Project acronym AMAREC
Project Amenability, Approximation and Reconstruction
Researcher (PI) Wilhelm WINTER
Host Institution (HI) WESTFAELISCHE WILHELMS-UNIVERSITAET MUENSTER
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 CiliaTubulinCode
Project Self-organization of the cilium: the role of the tubulin code
Researcher (PI) Gaia PIGINO
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Consolidator Grant (CoG), LS1, ERC-2018-COG
Summary This project aims at understanding of the role of the tubulin code for self-organization of complex microtubule based structures. Cilia turn out to be the ideal structures for the proposed research.
A cilium is a sophisticated cellular machine that self-organizes from many protein complexes. It plays motility, sensory, and signaling roles in most eukaryotic cells, and its malfunction causes pathologies. The assembly of the cilium requires intraflagellar transport (IFT), a specialized bidirectional motility process that is mediated by adaptor proteins and direction specific molecular motors. Work from my lab shows that anterograde and retrograde IFT make exclusive use of the B-tubules and A-tubules, respectively. This insight answered a long standing question and shows that functional differentiation of tubules exists and is important for IFT.
Tubulin post-translational modifications (PTMs) contribute to a tubulin code, making microtubules suitable for specific functions. Mutation of tubulin-PTM enzymes can have dramatic effects on cilia function and assembly. However, we do not understand of the role of tubulin-PTMs in cilia. Therefore, I propose to address the hypotheses that the tubulin code contributes to regulating bidirectional IFT motility, and more generally, that the tubulin code is a key player in structuring complex cellular assembly processes in space and time.
This proposal aims at (i) understanding if tubulin-PTMs are necessary and/or sufficient to regulate the bidirectionality of IFT (ii) examining how the tubulin code regulates the assembly of cilia and (iii) generating a high-resolution atlas of tubulin-PTMs and their respective enzymes.
We will combine advanced techniques encompassing state-of-the-art cryo-electron tomography, biochemical imaging, fluorescent microscopy, and in vitro assays to achieve molecular and structural understanding of the role of the tubulin code in the self-organization of cilia and of microtubule based cellular structures.
Summary
This project aims at understanding of the role of the tubulin code for self-organization of complex microtubule based structures. Cilia turn out to be the ideal structures for the proposed research.
A cilium is a sophisticated cellular machine that self-organizes from many protein complexes. It plays motility, sensory, and signaling roles in most eukaryotic cells, and its malfunction causes pathologies. The assembly of the cilium requires intraflagellar transport (IFT), a specialized bidirectional motility process that is mediated by adaptor proteins and direction specific molecular motors. Work from my lab shows that anterograde and retrograde IFT make exclusive use of the B-tubules and A-tubules, respectively. This insight answered a long standing question and shows that functional differentiation of tubules exists and is important for IFT.
Tubulin post-translational modifications (PTMs) contribute to a tubulin code, making microtubules suitable for specific functions. Mutation of tubulin-PTM enzymes can have dramatic effects on cilia function and assembly. However, we do not understand of the role of tubulin-PTMs in cilia. Therefore, I propose to address the hypotheses that the tubulin code contributes to regulating bidirectional IFT motility, and more generally, that the tubulin code is a key player in structuring complex cellular assembly processes in space and time.
This proposal aims at (i) understanding if tubulin-PTMs are necessary and/or sufficient to regulate the bidirectionality of IFT (ii) examining how the tubulin code regulates the assembly of cilia and (iii) generating a high-resolution atlas of tubulin-PTMs and their respective enzymes.
We will combine advanced techniques encompassing state-of-the-art cryo-electron tomography, biochemical imaging, fluorescent microscopy, and in vitro assays to achieve molecular and structural understanding of the role of the tubulin code in the self-organization of cilia and of microtubule based cellular structures.
Max ERC Funding
1 986 406 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym DNAProteinCrosslinks
Project DNA-protein crosslinks: endogenous origins and cellular responses.
Researcher (PI) Julian STINGELE
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), LS1, ERC-2018-STG
Summary This project aims to address the most pressing questions in the emerging field of research on DNA-protein crosslinks (DPCs) and their repair. Covalent DPCs are highly toxic DNA lesions that block virtually all chromatin processes. DPCs are induced by various exogenous and endogenous agents, but dedicated repair mechanisms were unknown. It was previously assumed that DPCs are repaired by canonical DNA repair pathways. This has changed with my recent discovery of a specific and conserved DPC repair mechanism. I established that proteases of the SPRTN family degrade the protein components of DPCs, which maintains genome stability and ensures tumour suppression. Strikingly, DPC repair by SPRTN is essential for cellular viability, which suggests that cells are constantly challenged with substantial amounts of endogenous DPCs.
I hypothesize there is an entire unexplored pathway regulating protease-based DPC repair and that DPCs are key drivers of endogenous genome instability. I will employ genetic screening approaches and develop novel functional assays to systematically define the components and working principles of this novel DNA repair pathway in mammalian cells. I will determine how DPCs are detected in a chromatin context, how different repair activities are coordinated and connected to cellular processes such as replication or transcription. Moreover, I will identify the currently elusive origins of endogenous DPCs, by investigating the essential role of the SPRTN protease.
My results will not only provide insights into an essential cellular quality-control mechanism but also unravel processes causing genomic instability in human cells. Importantly, many chemotherapeutics used in the clinic exert their cytotoxicity by inducing DPCs. My results will thus have imminent implications for human health and have the potential to reveal novel drug target candidates for combination anti-cancer therapy.
Summary
This project aims to address the most pressing questions in the emerging field of research on DNA-protein crosslinks (DPCs) and their repair. Covalent DPCs are highly toxic DNA lesions that block virtually all chromatin processes. DPCs are induced by various exogenous and endogenous agents, but dedicated repair mechanisms were unknown. It was previously assumed that DPCs are repaired by canonical DNA repair pathways. This has changed with my recent discovery of a specific and conserved DPC repair mechanism. I established that proteases of the SPRTN family degrade the protein components of DPCs, which maintains genome stability and ensures tumour suppression. Strikingly, DPC repair by SPRTN is essential for cellular viability, which suggests that cells are constantly challenged with substantial amounts of endogenous DPCs.
I hypothesize there is an entire unexplored pathway regulating protease-based DPC repair and that DPCs are key drivers of endogenous genome instability. I will employ genetic screening approaches and develop novel functional assays to systematically define the components and working principles of this novel DNA repair pathway in mammalian cells. I will determine how DPCs are detected in a chromatin context, how different repair activities are coordinated and connected to cellular processes such as replication or transcription. Moreover, I will identify the currently elusive origins of endogenous DPCs, by investigating the essential role of the SPRTN protease.
My results will not only provide insights into an essential cellular quality-control mechanism but also unravel processes causing genomic instability in human cells. Importantly, many chemotherapeutics used in the clinic exert their cytotoxicity by inducing DPCs. My results will thus have imminent implications for human health and have the potential to reveal novel drug target candidates for combination anti-cancer therapy.
Max ERC Funding
1 497 375 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym IMMUNOTHROMBOSIS
Project Cross-talk between platelets and immunity - implications for host homeostasis and defense
Researcher (PI) Steffen MASSBERG
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS4, ERC-2018-ADG
Summary The overall aim of the IMMUNOTHROMBOSIS project is to clarify the mechanisms underlying the recently identified synergism between thrombosis and inflammation. Thrombus formation and inflammation are vital host responses that ensure homeostasis, but can also drive cardiovascular disease, including myocardial infarction and stroke, the major causes of death in Europe. My group and others discovered, that thrombosis and inflammation are not to be considered separate processes. They are tightly interrelated and synergize in immune defence, but also in inflammatory and thrombotic diseases in a process we termed immunothrombosis. Targeting this synergism has great potential to identify innovative and unconventional strategies to more specifically prevent undesired activation of thrombotic and inflammatory pathways. However, this requires a deeper mechanistic understanding of immunothrombosis. I recently identified two ground-breaking novel immunothrombotic principles: I discovered that platelets have the ability to migrate autonomously, which assists immune cells in fighting pathogens. Further, I revealed that immune cells play a central role in controlling the production of platelets from their megakaryocyte precursors. The physiological and pathophysiological relevance of both processes is unclear. This is the starting point and focus of the IMMUNOTHROMBOSIS project. My aim is to define how platelets use their ability to migrate to support immune cells in protection of vascular integrity (objective 1) and to identify the contribution of platelet migration to different cardiovascular diseases involving immunothrombotic tissue damage (objective 2). Finally, I will clarify how inflammatory responses feedback to the production of thrombotic effectors and dissect inflammatory mechanisms that control platelet production (objective 3). IMMUNOTHROMBOSIS will identify new options for specific prevention or treatment of thrombotic and inflammatory cardiovascular diseases.
Summary
The overall aim of the IMMUNOTHROMBOSIS project is to clarify the mechanisms underlying the recently identified synergism between thrombosis and inflammation. Thrombus formation and inflammation are vital host responses that ensure homeostasis, but can also drive cardiovascular disease, including myocardial infarction and stroke, the major causes of death in Europe. My group and others discovered, that thrombosis and inflammation are not to be considered separate processes. They are tightly interrelated and synergize in immune defence, but also in inflammatory and thrombotic diseases in a process we termed immunothrombosis. Targeting this synergism has great potential to identify innovative and unconventional strategies to more specifically prevent undesired activation of thrombotic and inflammatory pathways. However, this requires a deeper mechanistic understanding of immunothrombosis. I recently identified two ground-breaking novel immunothrombotic principles: I discovered that platelets have the ability to migrate autonomously, which assists immune cells in fighting pathogens. Further, I revealed that immune cells play a central role in controlling the production of platelets from their megakaryocyte precursors. The physiological and pathophysiological relevance of both processes is unclear. This is the starting point and focus of the IMMUNOTHROMBOSIS project. My aim is to define how platelets use their ability to migrate to support immune cells in protection of vascular integrity (objective 1) and to identify the contribution of platelet migration to different cardiovascular diseases involving immunothrombotic tissue damage (objective 2). Finally, I will clarify how inflammatory responses feedback to the production of thrombotic effectors and dissect inflammatory mechanisms that control platelet production (objective 3). IMMUNOTHROMBOSIS will identify new options for specific prevention or treatment of thrombotic and inflammatory cardiovascular diseases.
Max ERC Funding
2 321 416 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym INO3D
Project Mechanism of ATP Dependent Chromatin Modelling and Editing by INO80 Remodellers
Researcher (PI) Karl-Peter HOPFNER
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS1, ERC-2018-ADG
Summary Nucleosomes, ~147 base pairs of DNA wrapped around an histone protein octamer, package and protect nuclear DNA but also carry important biological information. The position and composition of nucleosomes along chromosomal DNA is a key element of defining the state and identity of a cell. Chromatin remodellers are ATP dependent molecular machines that position, move or edit nucleosomes in a genome wide manner. Collectively, they shape the nucleosome landscape and play central roles in the maintenance and differentiation of cells, but also in pathological transformations. INO80, a megadalton large remodeller consisting of 15 or more subunits, is involved in replication, gene expression and DNA repair. It models chromatin by positioning barrier nucleosomes around nucleosome free regions, editing nucleosomes and generating nucleosome arrays. However, structural mechanisms for INO80 and other remodelling machines are poorly understood due to their complexity. To provide a comprehensive mechanistic framework, to understand how INO80 senses nucleosome free regions to position barrier nucleosomes and how it generates arrays or senses DNA breaks, I propose a challenging but ground-breaking endeavour using a combination of cryo-EM and functional approaches. We address structures of fungal and human INO80 complexes at promoter regions, on di-nucleosomes and at DNA ends and develop quantitative positioning assays to reveal common and distinct features of shaping chromatin in different species. We also explore cryo-EM as tool towards revealing distinct steps the chemo-mechanical remodelling reactions. The proposed research will help derive fundamental molecular principles underlying the modelling of the nucleosome landscape.
Summary
Nucleosomes, ~147 base pairs of DNA wrapped around an histone protein octamer, package and protect nuclear DNA but also carry important biological information. The position and composition of nucleosomes along chromosomal DNA is a key element of defining the state and identity of a cell. Chromatin remodellers are ATP dependent molecular machines that position, move or edit nucleosomes in a genome wide manner. Collectively, they shape the nucleosome landscape and play central roles in the maintenance and differentiation of cells, but also in pathological transformations. INO80, a megadalton large remodeller consisting of 15 or more subunits, is involved in replication, gene expression and DNA repair. It models chromatin by positioning barrier nucleosomes around nucleosome free regions, editing nucleosomes and generating nucleosome arrays. However, structural mechanisms for INO80 and other remodelling machines are poorly understood due to their complexity. To provide a comprehensive mechanistic framework, to understand how INO80 senses nucleosome free regions to position barrier nucleosomes and how it generates arrays or senses DNA breaks, I propose a challenging but ground-breaking endeavour using a combination of cryo-EM and functional approaches. We address structures of fungal and human INO80 complexes at promoter regions, on di-nucleosomes and at DNA ends and develop quantitative positioning assays to reveal common and distinct features of shaping chromatin in different species. We also explore cryo-EM as tool towards revealing distinct steps the chemo-mechanical remodelling reactions. The proposed research will help derive fundamental molecular principles underlying the modelling of the nucleosome landscape.
Max ERC Funding
2 201 875 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym MaMBoQ
Project Macroscopic Behavior of Many-Body Quantum Systems
Researcher (PI) Marcello PORTA
Host Institution (HI) EBERHARD KARLS UNIVERSITAET TUEBINGEN
Call Details Starting Grant (StG), PE1, ERC-2018-STG
Summary This project is devoted to the analysis of large quantum systems. It is divided in two parts: Part A focuses on the transport properties of interacting lattice models, while Part B concerns the derivation of effective evolution equations for many-body quantum systems. The common theme is the concept of emergent effective theory: simplified models capturing the macroscopic behavior of complex systems. Different systems might share the same effective theory, a phenomenon called universality. A central goal of mathematical physics is to validate these approximations, and to understand the emergence of universality from first principles.
Part A: Transport in interacting condensed matter systems. I will study charge and spin transport in 2d systems, such as graphene and topological insulators. These materials attracted enormous interest, because of their remarkable conduction properties. Neglecting many-body interactions, some of these properties can be explained mathematically. In real samples, however, electrons do interact. In order to deal with such complex systems, physicists often rely on uncontrolled expansions, numerical methods, or formal mappings in exactly solvable models. The goal is to rigorously understand the effect of many-body interactions, and to explain the emergence of universality.
Part B: Effective dynamics of interacting fermionic systems. I will work on the derivation of effective theories for interacting fermions, in suitable scaling regimes. In the last 18 years, there has been great progress on the rigorous validity of celebrated effective models, e.g. Hartree and Gross-Pitaevskii theory. A lot is known for interacting bosons, for the dynamics and for the equilibrium low energy properties. Much less is known for fermions. The goal is fill the gap by proving the validity of some well-known fermionic effective theories, such as Hartree-Fock and BCS theory in the mean-field scaling, and the quantum Boltzmann equation in the kinetic scaling.
Summary
This project is devoted to the analysis of large quantum systems. It is divided in two parts: Part A focuses on the transport properties of interacting lattice models, while Part B concerns the derivation of effective evolution equations for many-body quantum systems. The common theme is the concept of emergent effective theory: simplified models capturing the macroscopic behavior of complex systems. Different systems might share the same effective theory, a phenomenon called universality. A central goal of mathematical physics is to validate these approximations, and to understand the emergence of universality from first principles.
Part A: Transport in interacting condensed matter systems. I will study charge and spin transport in 2d systems, such as graphene and topological insulators. These materials attracted enormous interest, because of their remarkable conduction properties. Neglecting many-body interactions, some of these properties can be explained mathematically. In real samples, however, electrons do interact. In order to deal with such complex systems, physicists often rely on uncontrolled expansions, numerical methods, or formal mappings in exactly solvable models. The goal is to rigorously understand the effect of many-body interactions, and to explain the emergence of universality.
Part B: Effective dynamics of interacting fermionic systems. I will work on the derivation of effective theories for interacting fermions, in suitable scaling regimes. In the last 18 years, there has been great progress on the rigorous validity of celebrated effective models, e.g. Hartree and Gross-Pitaevskii theory. A lot is known for interacting bosons, for the dynamics and for the equilibrium low energy properties. Much less is known for fermions. The goal is fill the gap by proving the validity of some well-known fermionic effective theories, such as Hartree-Fock and BCS theory in the mean-field scaling, and the quantum Boltzmann equation in the kinetic scaling.
Max ERC Funding
982 625 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym MitoCRISTAE
Project Mitochondrial Cristae Biogenesis
Researcher (PI) Stefan Jakobs
Host Institution (HI) UNIVERSITAETSMEDIZIN GOETTINGEN - GEORG-AUGUST-UNIVERSITAET GOETTINGEN - STIFTUNG OEFFENTLICHEN RECHTS
Call Details Advanced Grant (AdG), LS1, ERC-2018-ADG
Summary Mitochondrial cristae biogenesis is an enigma ever since the first imaging of mitochondria, the ‘powerhouses’ of eukaryotic cells, by electron microscopy in the 1950s. The mitochondrial cristae, dynamic and structurally conserved invaginations of the mitochondrial inner membrane, are essential for respiratory ATP generation. Thereby, the form and function of the mitochondrial inner membrane are deeply intertwined. Indeed, irregular or disturbed cristae morphologies are believed to cause numerous human diseases, including neurodegeneration, cardiomyopathies, metabolic disorders and cancer.
Previous approaches to study cristae biogenesis have relied primarily on the use of 2D electron microscopy and biochemistry to analyse mutant cells defective in cristae formation. Based on striking pilot experiments, we propose to study cristae biogenesis by a radically different approach. We will induce synchronous cristae development in gene-edited cell lines initially defective in cristae formation. We will then follow de novo cristae biogenesis over time by combining a series of enabling approaches, including live cell and MINFLUX super-resolution microscopy, 3D (cryo) electron microscopy, label-free (SWATH) mass spectrometry, and single molecule counting. These technologies have just emerged in the last few years, and thus this proposal would not have been possible a few years ago. The primary aim of this proposal is to establish a deep, comprehensive and quantitative understanding of cristae biogenesis in human cells. Using theses insights, we will also investigate the effects of mutations in mitochondrial proteins associated with human diseases on cristae biogenesis.
Altogether, if successful, the outcome will represent a paradigm shift in our knowledge of how mitochondrial ultrastructure in healthy and diseased cells is generated and maintained. Our findings might spark innovative and novel strategies for the treatment of devastating human mitopathies.
Summary
Mitochondrial cristae biogenesis is an enigma ever since the first imaging of mitochondria, the ‘powerhouses’ of eukaryotic cells, by electron microscopy in the 1950s. The mitochondrial cristae, dynamic and structurally conserved invaginations of the mitochondrial inner membrane, are essential for respiratory ATP generation. Thereby, the form and function of the mitochondrial inner membrane are deeply intertwined. Indeed, irregular or disturbed cristae morphologies are believed to cause numerous human diseases, including neurodegeneration, cardiomyopathies, metabolic disorders and cancer.
Previous approaches to study cristae biogenesis have relied primarily on the use of 2D electron microscopy and biochemistry to analyse mutant cells defective in cristae formation. Based on striking pilot experiments, we propose to study cristae biogenesis by a radically different approach. We will induce synchronous cristae development in gene-edited cell lines initially defective in cristae formation. We will then follow de novo cristae biogenesis over time by combining a series of enabling approaches, including live cell and MINFLUX super-resolution microscopy, 3D (cryo) electron microscopy, label-free (SWATH) mass spectrometry, and single molecule counting. These technologies have just emerged in the last few years, and thus this proposal would not have been possible a few years ago. The primary aim of this proposal is to establish a deep, comprehensive and quantitative understanding of cristae biogenesis in human cells. Using theses insights, we will also investigate the effects of mutations in mitochondrial proteins associated with human diseases on cristae biogenesis.
Altogether, if successful, the outcome will represent a paradigm shift in our knowledge of how mitochondrial ultrastructure in healthy and diseased cells is generated and maintained. Our findings might spark innovative and novel strategies for the treatment of devastating human mitopathies.
Max ERC Funding
2 286 248 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym NUAGE
Project Nucleolar regulation of longevity
Researcher (PI) Adam Antebi
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Advanced Grant (AdG), LS4, ERC-2018-ADG
Summary Research over the last few decades has revealed that animal life span is malleable and regulated by conserved metabolic signaling pathways, including reduced insulin/IGF signaling, mTOR, mitochondrial function, dietary restriction, and signals from the reproductive system. Whether these various pathways converge on common processes, however, has remained elusive.
We recently discovered the nucleolus to be a crucial focal point of regulation in all these pathways. The nucleolus is a subnuclear organelle dedicated to rRNA production and ribogenesis, but also controls assembly of other ribonucleoprotein complexes including spliceosomes, signal recognition particle, small RNA processing, stress granules, and responds to growth and stress signaling. Remarkably we found that small nucleoli are a cellular hallmark of longevity in diverse species, and a correlate of metabolic health in humans. At the molecular level, long-lived animals show reduced levels of the nucleolar ribosomal RNA methylase, fibrillarin (FIB-1), and knockdown of C. elegans FIB-1 reduces nucleolar size, extends life span, and enhances innate immunity. Conversely, knockout of NCL-1/TRIM2 expands nucleolar size, suppresses life extension of major longevity pathways, and renders animals pathogen sensitive, revealing key regulators of nucleolargenesis, immunity and longevity.
Here I propose to (Aim 1) clarify the mechanism of action of NCL-1, FIB-1 and interacting molecules (2) perform novel genetic screens for nucleolargenesis in C. elegans (3) uncover global transcriptomic and proteomic changes induced by NCL-1 and FIB-1 and survey several candidate nucleolar processes in regulating longevity and immunity (4) probe NCL-1/TRIM2 regulation of longevity in the short-lived killifish, Notobranchius furzeri, and develop nucleolar biomarkers of metabolic health in humans. These groundbreaking studies should illuminate how conserved signaling pathways work through the nucleolus to regulate health and life span.
Summary
Research over the last few decades has revealed that animal life span is malleable and regulated by conserved metabolic signaling pathways, including reduced insulin/IGF signaling, mTOR, mitochondrial function, dietary restriction, and signals from the reproductive system. Whether these various pathways converge on common processes, however, has remained elusive.
We recently discovered the nucleolus to be a crucial focal point of regulation in all these pathways. The nucleolus is a subnuclear organelle dedicated to rRNA production and ribogenesis, but also controls assembly of other ribonucleoprotein complexes including spliceosomes, signal recognition particle, small RNA processing, stress granules, and responds to growth and stress signaling. Remarkably we found that small nucleoli are a cellular hallmark of longevity in diverse species, and a correlate of metabolic health in humans. At the molecular level, long-lived animals show reduced levels of the nucleolar ribosomal RNA methylase, fibrillarin (FIB-1), and knockdown of C. elegans FIB-1 reduces nucleolar size, extends life span, and enhances innate immunity. Conversely, knockout of NCL-1/TRIM2 expands nucleolar size, suppresses life extension of major longevity pathways, and renders animals pathogen sensitive, revealing key regulators of nucleolargenesis, immunity and longevity.
Here I propose to (Aim 1) clarify the mechanism of action of NCL-1, FIB-1 and interacting molecules (2) perform novel genetic screens for nucleolargenesis in C. elegans (3) uncover global transcriptomic and proteomic changes induced by NCL-1 and FIB-1 and survey several candidate nucleolar processes in regulating longevity and immunity (4) probe NCL-1/TRIM2 regulation of longevity in the short-lived killifish, Notobranchius furzeri, and develop nucleolar biomarkers of metabolic health in humans. These groundbreaking studies should illuminate how conserved signaling pathways work through the nucleolus to regulate health and life span.
Max ERC Funding
2 500 000 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym PACA-MET
Project Genome-wide surveys and functional analysis of pancreatic cancer metastasis drivers
Researcher (PI) Roland RAD
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Consolidator Grant (CoG), LS4, ERC-2018-COG
Summary Metastasis is the major cause of death in pancreatic ductal adenocarcinoma (PDAC). International sequencing efforts on >800 human primaries gave comprehensive insights into PDAC genetics. In contrast, equivalent studies for “metastasis genetics” were not possible, largely because of a lack of metastatic tissue resources, particularly of treatment-naive ones. Another bottleneck is the scarcity of adequate experimental models recapitulating the multi-step nature of metastasis. As a consequence, the molecular basis of metastasis remains poorly understood.
We developed unique resources and tools for metastasis research and propose to use them at three levels to systematically interrogate the molecular underpinnings of PDAC metastasis.
We will first perform complementary genome-scale surveys for genes and pathways driving metastasis and metastatic organotropism. We will (i) sequence our unique, largely unpublished resource of 1200 metastatic mouse PDAC, (ii) will perform genome-wide in vivo metastasis screens using transposon tools and approaches, which we pioneered in mice, and (iii) will perturb the human metastasis transcriptome and epigenome.
Second, we will validate newly discovered genes using human PDAC cohorts, and through functional studies in mice. We will deploy next-generation metastasis models based on advanced somatic genome engineering. They allow rapid functional studies at an organismal level, thus capturing the complexity of the metastatic cascade.
Third, building on our recent discovery of two prototype PDAC metastasis drivers, we will perform in depth mechanistic studies to identify underlying molecular networks and vulnerabilities.
This work will unravel - for the first time - comprehensive genetic and functional landscapes of PDAC metastasis. PACA-MET thus promises to uncover fundamental novel biological principles and identify therapeutic targets for one of biggest challenges in medicine.
Summary
Metastasis is the major cause of death in pancreatic ductal adenocarcinoma (PDAC). International sequencing efforts on >800 human primaries gave comprehensive insights into PDAC genetics. In contrast, equivalent studies for “metastasis genetics” were not possible, largely because of a lack of metastatic tissue resources, particularly of treatment-naive ones. Another bottleneck is the scarcity of adequate experimental models recapitulating the multi-step nature of metastasis. As a consequence, the molecular basis of metastasis remains poorly understood.
We developed unique resources and tools for metastasis research and propose to use them at three levels to systematically interrogate the molecular underpinnings of PDAC metastasis.
We will first perform complementary genome-scale surveys for genes and pathways driving metastasis and metastatic organotropism. We will (i) sequence our unique, largely unpublished resource of 1200 metastatic mouse PDAC, (ii) will perform genome-wide in vivo metastasis screens using transposon tools and approaches, which we pioneered in mice, and (iii) will perturb the human metastasis transcriptome and epigenome.
Second, we will validate newly discovered genes using human PDAC cohorts, and through functional studies in mice. We will deploy next-generation metastasis models based on advanced somatic genome engineering. They allow rapid functional studies at an organismal level, thus capturing the complexity of the metastatic cascade.
Third, building on our recent discovery of two prototype PDAC metastasis drivers, we will perform in depth mechanistic studies to identify underlying molecular networks and vulnerabilities.
This work will unravel - for the first time - comprehensive genetic and functional landscapes of PDAC metastasis. PACA-MET thus promises to uncover fundamental novel biological principles and identify therapeutic targets for one of biggest challenges in medicine.
Max ERC Funding
1 995 875 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
Project acronym PedSarc
Project Targeting genetic and epigenetic mechanisms in pediatric sarcomas.
Researcher (PI) Ana BANITO
Host Institution (HI) DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary Sarcomas are an extremely heterogeneous group of mesenchymal tumors that arise in a multitude of tissues from many different cell types. Several genetic events have been identified in different sarcoma sub-types, but very few models were developed to study their role in tumorigenesis aiming at exploiting them as therapeutic vulnerabilities. As a result, the treatment of sarcoma has extremely limited advancement in therapeutic options compared to other cancers. Therefore, the generation of faithful in vitro and in vivo models for sarcoma research is urgently needed to provide insights into the pathobiology of these tumors and discover novel vulnerabilities in these lethal but yet understudied disease. Many types of soft tissue sarcomas arising in children and young adults have a unifying underlying genetic mechanism, where chromosomal translocations generate fusion oncoproteins that serve as drivers of the disease. Exploiting this genetic simplicity provides an exceptional opportunity to develop effective and specific therapies. My past research has applied cutting edge technology to define epigenetic vulnerabilities associated with the SS18-SSX gene fusion, the defining event in synovial sarcoma (one subgroup of pediatric sarcomas), and to study its chromatin occupancy genome-wide. In this proposal my team will combine a toolbox consisting of CRISPR/Cas9, RNAi technology and expertise in mouse models to systematically elucidate key genetic and epigenetic mechanisms in the pathobiology of pediatric sarcomas. This work will help to understand key players in epigenetic deregulation in pediatric sarcomas, generate new sarcoma models to assist clinical translation, and identify new therapeutic targets for these deadly diseases.
Summary
Sarcomas are an extremely heterogeneous group of mesenchymal tumors that arise in a multitude of tissues from many different cell types. Several genetic events have been identified in different sarcoma sub-types, but very few models were developed to study their role in tumorigenesis aiming at exploiting them as therapeutic vulnerabilities. As a result, the treatment of sarcoma has extremely limited advancement in therapeutic options compared to other cancers. Therefore, the generation of faithful in vitro and in vivo models for sarcoma research is urgently needed to provide insights into the pathobiology of these tumors and discover novel vulnerabilities in these lethal but yet understudied disease. Many types of soft tissue sarcomas arising in children and young adults have a unifying underlying genetic mechanism, where chromosomal translocations generate fusion oncoproteins that serve as drivers of the disease. Exploiting this genetic simplicity provides an exceptional opportunity to develop effective and specific therapies. My past research has applied cutting edge technology to define epigenetic vulnerabilities associated with the SS18-SSX gene fusion, the defining event in synovial sarcoma (one subgroup of pediatric sarcomas), and to study its chromatin occupancy genome-wide. In this proposal my team will combine a toolbox consisting of CRISPR/Cas9, RNAi technology and expertise in mouse models to systematically elucidate key genetic and epigenetic mechanisms in the pathobiology of pediatric sarcomas. This work will help to understand key players in epigenetic deregulation in pediatric sarcomas, generate new sarcoma models to assist clinical translation, and identify new therapeutic targets for these deadly diseases.
Max ERC Funding
1 499 375 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym PRiSM
Project Programming Sensory regulation of Metabolism
Researcher (PI) Sophie Marie Francine STECULORUM
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary Sensory perception has recently emerged as a master regulator of integrative physiology and behavior, including feeding, by controlling fundamental and pleiotropic regulatory processes of energy and glucose homeostasis. Further, sensory perception is altered in obesity and type 2 diabetes, and childhood obesity correlates with early sensory deficit. Along this line, the discovery of the developmental origins of health and diseases revealed that metabolic diseases have recognized roots in the very early stages of life and can be predisposed to by changes in the perinatal hormonal and nutritional environments, such as occur in cases of maternal obesity and unhealthy diet. In this context, an accumulating body of evidence suggests that maternal health and nutrition could negatively impinge on the development of sensory perception, and subsequently, on the lifelong regulation of sensory-dependent control of metabolic, physiological, and behavioral regulatory processes. This innovative research program consists of four autonomous but complementary projects aimed at (1) deciphering the exact central regulatory processes mediating sensory control of feeding behavior and glucose homeostasis, (2) uncovering the influence of maternal health and nutrition on lifelong sensory regulation of metabolism, and (3) & (4) investigating two independent, yet synergistic, mechanisms that could mediate developmental programming of sensory metabolic regulation. This research program will employ a technology framework of physiological, behavioral, and developmental analyses in mice in concert with state-of-the-art systems neuroscience approaches, including optogenetics, chemogenetics, and in vivo calcium imaging. Collectively, the overarching goals of this research program are to provide new insights into the precise regulatory processes of sensory metabolic regulation and to shed light on critical basic mechanisms underlying the developmental programming of metabolic diseases.
Summary
Sensory perception has recently emerged as a master regulator of integrative physiology and behavior, including feeding, by controlling fundamental and pleiotropic regulatory processes of energy and glucose homeostasis. Further, sensory perception is altered in obesity and type 2 diabetes, and childhood obesity correlates with early sensory deficit. Along this line, the discovery of the developmental origins of health and diseases revealed that metabolic diseases have recognized roots in the very early stages of life and can be predisposed to by changes in the perinatal hormonal and nutritional environments, such as occur in cases of maternal obesity and unhealthy diet. In this context, an accumulating body of evidence suggests that maternal health and nutrition could negatively impinge on the development of sensory perception, and subsequently, on the lifelong regulation of sensory-dependent control of metabolic, physiological, and behavioral regulatory processes. This innovative research program consists of four autonomous but complementary projects aimed at (1) deciphering the exact central regulatory processes mediating sensory control of feeding behavior and glucose homeostasis, (2) uncovering the influence of maternal health and nutrition on lifelong sensory regulation of metabolism, and (3) & (4) investigating two independent, yet synergistic, mechanisms that could mediate developmental programming of sensory metabolic regulation. This research program will employ a technology framework of physiological, behavioral, and developmental analyses in mice in concert with state-of-the-art systems neuroscience approaches, including optogenetics, chemogenetics, and in vivo calcium imaging. Collectively, the overarching goals of this research program are to provide new insights into the precise regulatory processes of sensory metabolic regulation and to shed light on critical basic mechanisms underlying the developmental programming of metabolic diseases.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym QUADAG
Project Quadratic refinements in algebraic geometry
Researcher (PI) Marc Levine
Host Institution (HI) UNIVERSITAET DUISBURG-ESSEN
Call Details Advanced Grant (AdG), PE1, ERC-2018-ADG
Summary Enumerative geometry, the mathematics of counting numbers of solutions to geometric problems, and its modern descendents, Gromov-Witten theory, Donaldson-Thomas theory, quantum cohomology and many other related fields, analyze geometric problems by computing numerical invariants, such as intersection numbers or degrees of characteristic classes. This essentially algebraic approach has been successful mainly in the study of problems over the complex numbers and other algebraically closed fields. There has been progress in attacking enumerative problems over the real numbers; the methods are mainly non-algebraic. Arithmetic content underlying the numerical invariants is hidden when analyzed by these non-algebraic methods. Recent work by the PI and others has opened the door to a new, purely algebraic approach to enumerative geometry that recovers results in both the complex and real cases in one package and reveals this arithmetic content over arbitrary fields. Building on these new developments, the goals of this proposal are, firstly, to use motivic homotopy theory, algebraic geometry and symplectic geometry to develop new purely algebraic methods for handling enumerative problems over an arbitrary field, secondly, to apply these methods to central enumerative problems, recovering and unifying known results over both C and R and thirdly, to use this new approach to reveal the hidden arithmetic nature of enumerative problems. In 2009 R. Pandharipande and I applied algebraic cobordism to prove the degree zero MNOP conjecture in Donaldson-Thomas theory. More recently, I have developed several aspects of the theory of quadratic invariants using motivic homotopy theory.
Summary
Enumerative geometry, the mathematics of counting numbers of solutions to geometric problems, and its modern descendents, Gromov-Witten theory, Donaldson-Thomas theory, quantum cohomology and many other related fields, analyze geometric problems by computing numerical invariants, such as intersection numbers or degrees of characteristic classes. This essentially algebraic approach has been successful mainly in the study of problems over the complex numbers and other algebraically closed fields. There has been progress in attacking enumerative problems over the real numbers; the methods are mainly non-algebraic. Arithmetic content underlying the numerical invariants is hidden when analyzed by these non-algebraic methods. Recent work by the PI and others has opened the door to a new, purely algebraic approach to enumerative geometry that recovers results in both the complex and real cases in one package and reveals this arithmetic content over arbitrary fields. Building on these new developments, the goals of this proposal are, firstly, to use motivic homotopy theory, algebraic geometry and symplectic geometry to develop new purely algebraic methods for handling enumerative problems over an arbitrary field, secondly, to apply these methods to central enumerative problems, recovering and unifying known results over both C and R and thirdly, to use this new approach to reveal the hidden arithmetic nature of enumerative problems. In 2009 R. Pandharipande and I applied algebraic cobordism to prove the degree zero MNOP conjecture in Donaldson-Thomas theory. More recently, I have developed several aspects of the theory of quadratic invariants using motivic homotopy theory.
Max ERC Funding
2 124 663 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym REPLISOMEBYPASS
Project Challenges on the road to genome duplication: Single-molecule approaches to study replisome collisions
Researcher (PI) Karl DUDERSTADT
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS1, ERC-2018-STG
Summary Faithful duplication and transmission of genetic and epigenetic information is the most vital cellular
function for the preservation and proliferation of life. In cells, this process is conducted by large
macromolecular complexes, known as replisomes, that coordinate the sequence of enzymatic events
during chromosome duplication. While recently developed single-molecule techniques promise
unprecedented access to the complex inner workings of these sophisticated machines, most studies
conducted have focused on individual factors, operating on non-physiological substrates, which has
provided an incomplete molecular picture.
My recent development of a multidimensional, single-molecule imaging approach that allows
for real-time visualisation of coordination during replication represents a significant breakthrough
in our ability to study macromolecular machines in vitro. Building on this success, here I describe
single-molecule imaging approaches to address one of the long-standing questions in chromosome
biology: How do replisomes maintain efficiency and coordination during collisions with obstacles
on the chromosome?
Our objective is to develop a complete molecular understanding of the consequences of
replisome collisions and the underlying mechanisms that allow for bypass or trigger replication fork
collapse. We will begin this long-term research effort by addressing several issues fundamental to
chromosome replication: How does replisome coordination and composition change during
encounters with topological barriers in chromosomes? What are the dynamic events that underlie
nucleosome disassembly by histone chaperones during replication? How does the eukaryotic
replisome collaborate with histone chaperones to ensure faithful inheritance of epigenetic
information encoded on histones?
These studies will provide a framework for understanding the dynamics of replisome collisions
and the molecular origin of chromosome damage underlying many diseases.
Summary
Faithful duplication and transmission of genetic and epigenetic information is the most vital cellular
function for the preservation and proliferation of life. In cells, this process is conducted by large
macromolecular complexes, known as replisomes, that coordinate the sequence of enzymatic events
during chromosome duplication. While recently developed single-molecule techniques promise
unprecedented access to the complex inner workings of these sophisticated machines, most studies
conducted have focused on individual factors, operating on non-physiological substrates, which has
provided an incomplete molecular picture.
My recent development of a multidimensional, single-molecule imaging approach that allows
for real-time visualisation of coordination during replication represents a significant breakthrough
in our ability to study macromolecular machines in vitro. Building on this success, here I describe
single-molecule imaging approaches to address one of the long-standing questions in chromosome
biology: How do replisomes maintain efficiency and coordination during collisions with obstacles
on the chromosome?
Our objective is to develop a complete molecular understanding of the consequences of
replisome collisions and the underlying mechanisms that allow for bypass or trigger replication fork
collapse. We will begin this long-term research effort by addressing several issues fundamental to
chromosome replication: How does replisome coordination and composition change during
encounters with topological barriers in chromosomes? What are the dynamic events that underlie
nucleosome disassembly by histone chaperones during replication? How does the eukaryotic
replisome collaborate with histone chaperones to ensure faithful inheritance of epigenetic
information encoded on histones?
These studies will provide a framework for understanding the dynamics of replisome collisions
and the molecular origin of chromosome damage underlying many diseases.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym ScarLessWorld
Project A WORLD WITHOUT SCARS: Regenerating wounded skin rather than patching with scars
Researcher (PI) Yuval Rinkevich
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Call Details Consolidator Grant (CoG), LS4, ERC-2018-COG
Summary Scars are a mystery. They rarely develop in lower vertebrates, where the norm is a complete regeneration of damaged tissues, but are frequent in mammals including humans. Scar phenotypes depend on different injury types, anatomic locations, age, gender and species. The natural diversity of scars includes rare cases, where damaged tissues regenerate without scarring. The scar/regeneration decision remains unresolved and scar prevention is a clinical challenge.
Current research has been held up by conceptual and operational bottlenecks. The current conceptual notion comes from experiments showing that scarring depends on the internal environment of the injured organ. I challenged this notion by uncovering specialized fibroblast cell lineages that regenerate connective tissues without scars, anywhere, anytime. My hypothesis is that the decision to scar/regenerate lies in the compositions of specific fibroblast types. To further study this theory I had to resolve a second bottleneck, the current lack of assays that display the full complexity of scarring and regeneration. I have thus developed innovative technological approaches (four novel tools) that allow whole-animal live imaging, tracking and gene modification of fibroblasts.
Building on these innovative tools and my expertise in cell lineages as linchpins of this proposal, I aim to: (1) catalogue the repertoires of dermal fibroblast lineages, (2) image their dynamics during scarring/regeneration (3) identify the decision-making genes for scarring/regeneration in actual skin tissues, and finally (4) translate our findings from mouse to human skin. This new notion that specialized fibroblast lineages drive scarring/regeneration, combined with the technology breakthroughs, will greatly advance our current understanding of scar formation, which is a significant worldwide biomedical problem, creating new research avenues for regenerative medicine far beyond the current state-of-the-art.
Summary
Scars are a mystery. They rarely develop in lower vertebrates, where the norm is a complete regeneration of damaged tissues, but are frequent in mammals including humans. Scar phenotypes depend on different injury types, anatomic locations, age, gender and species. The natural diversity of scars includes rare cases, where damaged tissues regenerate without scarring. The scar/regeneration decision remains unresolved and scar prevention is a clinical challenge.
Current research has been held up by conceptual and operational bottlenecks. The current conceptual notion comes from experiments showing that scarring depends on the internal environment of the injured organ. I challenged this notion by uncovering specialized fibroblast cell lineages that regenerate connective tissues without scars, anywhere, anytime. My hypothesis is that the decision to scar/regenerate lies in the compositions of specific fibroblast types. To further study this theory I had to resolve a second bottleneck, the current lack of assays that display the full complexity of scarring and regeneration. I have thus developed innovative technological approaches (four novel tools) that allow whole-animal live imaging, tracking and gene modification of fibroblasts.
Building on these innovative tools and my expertise in cell lineages as linchpins of this proposal, I aim to: (1) catalogue the repertoires of dermal fibroblast lineages, (2) image their dynamics during scarring/regeneration (3) identify the decision-making genes for scarring/regeneration in actual skin tissues, and finally (4) translate our findings from mouse to human skin. This new notion that specialized fibroblast lineages drive scarring/regeneration, combined with the technology breakthroughs, will greatly advance our current understanding of scar formation, which is a significant worldwide biomedical problem, creating new research avenues for regenerative medicine far beyond the current state-of-the-art.
Max ERC Funding
1 997 890 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym SYZYGY
Project Syzygies, moduli and topological invariants of groups
Researcher (PI) Gavril FARKAS
Host Institution (HI) HUMBOLDT-UNIVERSITAET ZU BERLIN
Call Details Advanced Grant (AdG), PE1, ERC-2018-ADG
Summary This is a proposal aimed at harvesting interconnections between algebraic geometry and geometric group theory using syzygies. The impetus of the proposal is the recent breakthrough in which, inspired by rational homotopy theory, we introduced Koszul modules as novel homological objects establishing striking connections between algebraic geometry and geometric group theory. Deep statements in geometric group theory have startling counterparts in algebraic geometry and these connection led to a recent proof of Green's Conjecture for generic algebraic curves in arbitrary characteristic, as well as to a dramatically simpler proof in characteristic zero. Based on a dynamic view of mathematics in which ideas from one field trigger major developments in another, I propose to lead a group at HU Berlin dedicated to the following major themes, which are outlined in the proposal: (i) Find a solution to Green's Conjecture on the syzygies of an arbitrary smooth canonical curve of genus g. Find a full solution to the Prym-Green Conjecture on the syzygies of a general paracanonical algebraic curve of genus g. Formulate and prove a non-commutative Green's Conjecture for super algebraic curves. (ii) Compute the Kodaira dimension of the moduli space of curves in the transition case from unirationality to general type, when g is between 17 and 21. Construct the canonical model of the moduli space of curves and find its modular interpretation. (iii) Find algebro-geometric interpretations for Alexander invariants of the Torelli group of the mapping class group and that of the Torelli group of the free group. Understand the link between these invariants, the homotopy type and the cohomological dimension of the moduli space of curves. (iv) Get structural insight in the newly discovered topological version of Green's Conjecture involving the Alexander invariant of the group.
Summary
This is a proposal aimed at harvesting interconnections between algebraic geometry and geometric group theory using syzygies. The impetus of the proposal is the recent breakthrough in which, inspired by rational homotopy theory, we introduced Koszul modules as novel homological objects establishing striking connections between algebraic geometry and geometric group theory. Deep statements in geometric group theory have startling counterparts in algebraic geometry and these connection led to a recent proof of Green's Conjecture for generic algebraic curves in arbitrary characteristic, as well as to a dramatically simpler proof in characteristic zero. Based on a dynamic view of mathematics in which ideas from one field trigger major developments in another, I propose to lead a group at HU Berlin dedicated to the following major themes, which are outlined in the proposal: (i) Find a solution to Green's Conjecture on the syzygies of an arbitrary smooth canonical curve of genus g. Find a full solution to the Prym-Green Conjecture on the syzygies of a general paracanonical algebraic curve of genus g. Formulate and prove a non-commutative Green's Conjecture for super algebraic curves. (ii) Compute the Kodaira dimension of the moduli space of curves in the transition case from unirationality to general type, when g is between 17 and 21. Construct the canonical model of the moduli space of curves and find its modular interpretation. (iii) Find algebro-geometric interpretations for Alexander invariants of the Torelli group of the mapping class group and that of the Torelli group of the free group. Understand the link between these invariants, the homotopy type and the cohomological dimension of the moduli space of curves. (iv) Get structural insight in the newly discovered topological version of Green's Conjecture involving the Alexander invariant of the group.
Max ERC Funding
2 147 202 €
Duration
Start date: 2020-03-01, End date: 2025-02-28
Project acronym TransTempoFold
Project A need for speed: mechanisms to coordinate protein synthesis and folding in metazoans
Researcher (PI) Danny Doncheva NEDIALKOVA
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS1, ERC-2018-STG
Summary Proteins function only after folding into complex three-dimensional shapes. Loss of protein conformation is detrimental for cellular health, and a hallmark of aging and diverse human diseases. To ensure proteome integrity, cells rely on an intricate interplay between protein synthesis, folding, and quality control. Since proteins often begin to fold during mRNA translation, codon choice and tRNA supply can promote this process by modulating translation speed. How metazoans exploit this mechanism to ensure protein homeostasis over a wide range of cells and tissues, or why some cell types are more vulnerable to translation defects and proteome damage remains unknown. Here, I will define how tRNA pools and the regulatory networks for protein biogenesis and homeostasis are tailored to specialized proteomes in different cell types. I propose a multiscale systems approach centred around: i) stem cells and differentiated progeny lines as a powerful model system, and ii) a novel method to modulate cellular tRNA pools in vivo. Isogenic lines of a range of normal cellular states will be created through the differentiation of human pluripotent stem cells into neuronal and cardiac lineages. In these lineages, I will first quantitate tRNA expression and abundance, and dissect their impact on translation dynamics with ribosome profiling. Second, I will use systematic depletion of individual tRNAs to explore how different cell types respond to imbalanced tRNA pools, and define how mRNA sequence and protein structure patterns program protein folding. Third, I will use loss-of-function screens to uncover evolutionarily conserved regulators of proteome integrity as a function of cell identity. This project will define how diverse metazoan cell proteomes are established and maintained, and reveal why some cells tolerate misfolded proteins better than others.
Summary
Proteins function only after folding into complex three-dimensional shapes. Loss of protein conformation is detrimental for cellular health, and a hallmark of aging and diverse human diseases. To ensure proteome integrity, cells rely on an intricate interplay between protein synthesis, folding, and quality control. Since proteins often begin to fold during mRNA translation, codon choice and tRNA supply can promote this process by modulating translation speed. How metazoans exploit this mechanism to ensure protein homeostasis over a wide range of cells and tissues, or why some cell types are more vulnerable to translation defects and proteome damage remains unknown. Here, I will define how tRNA pools and the regulatory networks for protein biogenesis and homeostasis are tailored to specialized proteomes in different cell types. I propose a multiscale systems approach centred around: i) stem cells and differentiated progeny lines as a powerful model system, and ii) a novel method to modulate cellular tRNA pools in vivo. Isogenic lines of a range of normal cellular states will be created through the differentiation of human pluripotent stem cells into neuronal and cardiac lineages. In these lineages, I will first quantitate tRNA expression and abundance, and dissect their impact on translation dynamics with ribosome profiling. Second, I will use systematic depletion of individual tRNAs to explore how different cell types respond to imbalanced tRNA pools, and define how mRNA sequence and protein structure patterns program protein folding. Third, I will use loss-of-function screens to uncover evolutionarily conserved regulators of proteome integrity as a function of cell identity. This project will define how diverse metazoan cell proteomes are established and maintained, and reveal why some cells tolerate misfolded proteins better than others.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
