Project acronym AMAREC
Project Amenability, Approximation and Reconstruction
Researcher (PI) Wilhelm WINTER
Host Institution (HI) WESTFAELISCHE WILHELMS-UNIVERSITAET MUENSTER
Country Germany
Call Details Advanced Grant (AdG), PE1, ERC-2018-ADG
Summary Algebras of operators on Hilbert spaces were originally introduced as the right framework for the mathematical description of quantum mechanics. In modern mathematics the scope has much broadened due to the highly versatile nature of operator algebras. They are particularly useful in the analysis of groups and their actions. Amenability is a finiteness property which occurs in many different contexts and which can be characterised in many different ways. We will analyse amenability in terms of approximation properties, in the frameworks of abstract C*-algebras, of topological dynamical systems, and of discrete groups. Such approximation properties will serve as bridging devices between these setups, and they will be used to systematically recover geometric information about the underlying structures. When passing from groups, and more generally from dynamical systems, to operator algebras, one loses information, but one gains new tools to isolate and analyse pertinent properties of the underlying structure. We will mostly be interested in the topological setting, and in the associated C*-algebras. Amenability of groups or of dynamical systems then translates into the completely positive approximation property. Systems of completely positive approximations store all the essential data about a C*-algebra, and sometimes one can arrange the systems so that one can directly read of such information. For transformation group C*-algebras, one can achieve this by using approximation properties of the underlying dynamics. To some extent one can even go back, and extract dynamical approximation properties from completely positive approximations of the C*-algebra. This interplay between approximation properties in topological dynamics and in noncommutative topology carries a surprisingly rich structure. It connects directly to the heart of the classification problem for nuclear C*-algebras on the one hand, and to central open questions on amenable dynamics on the other.
Summary
Algebras of operators on Hilbert spaces were originally introduced as the right framework for the mathematical description of quantum mechanics. In modern mathematics the scope has much broadened due to the highly versatile nature of operator algebras. They are particularly useful in the analysis of groups and their actions. Amenability is a finiteness property which occurs in many different contexts and which can be characterised in many different ways. We will analyse amenability in terms of approximation properties, in the frameworks of abstract C*-algebras, of topological dynamical systems, and of discrete groups. Such approximation properties will serve as bridging devices between these setups, and they will be used to systematically recover geometric information about the underlying structures. When passing from groups, and more generally from dynamical systems, to operator algebras, one loses information, but one gains new tools to isolate and analyse pertinent properties of the underlying structure. We will mostly be interested in the topological setting, and in the associated C*-algebras. Amenability of groups or of dynamical systems then translates into the completely positive approximation property. Systems of completely positive approximations store all the essential data about a C*-algebra, and sometimes one can arrange the systems so that one can directly read of such information. For transformation group C*-algebras, one can achieve this by using approximation properties of the underlying dynamics. To some extent one can even go back, and extract dynamical approximation properties from completely positive approximations of the C*-algebra. This interplay between approximation properties in topological dynamics and in noncommutative topology carries a surprisingly rich structure. It connects directly to the heart of the classification problem for nuclear C*-algebras on the one hand, and to central open questions on amenable dynamics on the other.
Max ERC Funding
1 596 017 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym ARCHCAUCASUS
Project Technical and Social Innovations in the Caucasus: between the Eurasian Steppe and the Earliest Cities in the 4th and 3rd millennia BC
Researcher (PI) Svend HANSEN
Host Institution (HI) DEUTSCHES ARCHAOLOGISCHES INSTITUT
Country Germany
Call Details Advanced Grant (AdG), SH6, ERC-2018-ADG
Summary This project leads to one of the most dynamic regions in prehistory: the Caucasus of the 4th and early 3rd mill. BC. During this vibrant time, basic innovations emerged, which were crucial until the 19th century: wheel and wagon, copper alloys, the potter’s wheel, new breeds of woolly sheep, domestication of the horse, and others. At the same time, massive migrations from the East European steppe during the early 3rd mill. BC changed the European gene pool.
The project challenges the still predominant narrative that all technical achievements stemmed from urban centres in Mesopotamia. New studies have created space for alternative hypotheses: possibly it was not the development of new techniques, but instead their adaptation from different ‘peripheries’ and their re-combination and re-configuration that formed the basis for the success of these ‘civilisations’.
The Caucasus, linking Mesopotamia to the Eurasia and Europe, is for the first time in the focus of a study on innovation transfer. The study will make a major contribution by investigation of four axial innovations: wheel and wagon, metal alloys, silver metallurgy and woolly sheep. 40 wheels will be analysed by computer tomography and strontium isotopes. Some 300 copper alloys artefacts and 200 silver objects will be examined using mass spectrometry with laser ablation. 400 aDNA genom-wide analyses of humans from burials in the North Caucasus will offer the unique chance of elucidating the role of migrations for the spread of innovations. The pottery in the region, often linked to Mesopotamia, will be studied under technical aspects and is a complementary path to shed light on migration and the transfer of knowledge. Excavations in settlements will allow building up a chronology using 400 AMS 14C analyses. The project is multidisciplinary, making use of the most up-to-date analytical methods. Our long experience and reputation on both sides of the Caucasus is the ideal background for cutting-edge research.
Summary
This project leads to one of the most dynamic regions in prehistory: the Caucasus of the 4th and early 3rd mill. BC. During this vibrant time, basic innovations emerged, which were crucial until the 19th century: wheel and wagon, copper alloys, the potter’s wheel, new breeds of woolly sheep, domestication of the horse, and others. At the same time, massive migrations from the East European steppe during the early 3rd mill. BC changed the European gene pool.
The project challenges the still predominant narrative that all technical achievements stemmed from urban centres in Mesopotamia. New studies have created space for alternative hypotheses: possibly it was not the development of new techniques, but instead their adaptation from different ‘peripheries’ and their re-combination and re-configuration that formed the basis for the success of these ‘civilisations’.
The Caucasus, linking Mesopotamia to the Eurasia and Europe, is for the first time in the focus of a study on innovation transfer. The study will make a major contribution by investigation of four axial innovations: wheel and wagon, metal alloys, silver metallurgy and woolly sheep. 40 wheels will be analysed by computer tomography and strontium isotopes. Some 300 copper alloys artefacts and 200 silver objects will be examined using mass spectrometry with laser ablation. 400 aDNA genom-wide analyses of humans from burials in the North Caucasus will offer the unique chance of elucidating the role of migrations for the spread of innovations. The pottery in the region, often linked to Mesopotamia, will be studied under technical aspects and is a complementary path to shed light on migration and the transfer of knowledge. Excavations in settlements will allow building up a chronology using 400 AMS 14C analyses. The project is multidisciplinary, making use of the most up-to-date analytical methods. Our long experience and reputation on both sides of the Caucasus is the ideal background for cutting-edge research.
Max ERC Funding
2 487 875 €
Duration
Start date: 2019-07-01, End date: 2024-06-30
Project acronym BICAEHFID
Project Biogeographic and cultural adaptations of early humans during the first intercontinental dispersals
Researcher (PI) Ignacio DE LA TORRE
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Country Spain
Call Details Advanced Grant (AdG), SH6, ERC-2018-ADG
Summary Our understanding of the emergence and dispersal of the earliest tool-making hominins has been revolutionised in the last decade, with sites in eastern Africa and China pushing both events more than half a million years earlier than previously thought. Traditional models linking biological speciation, cultural innovation and migration events with climatic pulses have remained theoretical, and recent discoveries suggest that the picture of the earliest human colonization across the Old World is far more complex, demanding heuristic approaches to understand the biogeography and adaptive behaviours of early humans.
This project will be the first substantive attempt to produce a global synthesis of earliest human occupation dynamics by comparing the world’s longest sequences of early archaeological sites, namely eastern Africa and China. Our objective is to understand the alternative evolutionary trajectories adopted by hominins that shared an overarching biological and cultural background, but who faced different climatic and biogeographic challenges and opportunities.
The ambition of our global-scale objectives is accompanied by the unmatched quality of our datasets and the ground-breaking perspective we will adopt in their study. Fieldwork in the two most renowned sequences in each region alongside a primary study of additional top-quality assemblages in both subcontinents, will be combined with extensive metadata sets to produce comprehensive views of temporal trends and paleoecological patterns. Our state-of-the-art methodological sets (which combine an exceptionally diverse range of disciplines from geochemistry to niche modelling) and ground-breaking analytical perspective (which considers data from micro-stratigraphy to satellite imaging) will enable us to develop new approaches to challenge established paradigms and produce a new picture of the biogeographic adaptations of early stone-tool makers.
Summary
Our understanding of the emergence and dispersal of the earliest tool-making hominins has been revolutionised in the last decade, with sites in eastern Africa and China pushing both events more than half a million years earlier than previously thought. Traditional models linking biological speciation, cultural innovation and migration events with climatic pulses have remained theoretical, and recent discoveries suggest that the picture of the earliest human colonization across the Old World is far more complex, demanding heuristic approaches to understand the biogeography and adaptive behaviours of early humans.
This project will be the first substantive attempt to produce a global synthesis of earliest human occupation dynamics by comparing the world’s longest sequences of early archaeological sites, namely eastern Africa and China. Our objective is to understand the alternative evolutionary trajectories adopted by hominins that shared an overarching biological and cultural background, but who faced different climatic and biogeographic challenges and opportunities.
The ambition of our global-scale objectives is accompanied by the unmatched quality of our datasets and the ground-breaking perspective we will adopt in their study. Fieldwork in the two most renowned sequences in each region alongside a primary study of additional top-quality assemblages in both subcontinents, will be combined with extensive metadata sets to produce comprehensive views of temporal trends and paleoecological patterns. Our state-of-the-art methodological sets (which combine an exceptionally diverse range of disciplines from geochemistry to niche modelling) and ground-breaking analytical perspective (which considers data from micro-stratigraphy to satellite imaging) will enable us to develop new approaches to challenge established paradigms and produce a new picture of the biogeographic adaptations of early stone-tool makers.
Max ERC Funding
2 499 996 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym Breakborder
Project Breaking borders, Functional genetic screens of structural regulatory DNA elements
Researcher (PI) Reuven AGAMI
Host Institution (HI) STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Country Netherlands
Call Details Advanced Grant (AdG), LS4, ERC-2018-ADG
Summary The human genome carries genetic information in two distinct forms: Transcribed genes and regulatory DNA elements (rDEs). rDEs control the magnitude and pattern of gene expression, and are indispensable for organismal development and cellular homeostasis. Nevertheless, while large-scale functional genetic screens greatly advanced our knowledge in studying mammalian genes, such tools to study rDEs were lacking, impeding scientific progress. Interestingly, recent advance in genome editing technologies has not only expanded the available screening toolbox to examine genes, but also opened up novel opportunities in studying rDEs. We distinguish two types of rDEs: Transcriptional rDEs that recruit transcription factors to enhancers, and structural rDEs that maintain chromatin 3D structure to insulate transcriptional activities, a feature postulated to be essential for gene expression regulation by enhancers. Recently, we developed a CRISPR strategy to target enhancers. We showed its scalability and effectivity in identifying potential oncogenic and tumour-suppressive enhancers. Here, we will exploit this line of research and develop novel strategies to target structural rDEs (e.g. insulators). By setting up functional genetic screens, we will identify key players in cell proliferation, differentiation, and survival, which are related to cancer development, metastasis induction, and acquired therapy resistance. We will validate key insulators and decipher underlying mechanisms of action that control phenotypes. In a parallel approach, we will analyse whole genome sequencing datasets of cancer to identify and characterize genetic aberrations occurring in the identified regions. Altogether, the outlined research plan forms a natural extension of our successful functional approaches to study gene regulation. Our results will setup the foundation to better understand principles of chromatin architecture in gene expression regulation in development and cancer.
Summary
The human genome carries genetic information in two distinct forms: Transcribed genes and regulatory DNA elements (rDEs). rDEs control the magnitude and pattern of gene expression, and are indispensable for organismal development and cellular homeostasis. Nevertheless, while large-scale functional genetic screens greatly advanced our knowledge in studying mammalian genes, such tools to study rDEs were lacking, impeding scientific progress. Interestingly, recent advance in genome editing technologies has not only expanded the available screening toolbox to examine genes, but also opened up novel opportunities in studying rDEs. We distinguish two types of rDEs: Transcriptional rDEs that recruit transcription factors to enhancers, and structural rDEs that maintain chromatin 3D structure to insulate transcriptional activities, a feature postulated to be essential for gene expression regulation by enhancers. Recently, we developed a CRISPR strategy to target enhancers. We showed its scalability and effectivity in identifying potential oncogenic and tumour-suppressive enhancers. Here, we will exploit this line of research and develop novel strategies to target structural rDEs (e.g. insulators). By setting up functional genetic screens, we will identify key players in cell proliferation, differentiation, and survival, which are related to cancer development, metastasis induction, and acquired therapy resistance. We will validate key insulators and decipher underlying mechanisms of action that control phenotypes. In a parallel approach, we will analyse whole genome sequencing datasets of cancer to identify and characterize genetic aberrations occurring in the identified regions. Altogether, the outlined research plan forms a natural extension of our successful functional approaches to study gene regulation. Our results will setup the foundation to better understand principles of chromatin architecture in gene expression regulation in development and cancer.
Max ERC Funding
2 497 000 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym BreakingBarriers
Project Targeting endothelial barriers to combat disease
Researcher (PI) Anne Eichmann
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Country France
Call Details Advanced Grant (AdG), LS4, ERC-2018-ADG
Summary Tissue homeostasis requires coordinated barrier function in blood and lymphatic vessels. Opening of junctions between endothelial cells (ECs) lining blood vessels leads to tissue fluid accumulation that is drained by lymphatic vessels. A pathological increase in blood vessel permeability or lack or malfunction of lymphatic vessels leads to edema and associated defects in macromolecule and immune cell clearance. Unbalanced barrier function between blood and lymphatic vessels contributes to neurodegeneration, chronic inflammation, and cardiovascular disease. In this proposal, we seek to gain mechanistic understanding into coordination of barrier function between blood and lymphatic vessels, how this process is altered in disease models and how it can be manipulated for therapeutic purposes. We will focus on two critical barriers with diametrically opposing functions, the blood-brain barrier (BBB) and the lymphatic capillary barrier (LCB). ECs of the BBB form very tight junctions that restrict paracellular access to the brain. In contrast, open junctions of the LCB ensure uptake of extravasated fluid, macromolecules and immune cells, as well as lipid in the gut. We have identified novel effectors of BBB and LCB junctions and will determine their role in adult homeostasis and in disease models. Mouse genetic gain and loss of function approaches in combination with histological, ultrastructural, functional and molecular analysis will determine mechanisms underlying formation of tissue specific EC barriers. Deliverables include in vivo validated targets that could be used for i) opening the BBB on demand for drug delivery into the brain, and ii) to lower plasma lipid uptake via interfering with the LCB, with implications for prevention of obesity, cardiovascular disease and inflammation. These pioneering studies promise to open up new opportunities for research and treatment of neurovascular and cardiovascular disease.
Summary
Tissue homeostasis requires coordinated barrier function in blood and lymphatic vessels. Opening of junctions between endothelial cells (ECs) lining blood vessels leads to tissue fluid accumulation that is drained by lymphatic vessels. A pathological increase in blood vessel permeability or lack or malfunction of lymphatic vessels leads to edema and associated defects in macromolecule and immune cell clearance. Unbalanced barrier function between blood and lymphatic vessels contributes to neurodegeneration, chronic inflammation, and cardiovascular disease. In this proposal, we seek to gain mechanistic understanding into coordination of barrier function between blood and lymphatic vessels, how this process is altered in disease models and how it can be manipulated for therapeutic purposes. We will focus on two critical barriers with diametrically opposing functions, the blood-brain barrier (BBB) and the lymphatic capillary barrier (LCB). ECs of the BBB form very tight junctions that restrict paracellular access to the brain. In contrast, open junctions of the LCB ensure uptake of extravasated fluid, macromolecules and immune cells, as well as lipid in the gut. We have identified novel effectors of BBB and LCB junctions and will determine their role in adult homeostasis and in disease models. Mouse genetic gain and loss of function approaches in combination with histological, ultrastructural, functional and molecular analysis will determine mechanisms underlying formation of tissue specific EC barriers. Deliverables include in vivo validated targets that could be used for i) opening the BBB on demand for drug delivery into the brain, and ii) to lower plasma lipid uptake via interfering with the LCB, with implications for prevention of obesity, cardiovascular disease and inflammation. These pioneering studies promise to open up new opportunities for research and treatment of neurovascular and cardiovascular disease.
Max ERC Funding
2 499 969 €
Duration
Start date: 2019-07-01, End date: 2024-06-30
Project acronym BREEDIT
Project A NOVEL BREEDING STRATEGY USING MULTIPLEX GENOME EDITING IN MAIZE
Researcher (PI) Dirk INZE
Host Institution (HI) VIB VZW
Country Belgium
Call Details Advanced Grant (AdG), LS9, ERC-2018-ADG
Summary Feeding the growing world population under changing climate conditions poses an unprecedented challenge on global agriculture and our current pace to breed new high yielding crop varieties is too low to face the imminent threats on food security. This ERC project proposes a novel crossing scheme that allows for an expeditious evaluation of combinations of potential yield contributing alleles by unifying ‘classical’ breeding with gene-centric molecular biology. The acronym BREEDIT, a word fusion of breeding and editing, reflects the basic concept of combining breeding with multiplex genome editing of yield related genes. By introducing plants with distinct combinations of genome edited mutations in more than 80 known yield related genes into a crossing scheme, the combinatorial effect of these mutations on plant growth and yield will be evaluated. Subsequent rounds of crossings will increase the number of stacked gene-edits per plant, thus increasing the combinatorial complexity. Phenotypic evaluations throughout plant development will be done on our in-house automated image-analysis based phenotyping platform. The nature and frequency of Cas9-mediated mutations in the entire plant collection will be characterised by multiplex amplicon sequencing to follow the efficiency of CRISPR-cas9 genome editing and to identify the underlying combinations of genes that cause beneficial phenotypes (genetic gain). The obtained knowledge on yield regulatory networks can be directly implemented into current molecular breeding programs and the project will provide the basis to develop targeted breeding schemes implementing the optimal combinations of beneficial alleles into elite material.
BREEDIT will be a major step forward in integrating basic knowledge on genes with plant breeding and has the potential to provoke a paradigm shift in improving crop yield.
Summary
Feeding the growing world population under changing climate conditions poses an unprecedented challenge on global agriculture and our current pace to breed new high yielding crop varieties is too low to face the imminent threats on food security. This ERC project proposes a novel crossing scheme that allows for an expeditious evaluation of combinations of potential yield contributing alleles by unifying ‘classical’ breeding with gene-centric molecular biology. The acronym BREEDIT, a word fusion of breeding and editing, reflects the basic concept of combining breeding with multiplex genome editing of yield related genes. By introducing plants with distinct combinations of genome edited mutations in more than 80 known yield related genes into a crossing scheme, the combinatorial effect of these mutations on plant growth and yield will be evaluated. Subsequent rounds of crossings will increase the number of stacked gene-edits per plant, thus increasing the combinatorial complexity. Phenotypic evaluations throughout plant development will be done on our in-house automated image-analysis based phenotyping platform. The nature and frequency of Cas9-mediated mutations in the entire plant collection will be characterised by multiplex amplicon sequencing to follow the efficiency of CRISPR-cas9 genome editing and to identify the underlying combinations of genes that cause beneficial phenotypes (genetic gain). The obtained knowledge on yield regulatory networks can be directly implemented into current molecular breeding programs and the project will provide the basis to develop targeted breeding schemes implementing the optimal combinations of beneficial alleles into elite material.
BREEDIT will be a major step forward in integrating basic knowledge on genes with plant breeding and has the potential to provoke a paradigm shift in improving crop yield.
Max ERC Funding
2 474 790 €
Duration
Start date: 2019-09-01, End date: 2025-02-28
Project acronym CellularBiographies
Project Global views of cell type specification and differentiation
Researcher (PI) Alexander Schier
Host Institution (HI) UNIVERSITAT BASEL
Country Switzerland
Call Details Advanced Grant (AdG), LS3, ERC-2018-ADG
Summary Each cell in our body has a specific biography that is defined by its pedigree relationship with other cells (lineage) and by its history of gene expression (trajectory). A fundamental question in cellular and developmental biology has been how the lineage and trajectory of a cell lead to its specification and differentiation. Remarkable progress in genome editing and single-cell sequencing has generated the opportunity to understand this process at global scales and single-cell resolution. We have recently developed methods to reconstruct the cellular ancestry and transcriptional trajectories of cells during embryogenesis. The resulting lineage and trajectory trees can be analyzed to gain comprehensive views of how cellular diversity arises and how differentiation leads to physiologically specialized cell types. To generate such global views of cellular development, we will: 1. Define the cellular diversity and gene expression trajectories during zebrafish embryogenesis and organogenesis. Trajectory trees will be generated from scRNA-seq data and analyzed to reconstruct the gene expression pathways underlying fate specification. 2. Reveal the relationships between lineage and transcriptional trajectories during fate specification. Lineage trees will be generated by marking cells via genome editing and combined with trajectory trees to reveal the cellular paths towards fate specification. 3. Discover the gene expression cascades that remodel cells into physiologically functional types. Cell biological modules will be identified by comparing gene enrichment in differentiation trajectories and reveal the specialized and shared mechanisms of differentiation. These studies will help provide the first comprehensive and global view of the trajectories and lineages underlying vertebrate development. Our focus is on the zebrafish model system, but the data and concepts developed in this project will be applicable to other developmental and cellular systems.
Summary
Each cell in our body has a specific biography that is defined by its pedigree relationship with other cells (lineage) and by its history of gene expression (trajectory). A fundamental question in cellular and developmental biology has been how the lineage and trajectory of a cell lead to its specification and differentiation. Remarkable progress in genome editing and single-cell sequencing has generated the opportunity to understand this process at global scales and single-cell resolution. We have recently developed methods to reconstruct the cellular ancestry and transcriptional trajectories of cells during embryogenesis. The resulting lineage and trajectory trees can be analyzed to gain comprehensive views of how cellular diversity arises and how differentiation leads to physiologically specialized cell types. To generate such global views of cellular development, we will: 1. Define the cellular diversity and gene expression trajectories during zebrafish embryogenesis and organogenesis. Trajectory trees will be generated from scRNA-seq data and analyzed to reconstruct the gene expression pathways underlying fate specification. 2. Reveal the relationships between lineage and transcriptional trajectories during fate specification. Lineage trees will be generated by marking cells via genome editing and combined with trajectory trees to reveal the cellular paths towards fate specification. 3. Discover the gene expression cascades that remodel cells into physiologically functional types. Cell biological modules will be identified by comparing gene enrichment in differentiation trajectories and reveal the specialized and shared mechanisms of differentiation. These studies will help provide the first comprehensive and global view of the trajectories and lineages underlying vertebrate development. Our focus is on the zebrafish model system, but the data and concepts developed in this project will be applicable to other developmental and cellular systems.
Max ERC Funding
2 411 440 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym CENGIN
Project Deciphering and engineering centriole assembly
Researcher (PI) Pierre Joerg GoeNCZY
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), LS3, ERC-2018-ADG
Summary Deciphering and engineering the assembly of cellular organelles is a key pursuit in biology. The centriole is an evolutionarily conserved organelle well suited for this goal, and which is crucial for cell signaling, motility and division. The centriole exhibits a striking 9-fold radial symmetry of microtubules around a likewise symmetrical cartwheel containing stacked ring-bearing structures. Components essential for generating this remarkable architecture from alga to man have been identified. A next critical step is to engineer assays to probe the dynamics of centriole assembly with molecular precision to fully understand how these components together build a functional organelle. Our ambitious research proposal aims at taking groundbreaking steps in this direction through four specific aims:
1) Reconstituting cartwheel ring assembly dynamics. We will use high-speed AFM (HS-AFM) to dissect the biophysics of SAS-6 ring polymer dynamics at the root of cartwheel assembly. We will also use HS-AFM to analyze monobodies against SAS-6, as well as engineer surfaces and DNA origamis to further dissect ring assembly.
2) Deciphering ring stacking mechanisms. We will use cryo-ET to identify SAS-6 features that direct stacking of ring structures and set cartwheel height. Moreover, we will develop an HS-AFM stacking assay and a reconstituted stacking assay from human cells.
3) Understanding peripheral element contributions to centriole biogenesis. We will dissect the function of the peripheral centriole pinhead protein Cep135/Bld10p, as well as identify and likewise dissect peripheral A-C linker proteins. Furthermore, we will further engineer the HS-AFM assay to include such peripheral components.
4) Dissecting de novo centriole assembly mechanisms. We will dissect de novo centriole formation in human cells and water fern. We will also explore whether de novo formation involves a phase separation mechanism and repurpose the HS-AFM assay to probe de novo organelle biogenes
Summary
Deciphering and engineering the assembly of cellular organelles is a key pursuit in biology. The centriole is an evolutionarily conserved organelle well suited for this goal, and which is crucial for cell signaling, motility and division. The centriole exhibits a striking 9-fold radial symmetry of microtubules around a likewise symmetrical cartwheel containing stacked ring-bearing structures. Components essential for generating this remarkable architecture from alga to man have been identified. A next critical step is to engineer assays to probe the dynamics of centriole assembly with molecular precision to fully understand how these components together build a functional organelle. Our ambitious research proposal aims at taking groundbreaking steps in this direction through four specific aims:
1) Reconstituting cartwheel ring assembly dynamics. We will use high-speed AFM (HS-AFM) to dissect the biophysics of SAS-6 ring polymer dynamics at the root of cartwheel assembly. We will also use HS-AFM to analyze monobodies against SAS-6, as well as engineer surfaces and DNA origamis to further dissect ring assembly.
2) Deciphering ring stacking mechanisms. We will use cryo-ET to identify SAS-6 features that direct stacking of ring structures and set cartwheel height. Moreover, we will develop an HS-AFM stacking assay and a reconstituted stacking assay from human cells.
3) Understanding peripheral element contributions to centriole biogenesis. We will dissect the function of the peripheral centriole pinhead protein Cep135/Bld10p, as well as identify and likewise dissect peripheral A-C linker proteins. Furthermore, we will further engineer the HS-AFM assay to include such peripheral components.
4) Dissecting de novo centriole assembly mechanisms. We will dissect de novo centriole formation in human cells and water fern. We will also explore whether de novo formation involves a phase separation mechanism and repurpose the HS-AFM assay to probe de novo organelle biogenes
Max ERC Funding
2 500 000 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym CHRONO
Project Chronotype, health and family: The role of biology, socio- and natural environment and their interaction
Researcher (PI) Melinda MILLS
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Advanced Grant (AdG), SH3, ERC-2018-ADG
Summary The widespread use of electronic devices, artificial light and rise of the 24-hour economy means that more individuals experience disruption of their chronotype, which is the natural circadian rhythm that regulates sleep and activity levels. The natural and medical sciences focus on the natural environment (e.g., light exposure), genetics, biology and health consequences, whereas the social sciences have largely explored the socio-environment (e.g., working regulations) and psychological and familial consequences of nonstandard work schedules. For the first time CHRONO bridges these disparate disciplines to ask: What is the role of biology, the natural and socio-environment and their interaction on predicting and understanding resilience to chronotype disruption and how does this in turn impact an individual’s health (sleep, cancer, obesity, digestive problems) and family (partnership, children) outcomes? I propose to: (1) develop a multifactor interdisciplinary theoretical model; (2) disrupt data collection by crowdsourcing a sociogenomic dataset with novel measures; (3) discover and validate with informed machine learning innovative measures of chronotype (molecular genetic, accelerometer, microbiome, patient-record, self-reported) and the natural and socio-environment; (4) ask fundamentally new substantive questions to determine how chronotype disruption influences health and family outcomes and, via Biology x Environment interaction (BxE), whether this is moderated by the natural or socio-environment; and, (5) develop new statistical models and methods to cope with contentious issues, answer longitudinal questions and engage in novel quasi-experiments (e.g., policy and life course changes) to transcend description to identify endogenous factors and causal mechanisms. Interdisciplinary in the truest sense, CHRONO will overturn long-held substantive findings of the causes and consequences of chronotype disruption.
Summary
The widespread use of electronic devices, artificial light and rise of the 24-hour economy means that more individuals experience disruption of their chronotype, which is the natural circadian rhythm that regulates sleep and activity levels. The natural and medical sciences focus on the natural environment (e.g., light exposure), genetics, biology and health consequences, whereas the social sciences have largely explored the socio-environment (e.g., working regulations) and psychological and familial consequences of nonstandard work schedules. For the first time CHRONO bridges these disparate disciplines to ask: What is the role of biology, the natural and socio-environment and their interaction on predicting and understanding resilience to chronotype disruption and how does this in turn impact an individual’s health (sleep, cancer, obesity, digestive problems) and family (partnership, children) outcomes? I propose to: (1) develop a multifactor interdisciplinary theoretical model; (2) disrupt data collection by crowdsourcing a sociogenomic dataset with novel measures; (3) discover and validate with informed machine learning innovative measures of chronotype (molecular genetic, accelerometer, microbiome, patient-record, self-reported) and the natural and socio-environment; (4) ask fundamentally new substantive questions to determine how chronotype disruption influences health and family outcomes and, via Biology x Environment interaction (BxE), whether this is moderated by the natural or socio-environment; and, (5) develop new statistical models and methods to cope with contentious issues, answer longitudinal questions and engage in novel quasi-experiments (e.g., policy and life course changes) to transcend description to identify endogenous factors and causal mechanisms. Interdisciplinary in the truest sense, CHRONO will overturn long-held substantive findings of the causes and consequences of chronotype disruption.
Max ERC Funding
2 499 811 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
Project acronym CLaQS
Project Correlations in Large Quantum Systems
Researcher (PI) Benjamin Schlein
Host Institution (HI) UNIVERSITAT ZURICH
Country Switzerland
Call Details Advanced Grant (AdG), PE1, ERC-2018-ADG
Summary This project is devoted to the mathematical analysis of important physical properties of many-body quantum systems. We will be interested in properties of the ground state and low-energy excitations but also of non-equilibrium dynamics. We are going to consider systems with different statistics and in different regimes. The questions we are going to address have a common aspect: correlations among particles play a crucial role. Our main goal consists in developing new tools that allow us to correctly describe many-body correlations and to understand their effects. The starting point of our proposal are ideas and techniques that have been introduced in a series of papers establishing the validity of Bogoliubov theory for Bose gases in the Gross-Pitaevskii regime, and in a recent preprint showing how (bosonic) Bogoliubov theory can also be used to study the correlation energy of Fermi gases. In this project, we plan to develop these techniques further and to apply them to new contexts. We believe they have the potential to approach some fundamental open problem in mathematical physics. Among our most ambitious objectives, we include the proof of the Lee-Huang-Yang formula for the energy of dilute Bose gases and of the corresponding Huang-Yang formula for dilute Fermi gases, as well as the derivation of the Gell-Mann--Brueckner expression for the correlation energy of a high density Fermi system. Furthermore, we propose to work on long-term projects (going beyond the duration of the grant) aiming at a rigorous justification of the quantum Boltzmann equation for fermions in the weak coupling limit and at a proof of Bose-Einstein condensation in the thermodynamic limit, two very challenging and important questions in the field.
Summary
This project is devoted to the mathematical analysis of important physical properties of many-body quantum systems. We will be interested in properties of the ground state and low-energy excitations but also of non-equilibrium dynamics. We are going to consider systems with different statistics and in different regimes. The questions we are going to address have a common aspect: correlations among particles play a crucial role. Our main goal consists in developing new tools that allow us to correctly describe many-body correlations and to understand their effects. The starting point of our proposal are ideas and techniques that have been introduced in a series of papers establishing the validity of Bogoliubov theory for Bose gases in the Gross-Pitaevskii regime, and in a recent preprint showing how (bosonic) Bogoliubov theory can also be used to study the correlation energy of Fermi gases. In this project, we plan to develop these techniques further and to apply them to new contexts. We believe they have the potential to approach some fundamental open problem in mathematical physics. Among our most ambitious objectives, we include the proof of the Lee-Huang-Yang formula for the energy of dilute Bose gases and of the corresponding Huang-Yang formula for dilute Fermi gases, as well as the derivation of the Gell-Mann--Brueckner expression for the correlation energy of a high density Fermi system. Furthermore, we propose to work on long-term projects (going beyond the duration of the grant) aiming at a rigorous justification of the quantum Boltzmann equation for fermions in the weak coupling limit and at a proof of Bose-Einstein condensation in the thermodynamic limit, two very challenging and important questions in the field.
Max ERC Funding
1 876 050 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
