG
Summary "The objective of this proposal is to study ""continuous"" (or C^0) objects, as well as C^0 properties of smooth objects, in the field of symplectic geometry and topology. C^0 symplectic geometry has seen spectacular progress in recent years, drawing attention of mathematicians from various background. The proposed study aims to discover new fascinating C^0 phenomena in symplectic geometry.
One circle of questions concerns symplectic and Hamiltonian homeomorphisms. Recent studies indicate that these objects possess both rigidity and flexibility, appearing in surprising and counter-intuitive ways. Our understanding of symplectic and Hamiltonian homeomorphisms is far from being satisfactory, and here we intend to study questions related to action of symplectic homeomorphisms on submanifolds. Some other questions are about Hamiltonian homeomorphisms in relation to the celebrated Arnold conjecture. The PI suggests to study spectral invariants of continuous Hamiltonian flows, which allow to formulate the C^0 Arnold conjecture in higher dimensions. Another central problem that the PI will work on is the C^0 flux conjecture.
A second circle of questions is about the Poisson bracket operator, and its functional-theoretic properties. The first question concerns the lower bound for the Poisson bracket invariant of a cover, conjectured by L. Polterovich who indicated relations between this problem and quantum mechanics. Another direction aims to study the C^0 rigidity versus flexibility of the L_p norm of the Poisson bracket. Despite a recent progress in dimension two showing rigidity, very little is known in higher dimensions. The PI proposes to use combination of tools from topology and from hard analysis in order to address this question, whose solution will be a big step towards understanding functional-theoretic properties of the Poisson bracket operator."
Summary
"The objective of this proposal is to study ""continuous"" (or C^0) objects, as well as C^0 properties of smooth objects, in the field of symplectic geometry and topology. C^0 symplectic geometry has seen spectacular progress in recent years, drawing attention of mathematicians from various background. The proposed study aims to discover new fascinating C^0 phenomena in symplectic geometry.
One circle of questions concerns symplectic and Hamiltonian homeomorphisms. Recent studies indicate that these objects possess both rigidity and flexibility, appearing in surprising and counter-intuitive ways. Our understanding of symplectic and Hamiltonian homeomorphisms is far from being satisfactory, and here we intend to study questions related to action of symplectic homeomorphisms on submanifolds. Some other questions are about Hamiltonian homeomorphisms in relation to the celebrated Arnold conjecture. The PI suggests to study spectral invariants of continuous Hamiltonian flows, which allow to formulate the C^0 Arnold conjecture in higher dimensions. Another central problem that the PI will work on is the C^0 flux conjecture.
A second circle of questions is about the Poisson bracket operator, and its functional-theoretic properties. The first question concerns the lower bound for the Poisson bracket invariant of a cover, conjectured by L. Polterovich who indicated relations between this problem and quantum mechanics. Another direction aims to study the C^0 rigidity versus flexibility of the L_p norm of the Poisson bracket. Despite a recent progress in dimension two showing rigidity, very little is known in higher dimensions. The PI proposes to use combination of tools from topology and from hard analysis in order to address this question, whose solution will be a big step towards understanding functional-theoretic properties of the Poisson bracket operator."
Max ERC Funding
1 345 282 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym DEATHSWITCHING
Project Identifying genes and pathways that drive molecular switches and back-up mechanisms between apoptosis and autophagy
Researcher (PI) Adi Kimchi
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS3, ERC-2012-ADG_20120314
Summary A cell’s decision to die is governed by multiple input signals received from a complex network of programmed cell death (PCD) pathways, including apoptosis and programmed necrosis. Additionally, under some conditions, autophagy, whose function is mainly pro-survival, may act as a back-up death pathway. We propose to apply new approaches to study the molecular basis of two important questions that await resolution in the field: a) how the cell switches from a pro-survival autophagic response to an apoptotic response and b) whether and how pro-survival autophagy is converted to a death mechanism when apoptosis is blocked. To address the first issue, we will screen for direct physical interactions between autophagic and apoptotic proteins, using the protein fragment complementation assay. Validated pairs will be studied in depth to identify built-in molecular switches that activate apoptosis when autophagy fails to restore homeostasis. As a pilot case to address the concept of molecular ‘sensors’ and ‘switches’, we will focus on the previously identified Atg12/Bcl-2 interaction. In the second line of research we will categorize autophagy-dependent cell death triggers into those that directly result from autophagy-dependent degradation, either by excessive self-digestion or by selective protein degradation, and those that utilize the autophagy machinery to activate programmed necrosis. We will identify the genes regulating these scenarios by whole genome RNAi screens for increased cell survival. In parallel, we will use a cell library of annotated fluorescent-tagged proteins for measuring selective protein degradation. These will be the starting point for identification of the molecular pathways that convert survival autophagy to a death program. Finally, we will explore the physiological relevance of back-up death mechanisms and the newly identified molecular mechanisms to developmental PCD during the cavitation process in early stages of embryogenesis.
Summary
A cell’s decision to die is governed by multiple input signals received from a complex network of programmed cell death (PCD) pathways, including apoptosis and programmed necrosis. Additionally, under some conditions, autophagy, whose function is mainly pro-survival, may act as a back-up death pathway. We propose to apply new approaches to study the molecular basis of two important questions that await resolution in the field: a) how the cell switches from a pro-survival autophagic response to an apoptotic response and b) whether and how pro-survival autophagy is converted to a death mechanism when apoptosis is blocked. To address the first issue, we will screen for direct physical interactions between autophagic and apoptotic proteins, using the protein fragment complementation assay. Validated pairs will be studied in depth to identify built-in molecular switches that activate apoptosis when autophagy fails to restore homeostasis. As a pilot case to address the concept of molecular ‘sensors’ and ‘switches’, we will focus on the previously identified Atg12/Bcl-2 interaction. In the second line of research we will categorize autophagy-dependent cell death triggers into those that directly result from autophagy-dependent degradation, either by excessive self-digestion or by selective protein degradation, and those that utilize the autophagy machinery to activate programmed necrosis. We will identify the genes regulating these scenarios by whole genome RNAi screens for increased cell survival. In parallel, we will use a cell library of annotated fluorescent-tagged proteins for measuring selective protein degradation. These will be the starting point for identification of the molecular pathways that convert survival autophagy to a death program. Finally, we will explore the physiological relevance of back-up death mechanisms and the newly identified molecular mechanisms to developmental PCD during the cavitation process in early stages of embryogenesis.
Max ERC Funding
2 500 000 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym DEPENDENTCLASSES
Project Model theory and its applications: dependent classes
Researcher (PI) Saharon Shelah
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), PE1, ERC-2013-ADG
Summary Model theory deals with general classes of structures (called models).
Specific examples of such classes are: the class of rings or the class of
algebraically closed fields.
It turns out that counting the so-called complete types over models in the
class has an important role in the development of model theory in general and
stability theory in particular.
Stable classes are those with relatively few complete types (over structures
from the class); understanding stable classes has been central in model theory
and its applications.
Recently, I have proved a new dichotomy among the unstable classes:
Instead of counting all the complete types, they are counted up to conjugacy.
Classes which have few types up to conjugacy are proved to be so-called
``dependent'' classes (which have also been called NIP classes).
I have developed (under reasonable restrictions) a ``recounting theorem'',
parallel to the basic theorems of stability theory.
I have started to develop some of the basic properties of this new approach.
The goal of the current project is to develop systematically the theory of
dependent classes. The above mentioned results give strong indication that this
new theory can be eventually as useful as the (by now the classical) stability
theory. In particular, it covers many well known classes which stability theory
cannot treat.
Summary
Model theory deals with general classes of structures (called models).
Specific examples of such classes are: the class of rings or the class of
algebraically closed fields.
It turns out that counting the so-called complete types over models in the
class has an important role in the development of model theory in general and
stability theory in particular.
Stable classes are those with relatively few complete types (over structures
from the class); understanding stable classes has been central in model theory
and its applications.
Recently, I have proved a new dichotomy among the unstable classes:
Instead of counting all the complete types, they are counted up to conjugacy.
Classes which have few types up to conjugacy are proved to be so-called
``dependent'' classes (which have also been called NIP classes).
I have developed (under reasonable restrictions) a ``recounting theorem'',
parallel to the basic theorems of stability theory.
I have started to develop some of the basic properties of this new approach.
The goal of the current project is to develop systematically the theory of
dependent classes. The above mentioned results give strong indication that this
new theory can be eventually as useful as the (by now the classical) stability
theory. In particular, it covers many well known classes which stability theory
cannot treat.
Max ERC Funding
1 748 000 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym DIMENSION
Project High-Dimensional Phenomena and Convexity
Researcher (PI) Boaz Binyamin Klartag
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), PE1, ERC-2012-StG_20111012
Summary High-dimensional problems with a geometric flavor appear in quite a few branches of mathematics, mathematical physics and theoretical computer science. A priori, one would think that the diversity and the rapid increase of the number of configurations would make it impossible to formulate general, interesting theorems that apply to large classes of high-dimensional geometric objects. The underlying theme of the proposed project is that the contrary is often true. Mathematical developments of the last decades indicate that high dimensionality, when viewed correctly, may create remarkable order and simplicity, rather than complication. For example, Dvoretzky's theorem demonstrates that any high-dimensional convex body has nearly-Euclidean sections of a high dimension. Another example is the central limit theorem for convex bodies due to the PI, according to which any high-dimensional convex body has approximately Gaussian marginals. There are a number of strong motifs in high-dimensional geometry, such as the concentration of measure, which seem to compensate for the vast amount of different possibilities. Convexity is one of the ways in which to harness these motifs and thereby formulate clean, non-trivial theorems. The scientific goals of the project are to develop new methods for the study of convexity in high dimensions beyond the concentration of measure, to explore emerging connections with other fields of mathematics, and to solve the outstanding problems related to the distribution of volume in high-dimensional convex sets.
Summary
High-dimensional problems with a geometric flavor appear in quite a few branches of mathematics, mathematical physics and theoretical computer science. A priori, one would think that the diversity and the rapid increase of the number of configurations would make it impossible to formulate general, interesting theorems that apply to large classes of high-dimensional geometric objects. The underlying theme of the proposed project is that the contrary is often true. Mathematical developments of the last decades indicate that high dimensionality, when viewed correctly, may create remarkable order and simplicity, rather than complication. For example, Dvoretzky's theorem demonstrates that any high-dimensional convex body has nearly-Euclidean sections of a high dimension. Another example is the central limit theorem for convex bodies due to the PI, according to which any high-dimensional convex body has approximately Gaussian marginals. There are a number of strong motifs in high-dimensional geometry, such as the concentration of measure, which seem to compensate for the vast amount of different possibilities. Convexity is one of the ways in which to harness these motifs and thereby formulate clean, non-trivial theorems. The scientific goals of the project are to develop new methods for the study of convexity in high dimensions beyond the concentration of measure, to explore emerging connections with other fields of mathematics, and to solve the outstanding problems related to the distribution of volume in high-dimensional convex sets.
Max ERC Funding
998 000 €
Duration
Start date: 2013-01-01, End date: 2018-12-31
Project acronym DLGAPS
Project Dynamics of Lie group actions on parameter spaces
Researcher (PI) Barak Weiss
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Starting Grant (StG), PE1, ERC-2011-StG_20101014
Summary There are many parallels between Lie group actions on homogeneous spaces and the action of $\SL_2(\R)$ and its subgroups on strata of translation or half-translation surfaces. I propose to investigate these two spaces in parallel, focusing on the dynamical
behavior, and more specifically, the description of orbit-closures.
I intend to utilize existing and emerging measure rigidity results, and to develop new topological
approaches. These should also shed light on the geometry and topology of the spaces. I propose to apply results concerning these spaces to the study of diophantine approximations (approximation on fractals), geometry of numbers (Minkowski's conjecture), interval exchanges, and rational billiards.
Summary
There are many parallels between Lie group actions on homogeneous spaces and the action of $\SL_2(\R)$ and its subgroups on strata of translation or half-translation surfaces. I propose to investigate these two spaces in parallel, focusing on the dynamical
behavior, and more specifically, the description of orbit-closures.
I intend to utilize existing and emerging measure rigidity results, and to develop new topological
approaches. These should also shed light on the geometry and topology of the spaces. I propose to apply results concerning these spaces to the study of diophantine approximations (approximation on fractals), geometry of numbers (Minkowski's conjecture), interval exchanges, and rational billiards.
Max ERC Funding
850 000 €
Duration
Start date: 2011-10-01, End date: 2016-09-30
Project acronym DMMCA
Project Discrete Mathematics: methods, challenges and applications
Researcher (PI) Noga Alon
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Advanced Grant (AdG), PE1, ERC-2008-AdG
Summary Discrete Mathematics is a fundamental mathematical discipline as well as an essential component of many mathematical areas, and its study has experienced an impressive growth in recent years. Some of the main reasons for this growth are the broad applications of tools and techniques from extremal and probabilistic combinatorics in the rapid development of theoretical Computer Science, in the spectacular recent results in Additive Number Theory and in the study of basic questions in Information Theory. While in the past many of the basic combinatorial results were obtained mainly by ingenuity and detailed reasoning, the modern theory has grown out of this early stage, and often relies on deep, well developed tools, like the probabilistic method, algebraic, topological and geometric techniques. The work of the principal investigator, partly jointly with several collaborators and students, and partly in individual efforts, has played a significant role in the introduction of powerful algebraic, probabilistic, spectral and geometric techniques that influenced the development of modern combinatorics. In the present project he aims to try and further develop such tools, trying to tackle some basic open problems in Combinatorics, as well as significant questions in Additive Combinatorics, Information Theory, and theoretical Computer Science. Progress on the problems mentioned in this proposal, and the study of related ones, is expected to provide new insights on these problems and to lead to the development of novel fruitful techniques that are likely to be useful in Discrete Mathematics as well as in related areas.
Summary
Discrete Mathematics is a fundamental mathematical discipline as well as an essential component of many mathematical areas, and its study has experienced an impressive growth in recent years. Some of the main reasons for this growth are the broad applications of tools and techniques from extremal and probabilistic combinatorics in the rapid development of theoretical Computer Science, in the spectacular recent results in Additive Number Theory and in the study of basic questions in Information Theory. While in the past many of the basic combinatorial results were obtained mainly by ingenuity and detailed reasoning, the modern theory has grown out of this early stage, and often relies on deep, well developed tools, like the probabilistic method, algebraic, topological and geometric techniques. The work of the principal investigator, partly jointly with several collaborators and students, and partly in individual efforts, has played a significant role in the introduction of powerful algebraic, probabilistic, spectral and geometric techniques that influenced the development of modern combinatorics. In the present project he aims to try and further develop such tools, trying to tackle some basic open problems in Combinatorics, as well as significant questions in Additive Combinatorics, Information Theory, and theoretical Computer Science. Progress on the problems mentioned in this proposal, and the study of related ones, is expected to provide new insights on these problems and to lead to the development of novel fruitful techniques that are likely to be useful in Discrete Mathematics as well as in related areas.
Max ERC Funding
1 061 300 €
Duration
Start date: 2008-12-01, End date: 2013-11-30
Project acronym EffectiveTG
Project Effective Methods in Tame Geometry and Applications in Arithmetic and Dynamics
Researcher (PI) Gal BINYAMINI
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), PE1, ERC-2018-STG
Summary Tame geometry studies structures in which every definable set has a
finite geometric complexity. The study of tame geometry spans several
interrelated mathematical fields, including semialgebraic,
subanalytic, and o-minimal geometry. The past decade has seen the
emergence of a spectacular link between tame geometry and arithmetic
following the discovery of the fundamental Pila-Wilkie counting
theorem and its applications in unlikely diophantine
intersections. The P-W theorem itself relies crucially on the
Yomdin-Gromov theorem, a classical result of tame geometry with
fundamental applications in smooth dynamics.
It is natural to ask whether the complexity of a tame set can be
estimated effectively in terms of the defining formulas. While a large
body of work is devoted to answering such questions in the
semialgebraic case, surprisingly little is known concerning more
general tame structures - specifically those needed in recent
applications to arithmetic. The nature of the link between tame
geometry and arithmetic is such that any progress toward effectivizing
the theory of tame structures will likely lead to effective results
in the domain of unlikely intersections. Similarly, a more effective
version of the Yomdin-Gromov theorem is known to imply important
consequences in smooth dynamics.
The proposed research will approach effectivity in tame geometry from
a fundamentally new direction, bringing to bear methods from the
theory of differential equations which have until recently never been
used in this context. Toward this end, our key goals will be to gain
insight into the differential algebraic and complex analytic structure
of tame sets; and to apply this insight in combination with results
from the theory of differential equations to effectivize key results
in tame geometry and its applications to arithmetic and dynamics. I
believe that my preliminary work in this direction amply demonstrates
the feasibility and potential of this approach.
Summary
Tame geometry studies structures in which every definable set has a
finite geometric complexity. The study of tame geometry spans several
interrelated mathematical fields, including semialgebraic,
subanalytic, and o-minimal geometry. The past decade has seen the
emergence of a spectacular link between tame geometry and arithmetic
following the discovery of the fundamental Pila-Wilkie counting
theorem and its applications in unlikely diophantine
intersections. The P-W theorem itself relies crucially on the
Yomdin-Gromov theorem, a classical result of tame geometry with
fundamental applications in smooth dynamics.
It is natural to ask whether the complexity of a tame set can be
estimated effectively in terms of the defining formulas. While a large
body of work is devoted to answering such questions in the
semialgebraic case, surprisingly little is known concerning more
general tame structures - specifically those needed in recent
applications to arithmetic. The nature of the link between tame
geometry and arithmetic is such that any progress toward effectivizing
the theory of tame structures will likely lead to effective results
in the domain of unlikely intersections. Similarly, a more effective
version of the Yomdin-Gromov theorem is known to imply important
consequences in smooth dynamics.
The proposed research will approach effectivity in tame geometry from
a fundamentally new direction, bringing to bear methods from the
theory of differential equations which have until recently never been
used in this context. Toward this end, our key goals will be to gain
insight into the differential algebraic and complex analytic structure
of tame sets; and to apply this insight in combination with results
from the theory of differential equations to effectivize key results
in tame geometry and its applications to arithmetic and dynamics. I
believe that my preliminary work in this direction amply demonstrates
the feasibility and potential of this approach.
Max ERC Funding
1 155 027 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym ELEGANSFUSION
Project Mechanisms of cell fusion in eukaryotes
Researcher (PI) Benjamin Podbilewicz
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Advanced Grant (AdG), LS3, ERC-2010-AdG_20100317
Summary Membrane fusion is a universal process essential inside cells (endoplasmic) and between cells in fertilization and organ formation (exoplasmic). With the exception of SNARE-mediated endoplasmic fusion the proteins that mediate cellular fusion (fusogens) are unknown. Despite many years of research, little is known about the mechanism of cell-cell fusion. Our studies of developmental cell fusion in the nematode C. elegans have led to the discovery of the first family of eukaryotic fusogens (FF). These fusogens, EFF-1 and AFF-1, are type I membrane glycoproteins that are essential for cell fusion and can fuse cells when ectopically expressed on the membranes of C. elegans and heterologous cells.
Our main goals are:
(1) To determine the physicochemical mechanism of cell membrane fusion mediated by FF proteins.
(2) To find the missing fusogens that act in cell fusion events across all kingdoms of life.
We hypothesize that FF proteins fuse membranes by a mechanism analogous to viral or endoplasmic fusogens and that unidentified fusogens fuse cells following the same principles as FF proteins.
Our specific aims are:
AIM 1 Determine the mechanism of FF-mediated cell fusion: A paradigm for cell membrane fusion
AIM 2 Find the sperm-egg fusion proteins (fusogens) in C. elegans
AIM 3 Identify the myoblast fusogens in mammals
AIM 4 Test fusogens using functional cell fusion assays in heterologous systems
Identifying critical domains required for FF fusion, intermediates in membrane remodeling, and atomic structures of FF proteins will advance the fundamental understanding of the mechanisms of eukaryotic cell fusion. We propose to find the Holy Grail of fertilization and mammalian myoblast fusion. We estimate that this project, if successful, will bring a breakthrough to the sperm-egg and muscle fusion fields with potential applications in basic and applied biomedical sciences.
Summary
Membrane fusion is a universal process essential inside cells (endoplasmic) and between cells in fertilization and organ formation (exoplasmic). With the exception of SNARE-mediated endoplasmic fusion the proteins that mediate cellular fusion (fusogens) are unknown. Despite many years of research, little is known about the mechanism of cell-cell fusion. Our studies of developmental cell fusion in the nematode C. elegans have led to the discovery of the first family of eukaryotic fusogens (FF). These fusogens, EFF-1 and AFF-1, are type I membrane glycoproteins that are essential for cell fusion and can fuse cells when ectopically expressed on the membranes of C. elegans and heterologous cells.
Our main goals are:
(1) To determine the physicochemical mechanism of cell membrane fusion mediated by FF proteins.
(2) To find the missing fusogens that act in cell fusion events across all kingdoms of life.
We hypothesize that FF proteins fuse membranes by a mechanism analogous to viral or endoplasmic fusogens and that unidentified fusogens fuse cells following the same principles as FF proteins.
Our specific aims are:
AIM 1 Determine the mechanism of FF-mediated cell fusion: A paradigm for cell membrane fusion
AIM 2 Find the sperm-egg fusion proteins (fusogens) in C. elegans
AIM 3 Identify the myoblast fusogens in mammals
AIM 4 Test fusogens using functional cell fusion assays in heterologous systems
Identifying critical domains required for FF fusion, intermediates in membrane remodeling, and atomic structures of FF proteins will advance the fundamental understanding of the mechanisms of eukaryotic cell fusion. We propose to find the Holy Grail of fertilization and mammalian myoblast fusion. We estimate that this project, if successful, will bring a breakthrough to the sperm-egg and muscle fusion fields with potential applications in basic and applied biomedical sciences.
Max ERC Funding
2 380 000 €
Duration
Start date: 2011-05-01, End date: 2016-04-30