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
