Project acronym GermlineAgeingSoma
Project Getting to the root of ageing: somatic decay as a cost of germline maintenance
Researcher (PI) Alexei MAKLAKOV
Host Institution (HI) UNIVERSITY OF EAST ANGLIA
Call Details Consolidator Grant (CoG), LS8, ERC-2016-COG
Summary The trade-off between survival and reproduction lies at the core of the evolutionary theory of ageing. Removal of germ cells extends somatic lifespan implying that reduced reproduction frees up resources for survival. Remarkably, however, the disruption of germline signalling increases lifespan without the obligatory reduction in fecundity, thus challenging the key role of the survival-reproduction trade-off. Recent breakthroughs suggest that protection and repair of the genome and the proteome of the germ cells is costly and compromised germline maintenance increases mutation rate, which can reduce offspring fitness. Thus, expensive germline maintenance can be a missing link in the puzzle of cost-free lifespan extension. This hypothesis predicts that when germline signalling is manipulated to increase investment into somatic cells, the germline maintenance will suffer resulting in increased mutation rate and reduced offspring fitness, even if total fecundity is unaffected. I propose a research program at the interface of evolutionary biology and biogerontology that focuses on phenotypic and evolutionary costs of germline maintenance. First, I will genetically manipulate germline signalling to boost investment into soma and estimate mutation rate and competitive fitness of the resulting offspring using Caenorhabditis elegans nematodes. Second, I will employ experimental evolution in nematodes to assess the long-term evolutionary costs of increased germline maintenance. Third, I will use germline transplantation in zebrafish Dario rerio to directly test whether germline proliferation reduces investment into soma in a vertebrate. Understanding how increased investment into the soma damages the germline and reduces offspring fitness will provide a major advance in our understanding of ageing evolution and will have serious implications for applied research programs aimed at harnessing the power of germline signalling to postpone ageing.
Summary
The trade-off between survival and reproduction lies at the core of the evolutionary theory of ageing. Removal of germ cells extends somatic lifespan implying that reduced reproduction frees up resources for survival. Remarkably, however, the disruption of germline signalling increases lifespan without the obligatory reduction in fecundity, thus challenging the key role of the survival-reproduction trade-off. Recent breakthroughs suggest that protection and repair of the genome and the proteome of the germ cells is costly and compromised germline maintenance increases mutation rate, which can reduce offspring fitness. Thus, expensive germline maintenance can be a missing link in the puzzle of cost-free lifespan extension. This hypothesis predicts that when germline signalling is manipulated to increase investment into somatic cells, the germline maintenance will suffer resulting in increased mutation rate and reduced offspring fitness, even if total fecundity is unaffected. I propose a research program at the interface of evolutionary biology and biogerontology that focuses on phenotypic and evolutionary costs of germline maintenance. First, I will genetically manipulate germline signalling to boost investment into soma and estimate mutation rate and competitive fitness of the resulting offspring using Caenorhabditis elegans nematodes. Second, I will employ experimental evolution in nematodes to assess the long-term evolutionary costs of increased germline maintenance. Third, I will use germline transplantation in zebrafish Dario rerio to directly test whether germline proliferation reduces investment into soma in a vertebrate. Understanding how increased investment into the soma damages the germline and reduces offspring fitness will provide a major advance in our understanding of ageing evolution and will have serious implications for applied research programs aimed at harnessing the power of germline signalling to postpone ageing.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym GMLP
Project Global Methods in the Langlands Program
Researcher (PI) Jack THORNE
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Starting Grant (StG), PE1, ERC-2016-STG
Summary The Langlands program is a conjectural framework for understanding the deep relations between automorphic forms and arithmetic. It implies a parameterization of representations of Galois groups of (local or global) fields in terms of representations of (p-adic or adelic) reductive groups. While making progress in the Langlands program often means overcoming significant technical obstacles, new results can have concrete applications to number theory, the proof of Fermat's Last Theorem by Wiles being a key example.
Recently, V. Lafforgue has made a striking breakthrough in the Langlands program over function fields, by constructing an `automorphic-to-Galois' Langlands correspondence. As a consequence, this should imply the existence of a local Langlands correspondence over equicharacteristic non-archimedean local fields.
The goal of this proposal is to show the surjectivity of this local Langlands correspondence. My strategy will be global, and will involve solving global problems of strong independent interest. I intend to establish a research group to carry out the following objectives, in the setting of global function fields:
I. Establish automorphy lifting theorems for Galois representations valued in the (Langlands) dual group of an arbitrary split reductive group.
II. Establish cases of automorphic induction for arbitrary reductive groups.
III. Prove potential automorphy theorems for Galois representations valued in the dual group of an arbitrary reductive group.
IV. Establish cases of soluble base change and descent for automorphic representations of arbitrary reductive groups.
I will then combine these results to obtain the desired surjectivity. This will be a milestone in our understanding of the Langlands correspondence for function fields.
Summary
The Langlands program is a conjectural framework for understanding the deep relations between automorphic forms and arithmetic. It implies a parameterization of representations of Galois groups of (local or global) fields in terms of representations of (p-adic or adelic) reductive groups. While making progress in the Langlands program often means overcoming significant technical obstacles, new results can have concrete applications to number theory, the proof of Fermat's Last Theorem by Wiles being a key example.
Recently, V. Lafforgue has made a striking breakthrough in the Langlands program over function fields, by constructing an `automorphic-to-Galois' Langlands correspondence. As a consequence, this should imply the existence of a local Langlands correspondence over equicharacteristic non-archimedean local fields.
The goal of this proposal is to show the surjectivity of this local Langlands correspondence. My strategy will be global, and will involve solving global problems of strong independent interest. I intend to establish a research group to carry out the following objectives, in the setting of global function fields:
I. Establish automorphy lifting theorems for Galois representations valued in the (Langlands) dual group of an arbitrary split reductive group.
II. Establish cases of automorphic induction for arbitrary reductive groups.
III. Prove potential automorphy theorems for Galois representations valued in the dual group of an arbitrary reductive group.
IV. Establish cases of soluble base change and descent for automorphic representations of arbitrary reductive groups.
I will then combine these results to obtain the desired surjectivity. This will be a milestone in our understanding of the Langlands correspondence for function fields.
Max ERC Funding
1 094 610 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym Group-Dynamics-TCB
Project Effects of group dynamics on selection, development and demography in cooperative vertebrates
Researcher (PI) Timothy Hugh CLUTTON-BROCK
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), LS8, ERC-2016-ADG
Summary In social animals, the characteristics and dynamics of groups affect the development of individuals, the selection pressures operating on them and the demography of populations. Using existing study populations of two social mammals (Kalahari meerkats and Damaraland mole-rats) that offer unique and complementary opportunities for research, we shall (1) explore the effects of variation in group size on growth, behaviour, hormonal status and gene regulation in both species and test suggestions that (i) increasing group size generates divergence in development among group members and the formation of incipient castes and (ii) that breeding extends female longevity rather than reducing it; (2) assess the extent and causes of variation in group longevity and in the frequency with which groups generate new breeding units, model the relative impact of selection operating at different levels on the evolution of cooperation, and investigate whether there is any indication that the behaviour of individuals is adapted to increasing group persistence or proliferation; (3) examine the effects of group size and group dynamics on the dynamics of populations and their responses to variation in rainfall, temperature and epidemic disease (TB), generalise these models to explore the population dynamics of cooperative breeders and explore their consequences for the evolution of cooperative breeding. Our work involves novel approaches to the measurement and analysis of development, communication and gene regulation in wild animals, and to modelling multi-level selection and the dynamics of hierarchically structured populations. It will provide insight into the social mechanisms affecting individual development, multi-level selection and the population dynamics and management of group-living animals.
Summary
In social animals, the characteristics and dynamics of groups affect the development of individuals, the selection pressures operating on them and the demography of populations. Using existing study populations of two social mammals (Kalahari meerkats and Damaraland mole-rats) that offer unique and complementary opportunities for research, we shall (1) explore the effects of variation in group size on growth, behaviour, hormonal status and gene regulation in both species and test suggestions that (i) increasing group size generates divergence in development among group members and the formation of incipient castes and (ii) that breeding extends female longevity rather than reducing it; (2) assess the extent and causes of variation in group longevity and in the frequency with which groups generate new breeding units, model the relative impact of selection operating at different levels on the evolution of cooperation, and investigate whether there is any indication that the behaviour of individuals is adapted to increasing group persistence or proliferation; (3) examine the effects of group size and group dynamics on the dynamics of populations and their responses to variation in rainfall, temperature and epidemic disease (TB), generalise these models to explore the population dynamics of cooperative breeders and explore their consequences for the evolution of cooperative breeding. Our work involves novel approaches to the measurement and analysis of development, communication and gene regulation in wild animals, and to modelling multi-level selection and the dynamics of hierarchically structured populations. It will provide insight into the social mechanisms affecting individual development, multi-level selection and the population dynamics and management of group-living animals.
Max ERC Funding
2 499 244 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym Honeyguides-Humans
Project How a mutualism evolves: learning, coevolution, and their ecosystem consequences in human-honeyguide interactions
Researcher (PI) Claire Noelle SPOTTISWOODE
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Consolidator Grant (CoG), LS8, ERC-2016-COG
Summary Species interactions such as mutualism, parasitism and predation underpin much of life’s diversity. We aim to understand the mechanistic role of learnt traits in the origin and maintenance of mutualistic interactions between species, and to test their evolutionary and ecological consequences. To do so, we shall study a remarkable mutualism: the foraging partnership between an African bird species, the greater honeyguide Indicator indicator, and the human honey-hunters whom it guides to bees’ nests. Honeyguides know where bees’ nests are located and like to eat beeswax; humans have the ability to subdue the bees and open the nest, thus exposing beeswax for the honeyguides and honey for the humans. This model system gives us a wonderful opportunity to study mutualisms, because local human and honeyguide populations vary strikingly in whether and how they interact, and because we can readily manipulate these interactions experimentally. We have already demonstrated that it is fully feasible to carry out observational and experimental work at a study site we have established in cooperation with a honey-hunting community in northern Mozambique. Here, and at a series of comparative field sites we have identified in south-eastern Africa, we shall ask: is learning involved in maintaining a geographical mosaic of honeyguide adaptation to local human cultures? How does reciprocal communication between humans and honeyguides mediate their interactions? What are the effects of cultural co-extinctions on each partner and their ecosystems, and how quickly can such cultures be re-ignited following their loss? In so doing we shall test for the first time the hypothesis that reciprocal learning can give rise to matching cultural traits between interacting species. Understanding the role of such phenotypic plasticity is crucial to explain how and why the outcome of species interactions varies in space and time, and to predict how they will respond to a rapidly changing world.
Summary
Species interactions such as mutualism, parasitism and predation underpin much of life’s diversity. We aim to understand the mechanistic role of learnt traits in the origin and maintenance of mutualistic interactions between species, and to test their evolutionary and ecological consequences. To do so, we shall study a remarkable mutualism: the foraging partnership between an African bird species, the greater honeyguide Indicator indicator, and the human honey-hunters whom it guides to bees’ nests. Honeyguides know where bees’ nests are located and like to eat beeswax; humans have the ability to subdue the bees and open the nest, thus exposing beeswax for the honeyguides and honey for the humans. This model system gives us a wonderful opportunity to study mutualisms, because local human and honeyguide populations vary strikingly in whether and how they interact, and because we can readily manipulate these interactions experimentally. We have already demonstrated that it is fully feasible to carry out observational and experimental work at a study site we have established in cooperation with a honey-hunting community in northern Mozambique. Here, and at a series of comparative field sites we have identified in south-eastern Africa, we shall ask: is learning involved in maintaining a geographical mosaic of honeyguide adaptation to local human cultures? How does reciprocal communication between humans and honeyguides mediate their interactions? What are the effects of cultural co-extinctions on each partner and their ecosystems, and how quickly can such cultures be re-ignited following their loss? In so doing we shall test for the first time the hypothesis that reciprocal learning can give rise to matching cultural traits between interacting species. Understanding the role of such phenotypic plasticity is crucial to explain how and why the outcome of species interactions varies in space and time, and to predict how they will respond to a rapidly changing world.
Max ERC Funding
1 998 885 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym LogCorRM
Project Log Correlations and Random Matrices
Researcher (PI) Jon KEATING
Host Institution (HI) UNIVERSITY OF BRISTOL
Call Details Advanced Grant (AdG), PE1, ERC-2016-ADG
Summary Random Matrix Theory has been of central importance in Mathematical Physics for over 50 years. It has deep connections with many other areas of Mathematics and a remarkably wide range of applications. In 2012, a new avenue of research was initiated linking Random Matrix Theory to the highly active area of Probability Theory concerned with the extreme values of logarithmically correlated Gaussian fields, such as the branching random walk and the two-dimensional Gaussian Free Field. This connects the extreme value statistics of the characteristic polynomials of random matrices asymptotically to those of the Gaussian fields in question, allowing some important and long-standing open questions to be addressed for the first time. It has led to a flurry of activity and significant progress towards proving some of the main conjectures. A remarkable discovery has been that the characteristic polynomials of random matrices exhibit, asymptotically, a hierarchical branching/tree structure like that of the branching random walk. However, many of the most important questions remain open. My aim is to attack some of these problems using ideas and techniques that have so far not been applied to them: I believe it is possible to compute some important statistical quantities relating to the extreme values of characteristic polynomials exactly, for the first time, by establishing connections with integrable systems, representation theory, and enumerative combinatorics. Such connections have not previously been explored. I anticipate that this will have a significant impact on an area that is currently in a rapid phase of development and that it will settle some of the principal unresolved conjectures. I further believe that ideas exploiting the hierarchical branching structure may have new and unexpected implications for areas connected with Random Matrix Theory, including, in particular, Number Theory, and I plan to explore these too.
Summary
Random Matrix Theory has been of central importance in Mathematical Physics for over 50 years. It has deep connections with many other areas of Mathematics and a remarkably wide range of applications. In 2012, a new avenue of research was initiated linking Random Matrix Theory to the highly active area of Probability Theory concerned with the extreme values of logarithmically correlated Gaussian fields, such as the branching random walk and the two-dimensional Gaussian Free Field. This connects the extreme value statistics of the characteristic polynomials of random matrices asymptotically to those of the Gaussian fields in question, allowing some important and long-standing open questions to be addressed for the first time. It has led to a flurry of activity and significant progress towards proving some of the main conjectures. A remarkable discovery has been that the characteristic polynomials of random matrices exhibit, asymptotically, a hierarchical branching/tree structure like that of the branching random walk. However, many of the most important questions remain open. My aim is to attack some of these problems using ideas and techniques that have so far not been applied to them: I believe it is possible to compute some important statistical quantities relating to the extreme values of characteristic polynomials exactly, for the first time, by establishing connections with integrable systems, representation theory, and enumerative combinatorics. Such connections have not previously been explored. I anticipate that this will have a significant impact on an area that is currently in a rapid phase of development and that it will settle some of the principal unresolved conjectures. I further believe that ideas exploiting the hierarchical branching structure may have new and unexpected implications for areas connected with Random Matrix Theory, including, in particular, Number Theory, and I plan to explore these too.
Max ERC Funding
1 778 516 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym LogNeuroDev
Project The molecular and cellular logic of vertebrate neural development
Researcher (PI) James BRISCOE
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Advanced Grant (AdG), LS3, ERC-2016-ADG
Summary A central problem in biology and key to realising the potential of regenerative medicine is understanding the mechanisms that produce and organize cells in the complex tissues of an embryo. In broad terms, initially uncommitted progenitors acquire their fate in response to signals that control transcriptional programmes. These programmes drive cells through spatial and temporal successions of states that gradually refine cell identity. How these states are established and cell fate decisions implemented is poorly understood. To address this we use an experimentally tractable system – the formation of defined populations of progenitors in the vertebrate spinal cord. We take an interdisciplinary approach that combines our in vivo expertise with three recent advances in our group. First, we have developed in vitro differentiation systems and microfluidic devices that use embryonic stem cells to recapitulate development processes. Second, we have embraced new technologies that provide unprecedented ability to manipulate and assay single cells. Finally, we have established interdisciplinary collaborations to develop computational tools and construct data driven mathematical models. Using these approaches, alongside established embryological methods, we will establish a platform for manipulating and analysing mechanisms by which the multipotent progenitors that form the spinal cord acquire specific identities. We will identify the rules by which cells make decisions and we will define the design logic and network architectures that lead to distinct cell fate choices. The ability to: (i) follow the trajectory of a cell as it transitions to a specific neuronal subtype in vivo; (ii) manipulate the process in vitro and in vivo; and (iii) model it in silico, offers a unique system for understanding organogenesis. Together these approaches will provide the knowledge and technical foundations for rational, predictive tissue engineering of the spinal cord.
Summary
A central problem in biology and key to realising the potential of regenerative medicine is understanding the mechanisms that produce and organize cells in the complex tissues of an embryo. In broad terms, initially uncommitted progenitors acquire their fate in response to signals that control transcriptional programmes. These programmes drive cells through spatial and temporal successions of states that gradually refine cell identity. How these states are established and cell fate decisions implemented is poorly understood. To address this we use an experimentally tractable system – the formation of defined populations of progenitors in the vertebrate spinal cord. We take an interdisciplinary approach that combines our in vivo expertise with three recent advances in our group. First, we have developed in vitro differentiation systems and microfluidic devices that use embryonic stem cells to recapitulate development processes. Second, we have embraced new technologies that provide unprecedented ability to manipulate and assay single cells. Finally, we have established interdisciplinary collaborations to develop computational tools and construct data driven mathematical models. Using these approaches, alongside established embryological methods, we will establish a platform for manipulating and analysing mechanisms by which the multipotent progenitors that form the spinal cord acquire specific identities. We will identify the rules by which cells make decisions and we will define the design logic and network architectures that lead to distinct cell fate choices. The ability to: (i) follow the trajectory of a cell as it transitions to a specific neuronal subtype in vivo; (ii) manipulate the process in vitro and in vivo; and (iii) model it in silico, offers a unique system for understanding organogenesis. Together these approaches will provide the knowledge and technical foundations for rational, predictive tissue engineering of the spinal cord.
Max ERC Funding
2 357 000 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym MAFRAN
Project Mathematical Frontiers in the Analysis of Many-particle Systems
Researcher (PI) Clement MOUHOT
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Consolidator Grant (CoG), PE1, ERC-2016-COG
Summary The recent growing mathematical activity around the partial differential equations of kinetic theory has lead to deeper and deeper conceptual breakthroughs. This has opened new paths, and has created new frontiers with other cutting-edge fields of research.
These frontiers correspond to three combined levels: the dialogue with another world-leading research community; the uncovering of deep new connexions and methods through this interplay; the possibilities of making significant progresses on a fundamental open problem:
I. with the elliptic regularity community (regularisation for nonlocal collision operators, De Giorgi- Nash theory): the main challenge is the well-posedness of the Landau-Coulomb equation;
II. with the dispersive and fluid mechanics equations communities (nonlinear stability driven by phase mixing): the main challenge is the damping stability of non spatially homogeneous structures;
III. with the dynamical system and probability communities (mean-field and Boltzmann-Grad limits): the main challenge is the rigorous derivation of the fundamental equations of statistical mechanics on macroscopic times;
IV. with the applications to biology, ecology and statistical physics (emerging collective phenomena for open many-particle systems): the main challenge is the understanding of steady or propagation front solutions and their stability outside the realm of the 2d principle of thermodynamics.
These frontiers can rapidly lead to key advances with potential impact in mathematical analysis and fundamental physics (plasma physics, statistical mechanics); the work program Horizon 2020 would strongly benefit from the construction of a world-class research centre devoted to them. This is my objective in this project: I have played a key role in the opening of these frontiers, I propose new approaches, I have experience in building a research group, and the University of Cambridge, where I am based, would provide a unique supportive environment.
Summary
The recent growing mathematical activity around the partial differential equations of kinetic theory has lead to deeper and deeper conceptual breakthroughs. This has opened new paths, and has created new frontiers with other cutting-edge fields of research.
These frontiers correspond to three combined levels: the dialogue with another world-leading research community; the uncovering of deep new connexions and methods through this interplay; the possibilities of making significant progresses on a fundamental open problem:
I. with the elliptic regularity community (regularisation for nonlocal collision operators, De Giorgi- Nash theory): the main challenge is the well-posedness of the Landau-Coulomb equation;
II. with the dispersive and fluid mechanics equations communities (nonlinear stability driven by phase mixing): the main challenge is the damping stability of non spatially homogeneous structures;
III. with the dynamical system and probability communities (mean-field and Boltzmann-Grad limits): the main challenge is the rigorous derivation of the fundamental equations of statistical mechanics on macroscopic times;
IV. with the applications to biology, ecology and statistical physics (emerging collective phenomena for open many-particle systems): the main challenge is the understanding of steady or propagation front solutions and their stability outside the realm of the 2d principle of thermodynamics.
These frontiers can rapidly lead to key advances with potential impact in mathematical analysis and fundamental physics (plasma physics, statistical mechanics); the work program Horizon 2020 would strongly benefit from the construction of a world-class research centre devoted to them. This is my objective in this project: I have played a key role in the opening of these frontiers, I propose new approaches, I have experience in building a research group, and the University of Cambridge, where I am based, would provide a unique supportive environment.
Max ERC Funding
1 950 637 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym PHYSBIOHSC
Project Understanding the physical biology of adult blood stem cells
Researcher (PI) David KENT
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Starting Grant (StG), LS3, ERC-2016-STG
Summary The discovery of functional heterogeneity in normal and malignant stem cells has shifted our understanding of how single cells are subverted to drive cancer. To design therapies for diseases of stem cell origin and to better provide cell populations for clinical applications, it is critical to understand this diversity at the single cell level. This proposal focuses on understanding the complex biology of normal and malignant stem cells and the impact of individual mutations on clonal evolution by studying the physical and quantitative aspects of single blood stem cells.
This proposal aims to study single blood stem cell biomechanics and clonal evolution by leveraging new inter-disciplinary technologies and approaches and applying them to functionally defined mouse and human blood stem cell populations. It will combine in vitro and in vivo biological assays with mathematical modelling and microfluidic technology in an iterative manner across both human and mouse stem cell populations.
Summary
The discovery of functional heterogeneity in normal and malignant stem cells has shifted our understanding of how single cells are subverted to drive cancer. To design therapies for diseases of stem cell origin and to better provide cell populations for clinical applications, it is critical to understand this diversity at the single cell level. This proposal focuses on understanding the complex biology of normal and malignant stem cells and the impact of individual mutations on clonal evolution by studying the physical and quantitative aspects of single blood stem cells.
This proposal aims to study single blood stem cell biomechanics and clonal evolution by leveraging new inter-disciplinary technologies and approaches and applying them to functionally defined mouse and human blood stem cell populations. It will combine in vitro and in vivo biological assays with mathematical modelling and microfluidic technology in an iterative manner across both human and mouse stem cell populations.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym PlasmoCycle
Project DNA dynamics in the unusual cell cycle of the malaria parasite Plasmodium falciparum
Researcher (PI) Catherine Jill Merrick
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Consolidator Grant (CoG), LS6, ERC-2016-COG
Summary This proposal promises to transform our understanding of the basic biology of the malaria parasite Plasmodium, and of how that biology affects virulence. Remarkably little is known about the Plasmodium cell cycle, despite a wealth of knowledge on the subject in model cells. This project will reveal, with unprecedented resolution, how DNA replication is organised in Plasmodium and how changing conditions in the human host and exposure to antimalarial drugs affect it.
Plasmodium is an early-diverging protozoan with a complex lifecycle & unusual cell-biological features. It replicates in its human host by ‘schizogony’: a single parasite generates many nuclei via independent, asynchronous rounds of genome replication prior to cytokinesis. This occurs over ~24hrs inside infected erythrocytes. However, the genome can also be copied extremely rapidly during the sexual cycle in the malaria-transmitting mosquito. Here 8 male gametes are produced from a single gametocyte in less than 10mins, necessitating extraordinarily rapid DNA synthesis.
This project will first elucidate the spatio-temporal dynamics of DNA replication in these contrasting cell cycles. To do this, I have developed a method for labelling nascent DNA replication, which was not previously possible in Plasmodium. It will permit: a) a detailed characterisation, at the whole-cell level, of the asynchronous genome replication that occurs in schizogony; b) a study of replication origin spacing & DNA synthesis speed at single-molecule resolution on DNA fibres, comparing these parameters in schizogony & gametogenesis; c) mapping sequences with replication origin activity in the Plasmodium genome; d) investigation of cell-cycle checkpoints & replicative responses to the changing environment in the human host and to antimalarial drugs. These are crucial issues for understanding parasite virulence and drug-resistance, and the work will inform vital new research into transmission-blocking interventions for malaria.
Summary
This proposal promises to transform our understanding of the basic biology of the malaria parasite Plasmodium, and of how that biology affects virulence. Remarkably little is known about the Plasmodium cell cycle, despite a wealth of knowledge on the subject in model cells. This project will reveal, with unprecedented resolution, how DNA replication is organised in Plasmodium and how changing conditions in the human host and exposure to antimalarial drugs affect it.
Plasmodium is an early-diverging protozoan with a complex lifecycle & unusual cell-biological features. It replicates in its human host by ‘schizogony’: a single parasite generates many nuclei via independent, asynchronous rounds of genome replication prior to cytokinesis. This occurs over ~24hrs inside infected erythrocytes. However, the genome can also be copied extremely rapidly during the sexual cycle in the malaria-transmitting mosquito. Here 8 male gametes are produced from a single gametocyte in less than 10mins, necessitating extraordinarily rapid DNA synthesis.
This project will first elucidate the spatio-temporal dynamics of DNA replication in these contrasting cell cycles. To do this, I have developed a method for labelling nascent DNA replication, which was not previously possible in Plasmodium. It will permit: a) a detailed characterisation, at the whole-cell level, of the asynchronous genome replication that occurs in schizogony; b) a study of replication origin spacing & DNA synthesis speed at single-molecule resolution on DNA fibres, comparing these parameters in schizogony & gametogenesis; c) mapping sequences with replication origin activity in the Plasmodium genome; d) investigation of cell-cycle checkpoints & replicative responses to the changing environment in the human host and to antimalarial drugs. These are crucial issues for understanding parasite virulence and drug-resistance, and the work will inform vital new research into transmission-blocking interventions for malaria.
Max ERC Funding
1 998 696 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym RepTime
Project Molecular control of DNA replication timing in mammalian cells
Researcher (PI) Sara Cristiana Barbara BUONOMO
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Call Details Consolidator Grant (CoG), LS3, ERC-2016-COG
Summary DNA replication is an essential process ensuring the transmission of genetic information and is highly regulated. Specifically, the DNA replication-timing program ensures that the sites of initiation of DNA replication, termed origins, are not all activated simultaneously but follow a cell-type specific schedule. This pathway is conserved throughout eukaryotic evolution, however its molecular control and biological role are not fully understood. In this proposal I aim to understand key aspects of replication-timing program by employing a combination of advanced mouse genetics, genomics, cell biology and proteomics. Currently one of the major limitations in the mammalian DNA replication field is the elusive identity of origins. I aim to comprehensively map origins in a variety of mouse cells/tissues and relate the regulation of origin firing to the control of gene expression and three-dimensional nuclear architecture. I have discovered that Rif1 controls replication timing and links it to nuclear three-dimensional organization. I have also revealed the existence of a novel Rif1-independent pathway that controls the timing of a significant fraction of the late-replicating genome, identified by constitutive association with a key nuclear architecture component, Lamin B1. Here, I propose complementary approaches to understand the molecular mechanism by which Rif1 coordinates replication timing and nuclear organization as well as the molecular underpinnings of the novel pathway instructing late-replication in Lamin B1-associated regions. Finally, my goal is to understand the in vivo biological role of the replication-timing program. Our preliminary data identify mammalian X inactivation as a process where replication timing may play a fundamental part. My ultimate objective is to contribute to the realization of a comprehensive understanding of nuclear function, integrating the co-regulation of DNA replication with gene expression, epigenetic inheritance and DNA repair.
Summary
DNA replication is an essential process ensuring the transmission of genetic information and is highly regulated. Specifically, the DNA replication-timing program ensures that the sites of initiation of DNA replication, termed origins, are not all activated simultaneously but follow a cell-type specific schedule. This pathway is conserved throughout eukaryotic evolution, however its molecular control and biological role are not fully understood. In this proposal I aim to understand key aspects of replication-timing program by employing a combination of advanced mouse genetics, genomics, cell biology and proteomics. Currently one of the major limitations in the mammalian DNA replication field is the elusive identity of origins. I aim to comprehensively map origins in a variety of mouse cells/tissues and relate the regulation of origin firing to the control of gene expression and three-dimensional nuclear architecture. I have discovered that Rif1 controls replication timing and links it to nuclear three-dimensional organization. I have also revealed the existence of a novel Rif1-independent pathway that controls the timing of a significant fraction of the late-replicating genome, identified by constitutive association with a key nuclear architecture component, Lamin B1. Here, I propose complementary approaches to understand the molecular mechanism by which Rif1 coordinates replication timing and nuclear organization as well as the molecular underpinnings of the novel pathway instructing late-replication in Lamin B1-associated regions. Finally, my goal is to understand the in vivo biological role of the replication-timing program. Our preliminary data identify mammalian X inactivation as a process where replication timing may play a fundamental part. My ultimate objective is to contribute to the realization of a comprehensive understanding of nuclear function, integrating the co-regulation of DNA replication with gene expression, epigenetic inheritance and DNA repair.
Max ERC Funding
1 999 785 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
