Project acronym AAMDDR
Project DNA damage response and genome stability: The role of ATM, ATR and the Mre11 complex
Researcher (PI) Vincenzo Costanzo
Host Institution (HI) CANCER RESEARCH UK LBG
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Summary
Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Max ERC Funding
1 000 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym AVIANEGG
Project Evolutionary genetics in a ‘classical’ avian study system by high throughput transcriptome sequencing and SNP genotyping
Researcher (PI) Jon Slate
Host Institution (HI) THE UNIVERSITY OF SHEFFIELD
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary Long-term studies of free-living vertebrate populations have proved a rich resource for understanding evolutionary and ecological processes, because individuals’ life histories can be measured by tracking them from birth/hatching through to death. In recent years the ‘animal model’ has been applied to pedigreed long-term study populations with great success, dramatically advancing our understanding of quantitative genetic parameters such as heritabilities, genetic correlations and plasticities of traits that are relevant to microevolutionary responses to environmental change. Unfortunately, quantitative genetic approaches have one major drawback – they cannot identify the actual genes responsible for genetic variation. Therefore, it is impossible to link evolutionary responses to a changing environment to molecular genetic variation, making our picture of the process incomplete. Many of the best long-term studies have been conducted in passerine birds. Unfortunately genomics resources are only available for two model avian species, and are absent for bird species that are studied in the wild. I will fill this gap by exploiting recent advances in genomics technology to sequence the entire transcriptome of the longest running study of wild birds – the great tit population in Wytham Woods, Oxford. Having identified most of the sequence variation in the great tit transcriptome, I will then genotype all birds for whom phenotype records and blood samples are available This will be, by far, the largest phenotype-genotype dataset of any free-living vertebrate population. I will then use gene mapping techniques to identify genes and genomic regions responsible for variation in a number of key traits such as lifetime recruitment, clutch size and breeding/laying date. This will result in a greater understanding, at the molecular level, how microevolutionary change can arise (or be constrained).
Summary
Long-term studies of free-living vertebrate populations have proved a rich resource for understanding evolutionary and ecological processes, because individuals’ life histories can be measured by tracking them from birth/hatching through to death. In recent years the ‘animal model’ has been applied to pedigreed long-term study populations with great success, dramatically advancing our understanding of quantitative genetic parameters such as heritabilities, genetic correlations and plasticities of traits that are relevant to microevolutionary responses to environmental change. Unfortunately, quantitative genetic approaches have one major drawback – they cannot identify the actual genes responsible for genetic variation. Therefore, it is impossible to link evolutionary responses to a changing environment to molecular genetic variation, making our picture of the process incomplete. Many of the best long-term studies have been conducted in passerine birds. Unfortunately genomics resources are only available for two model avian species, and are absent for bird species that are studied in the wild. I will fill this gap by exploiting recent advances in genomics technology to sequence the entire transcriptome of the longest running study of wild birds – the great tit population in Wytham Woods, Oxford. Having identified most of the sequence variation in the great tit transcriptome, I will then genotype all birds for whom phenotype records and blood samples are available This will be, by far, the largest phenotype-genotype dataset of any free-living vertebrate population. I will then use gene mapping techniques to identify genes and genomic regions responsible for variation in a number of key traits such as lifetime recruitment, clutch size and breeding/laying date. This will result in a greater understanding, at the molecular level, how microevolutionary change can arise (or be constrained).
Max ERC Funding
1 560 770 €
Duration
Start date: 2008-10-01, End date: 2014-06-30
Project acronym CHROMOSOME STABILITY
Project Coordination of DNA replication and DNA repair at single-forks: the role of the Smc5-Smc6 complex in replication fork stalling and resumption
Researcher (PI) Luis Fernando Aragon Alcaide
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary DNA replication represents a dangerous moment in the life of the cell as endogenous and exogenous events challenge genome integrity by interfering with the progression, stability and restart of the replication fork. Failure to protect stalled forks or to process the replication fork appropriately contribute to the pathological mechanisms giving rise to cancer, therefore an understanding of the intricate mechanisms that ensure fork integrity can provide targets for new chemotherapeutic assays. Smc5-Smc6 is a multi-subunit complex with a poorly understood function in DNA replication and repair. One of its subunits, Nse2, is able to promote the addition of a small ubiquitin-like protein modifier (SUMO) to specific target proteins. Recent work has revealed that the Smc5-Smc6 complex is required for the progression of replication forks through damaged DNA and is recruited de novo to forks that undergo collapse. In addition, Smc5-Smc6 mediate repair of DNA breaks by homologous recombination between sister-chromatids. Thus, Smc5-Smc6 is anticipated to promote recombinational repair at stalled/collapsed replication forks. My laboratory proposes to develop molecular techniques to study replication at the level of single replication forks. We will employ these assays to identify and dissect the function of factors involved in replication fork stability and repair. We will place an emphasis on the study of the Smc5-Smc6 complex in these processes because of its potential roles in recombination-dependent fork repair and restart. We also propose to identify novel Nse2 substrates involved in DNA repair using yeast model systems. Specifically, we will address the following points: (1) Development of assays for analysis of factors involved in stabilisation, collapse and re-start of single-forks, (2) Analysis of the roles of Smc5-Smc6 in fork biology using developed techniques, (3) Isolation and functional analysis of novel Nse2 substrates.
Summary
DNA replication represents a dangerous moment in the life of the cell as endogenous and exogenous events challenge genome integrity by interfering with the progression, stability and restart of the replication fork. Failure to protect stalled forks or to process the replication fork appropriately contribute to the pathological mechanisms giving rise to cancer, therefore an understanding of the intricate mechanisms that ensure fork integrity can provide targets for new chemotherapeutic assays. Smc5-Smc6 is a multi-subunit complex with a poorly understood function in DNA replication and repair. One of its subunits, Nse2, is able to promote the addition of a small ubiquitin-like protein modifier (SUMO) to specific target proteins. Recent work has revealed that the Smc5-Smc6 complex is required for the progression of replication forks through damaged DNA and is recruited de novo to forks that undergo collapse. In addition, Smc5-Smc6 mediate repair of DNA breaks by homologous recombination between sister-chromatids. Thus, Smc5-Smc6 is anticipated to promote recombinational repair at stalled/collapsed replication forks. My laboratory proposes to develop molecular techniques to study replication at the level of single replication forks. We will employ these assays to identify and dissect the function of factors involved in replication fork stability and repair. We will place an emphasis on the study of the Smc5-Smc6 complex in these processes because of its potential roles in recombination-dependent fork repair and restart. We also propose to identify novel Nse2 substrates involved in DNA repair using yeast model systems. Specifically, we will address the following points: (1) Development of assays for analysis of factors involved in stabilisation, collapse and re-start of single-forks, (2) Analysis of the roles of Smc5-Smc6 in fork biology using developed techniques, (3) Isolation and functional analysis of novel Nse2 substrates.
Max ERC Funding
893 396 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym CLIP
Project Mapping functional protein-RNA interactions to identify new targets for oligonucleotide-based therapy
Researcher (PI) Jernej Ule
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary An important question of modern neurobiology is how neurons regulate synaptic function in response to excitation. In particular, the roles of alternative pre-mRNA splicing and mRNA translation regulation in this response are poorly understood. We will study the RNA-binding proteins (RBPs) that control these post-transcriptional changes using a UV crosslinking-based purification method (CLIP) and ultra-high throughput sequencing. Computational analysis of the resulting data will define the sequence and structural features of RNA motifs recognized by each RBP. Splicing microarrays and translation reporter assays will then allow us to examine the regulatory functions of RBPs and RNA motifs. By integrating the biochemical and functional datasets, we will relate the position of RNA motifs to the activity of bound RBPs, and predict the interactions that act as central nodes in the regulatory network. The physiological role of these core RBP-RNA interactions will then be tested using antisense RNAs. Together, these projects will provide insights to the regulatory mechanisms underlying neuronal activity-dependent changes, and provide new opportunities for future treatments of neurodegenerative disorders.
Summary
An important question of modern neurobiology is how neurons regulate synaptic function in response to excitation. In particular, the roles of alternative pre-mRNA splicing and mRNA translation regulation in this response are poorly understood. We will study the RNA-binding proteins (RBPs) that control these post-transcriptional changes using a UV crosslinking-based purification method (CLIP) and ultra-high throughput sequencing. Computational analysis of the resulting data will define the sequence and structural features of RNA motifs recognized by each RBP. Splicing microarrays and translation reporter assays will then allow us to examine the regulatory functions of RBPs and RNA motifs. By integrating the biochemical and functional datasets, we will relate the position of RNA motifs to the activity of bound RBPs, and predict the interactions that act as central nodes in the regulatory network. The physiological role of these core RBP-RNA interactions will then be tested using antisense RNAs. Together, these projects will provide insights to the regulatory mechanisms underlying neuronal activity-dependent changes, and provide new opportunities for future treatments of neurodegenerative disorders.
Max ERC Funding
900 000 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym CODING_IN_V1
Project How visual information is represented by neuronal networks in the primary visual cortex
Researcher (PI) Thomas D. Mrsic-Flogel
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), LS4, ERC-2007-StG
Summary The vast majority of our knowledge about how the brain encodes information has been obtained from recordings of one or few neurons at a time or from global mapping methods such as fMRI. These approaches have left unexplored how neuronal activity is distributed in space and time within a cortical column and how hundreds of neurons interact to process sensory information. By taking advantage of the most recent advances in two-photon microscopy, the proposed project addresses two broad aims, with a particular focus on the function and development of primary visual cortex: 1) to understand how cortical neuronal networks encode visual information, and 2) to understand how they become specialised for sensory processing during postnatal development. For the first aim, we will use in vivo two-photon calcium imaging to record activity simultaneously from hundreds of neurons in visual cortex while showing different visual stimuli to anaesthetised mice. This approach enables us for the first time to characterise in detail how individual neurons and neuronal subsets interact within a large cortical network in response to artificial and natural stimuli. Genetically-encoded fluorescent proteins expressed in distinct cell-types will inform us how excitatory and inhibitory neurons interact to shape population responses during vision. For the second aim, the same approach will be used to describe the maturation of cortical network function after the onset of vision and to assess the role of visual experience in this process. We will additionally use Channelrhodopsin-2, a genetic tool for remote control of action potential firing, to examine the role of correlated neuronal activity on establishment of functional cortical circuits. Together, this work will bring us closer to unravelling how sensory coding emerges on the level of neuronal networks.
Summary
The vast majority of our knowledge about how the brain encodes information has been obtained from recordings of one or few neurons at a time or from global mapping methods such as fMRI. These approaches have left unexplored how neuronal activity is distributed in space and time within a cortical column and how hundreds of neurons interact to process sensory information. By taking advantage of the most recent advances in two-photon microscopy, the proposed project addresses two broad aims, with a particular focus on the function and development of primary visual cortex: 1) to understand how cortical neuronal networks encode visual information, and 2) to understand how they become specialised for sensory processing during postnatal development. For the first aim, we will use in vivo two-photon calcium imaging to record activity simultaneously from hundreds of neurons in visual cortex while showing different visual stimuli to anaesthetised mice. This approach enables us for the first time to characterise in detail how individual neurons and neuronal subsets interact within a large cortical network in response to artificial and natural stimuli. Genetically-encoded fluorescent proteins expressed in distinct cell-types will inform us how excitatory and inhibitory neurons interact to shape population responses during vision. For the second aim, the same approach will be used to describe the maturation of cortical network function after the onset of vision and to assess the role of visual experience in this process. We will additionally use Channelrhodopsin-2, a genetic tool for remote control of action potential firing, to examine the role of correlated neuronal activity on establishment of functional cortical circuits. Together, this work will bring us closer to unravelling how sensory coding emerges on the level of neuronal networks.
Max ERC Funding
1 080 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym CONSERVREGCIRCUITRY
Project Conservation and Divergence of Tissue-Specific Transcriptional Regulation
Researcher (PI) Duncan Odom
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary Vertebrates contain hundreds of different cell types which maintain phenotypic identity by a combination of epigenetic programming and genomic regulation. Systems biology approaches are now used in a number of laboratories to determine how transcription factors and chromatin marks pattern the human genome. Despite high conservation of the cellular and molecular function of many mammalian transcription factors, our recent experiments in matched mouse and human tissues indicates that most transcription factor binding events to DNA are very poorly conserved. A hypothesis that could account for this apparent divergence is that the larger regional pattern of transcription factor binding may be conserved. To test this, (1) we are characterizing the global transcriptional profile, chromatin state, and complete genomic occupancy of a set of tissue-specific transcription factors in hepatocytes of strategically chosen mammals; (2) to further identify the precise mechanistic contribution of cis and trans effects, we are comparing transcription factor binding at homologous regions of human and mouse DNA in a mouse line that carries human chromosome 21. Together, these projects will provide insight into the general principles of how transcriptional networks are evolutionarily conserved to regulate cell fate specification and function using a clinically important cell type as a model.
Summary
Vertebrates contain hundreds of different cell types which maintain phenotypic identity by a combination of epigenetic programming and genomic regulation. Systems biology approaches are now used in a number of laboratories to determine how transcription factors and chromatin marks pattern the human genome. Despite high conservation of the cellular and molecular function of many mammalian transcription factors, our recent experiments in matched mouse and human tissues indicates that most transcription factor binding events to DNA are very poorly conserved. A hypothesis that could account for this apparent divergence is that the larger regional pattern of transcription factor binding may be conserved. To test this, (1) we are characterizing the global transcriptional profile, chromatin state, and complete genomic occupancy of a set of tissue-specific transcription factors in hepatocytes of strategically chosen mammals; (2) to further identify the precise mechanistic contribution of cis and trans effects, we are comparing transcription factor binding at homologous regions of human and mouse DNA in a mouse line that carries human chromosome 21. Together, these projects will provide insight into the general principles of how transcriptional networks are evolutionarily conserved to regulate cell fate specification and function using a clinically important cell type as a model.
Max ERC Funding
960 000 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym DEHALORES
Project Breathing chlorinated compounds: unravelling the biochemistry underpinning (de)halorespiration, an exciting bacterial metabolism with significant bioremediation potential
Researcher (PI) David Leys
Host Institution (HI) THE UNIVERSITY OF MANCHESTER
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Bacterial dehalorespiration is a microbial respiratory process in which halogenated hydrocarbons, from natural or anthropogenic origin, act as terminal electron acceptors. This leads to effective dehalogenation of these compounds, and as such their degradation and detoxification. The bacterial species, their enzymes and other components responsible for this unusual metabolism have only recently been identified. Unlocking the full potential of this process for bioremediation of persistent organohalides, such as polychlorinated biphenyls (PCBs) and tetrachloroethene, requires detailed understanding of the underpinning biochemistry. However, the regulation, mechanism and structure of the reductive dehalogenase (the enzyme responsible for delivering electrons to the halogenated substrates) are poorly understood. This ambitious proposal seeks to study representatives of the distinct reductive dehalogenase classes as well as key elements of the associated regulatory systems. Our group has been at the forefront of studying the biochemistry underpinning transcriptional regulation of dehalorespiration, providing detailed insights in the protein CprK at the atomic level. However, it is now apparent that only a subset of dehalogenases are regulated by CprK homologues with little known about the other regulators. In addition, studies on the reductive dehalogenases have been hampered by the inability to purify sufficient quantities. Using an interdisciplinary, biophysical approach focused around X-ray crystallography, enzymology and molecular biology, combined with novel reductive dehalogenase production methods, we aim to provide a detailed understanding and identification of the structural elements crucial to reductive dehalogenase mechanism and regulation. At the same time, we aim to apply the knowledge gathered and study the feasibility of generating improved dehalorespiratory components for biosensing or bioremediation applications through laboratory assisted evolution.
Summary
Bacterial dehalorespiration is a microbial respiratory process in which halogenated hydrocarbons, from natural or anthropogenic origin, act as terminal electron acceptors. This leads to effective dehalogenation of these compounds, and as such their degradation and detoxification. The bacterial species, their enzymes and other components responsible for this unusual metabolism have only recently been identified. Unlocking the full potential of this process for bioremediation of persistent organohalides, such as polychlorinated biphenyls (PCBs) and tetrachloroethene, requires detailed understanding of the underpinning biochemistry. However, the regulation, mechanism and structure of the reductive dehalogenase (the enzyme responsible for delivering electrons to the halogenated substrates) are poorly understood. This ambitious proposal seeks to study representatives of the distinct reductive dehalogenase classes as well as key elements of the associated regulatory systems. Our group has been at the forefront of studying the biochemistry underpinning transcriptional regulation of dehalorespiration, providing detailed insights in the protein CprK at the atomic level. However, it is now apparent that only a subset of dehalogenases are regulated by CprK homologues with little known about the other regulators. In addition, studies on the reductive dehalogenases have been hampered by the inability to purify sufficient quantities. Using an interdisciplinary, biophysical approach focused around X-ray crystallography, enzymology and molecular biology, combined with novel reductive dehalogenase production methods, we aim to provide a detailed understanding and identification of the structural elements crucial to reductive dehalogenase mechanism and regulation. At the same time, we aim to apply the knowledge gathered and study the feasibility of generating improved dehalorespiratory components for biosensing or bioremediation applications through laboratory assisted evolution.
Max ERC Funding
1 148 522 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym ECSUB
Project Encoded Cellular Synthesis of Unnatural Biopolymers
Researcher (PI) Jason William Karl Chin
Host Institution (HI) MEDICAL RESEARCH COUNCIL
Call Details Starting Grant (StG), LS7, ERC-2007-StG
Summary We are building a parallel and independent (orthogonal) translational machinery for the encoded biosynthesis of unnatural polymers in living cells. The orthogonal translation system has many potential applications beyond those possible with the natural translation system: I propose to use it: 1) To expand the chemical scope of monomers that can be polymerized by the ribosome in living cells, allowing the incorporation of monomers with unnatural backbones into proteins; 2) To increase the efficiency of in vivo unnatural amino acid mutagenesis via amber suppression, so that no truncated protein is produced and multi-site incorporation of unnatural amino acids is possible; 3) To create probes of protein function for use in vivo; 4) To free numerous codons for simultaneous encoding of multiple distinct unnatural monomers, and to experimentally explore alternate genetic codes; 5) To explore the evolution of encoded unnatural polymers toward new cellular functions.
Summary
We are building a parallel and independent (orthogonal) translational machinery for the encoded biosynthesis of unnatural polymers in living cells. The orthogonal translation system has many potential applications beyond those possible with the natural translation system: I propose to use it: 1) To expand the chemical scope of monomers that can be polymerized by the ribosome in living cells, allowing the incorporation of monomers with unnatural backbones into proteins; 2) To increase the efficiency of in vivo unnatural amino acid mutagenesis via amber suppression, so that no truncated protein is produced and multi-site incorporation of unnatural amino acids is possible; 3) To create probes of protein function for use in vivo; 4) To free numerous codons for simultaneous encoding of multiple distinct unnatural monomers, and to experimentally explore alternate genetic codes; 5) To explore the evolution of encoded unnatural polymers toward new cellular functions.
Max ERC Funding
1 782 918 €
Duration
Start date: 2009-01-01, End date: 2014-12-31
Project acronym HUMAN LIFESPAN
Project Mothers, grandmothers and the evolution of prolonged lifespan in humans
Researcher (PI) Virpi Lummaa
Host Institution (HI) THE UNIVERSITY OF SHEFFIELD
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary I propose a novel evolutionary approach for studying ecological and demographic factors that affect senescence and lifespan in humans. Women are unique among animals due to menopause and a prolonged lifespan after last birth. Evolutionarily, the quest of everyone is to maximise grandchildren numbers. Hence, human women life-history is enigmatic. One possibility is that older women increase their fitness by directing resources to already produced offspring rather than having more. Thus, although women gain most grandchildren from own reproduction, they also gain more by helping offspring. This has fascinating implications. All animals must split their energy between reproduction vs. self-maintenance. Most continue to reproduce until death and produce maximum grandchildren by optimising investment between current vs. future reproduction. Human women must also optimise investment between mothering and grandmothering. How this is done and affected by ecological, social and demographic factors is unknown, but is essential to understanding the ecological and genetic basis of reproduction, senescence and lifespan. My project has 5 aims: 1. How does reproductive effort affect reproductive and post-reproductive senescence? 2. What proportion of grandchildren is gained post-menopause and how is this modified? 3. Is there heritable variation in life-history traits and their senescence, and how do genetic correlations affect evolution? 4. How do patterns of fitness acquisition account for menopause, prolonged post-reproductive lifespan and age of death in humans? 5. How does fitness maximization differ between men and women and affect their lifespans? The questions will be answered using unique data on three generations of individuals that lived before healthcare and modern contraceptives in Finland. The results will have important implications for predicting demographic structure and will appeal to a wide range of people within and outwith the scientific community.
Summary
I propose a novel evolutionary approach for studying ecological and demographic factors that affect senescence and lifespan in humans. Women are unique among animals due to menopause and a prolonged lifespan after last birth. Evolutionarily, the quest of everyone is to maximise grandchildren numbers. Hence, human women life-history is enigmatic. One possibility is that older women increase their fitness by directing resources to already produced offspring rather than having more. Thus, although women gain most grandchildren from own reproduction, they also gain more by helping offspring. This has fascinating implications. All animals must split their energy between reproduction vs. self-maintenance. Most continue to reproduce until death and produce maximum grandchildren by optimising investment between current vs. future reproduction. Human women must also optimise investment between mothering and grandmothering. How this is done and affected by ecological, social and demographic factors is unknown, but is essential to understanding the ecological and genetic basis of reproduction, senescence and lifespan. My project has 5 aims: 1. How does reproductive effort affect reproductive and post-reproductive senescence? 2. What proportion of grandchildren is gained post-menopause and how is this modified? 3. Is there heritable variation in life-history traits and their senescence, and how do genetic correlations affect evolution? 4. How do patterns of fitness acquisition account for menopause, prolonged post-reproductive lifespan and age of death in humans? 5. How does fitness maximization differ between men and women and affect their lifespans? The questions will be answered using unique data on three generations of individuals that lived before healthcare and modern contraceptives in Finland. The results will have important implications for predicting demographic structure and will appeal to a wide range of people within and outwith the scientific community.
Max ERC Funding
1 143 824 €
Duration
Start date: 2008-07-01, End date: 2014-06-30
Project acronym IFA DYNAMICS
Project Countries’ external balance sheets, dynamics of international adjustment and capital flows
Researcher (PI) Helene Rey
Host Institution (HI) LONDON BUSINESS SCHOOL
Call Details Starting Grant (StG), SH1, ERC-2007-StG
Summary This project develops new theories and constructs new datasets to understand the determinants of net and gross foreign assets, the trade balance and the exchange rate. It also quantifies their respective roles in the dynamics of countries’ external deficits. In previous work, I constructed a database of US foreign assets and liabilities to analyse the sustainability of US current account deficits. I propose to build on this work along four related lines. First, I will generalize the analysis to other countries, contrasting the external balance sheets of large financially developed economies (US, UK) with those of small open economies (Canada, Australia). I will compare the historical role of the UK as a world banker to the current position of the US in the international monetary system. I will construct disaggregated databases of foreign assets at market value for these countries. Second, I will develop new theories of portfolio investment where international wealth transfers and predictable excess returns play a key role. These elements are rarely incorporated in open economy models but are essential for realism. I will develop and calibrate a new class of portfolio balance models compatible with the macroeconomic stylized facts on capital flows to study how countries’ capacity to accumulate foreign debt depends on changes in portfolio preferences (e.g. erosion of home bias). Third, I will use a disaggregated database of international investment positions of institutional investors to test for portfolio rebalancing at the microeconomic level. This exceptional database should also provide insights on the international propagation of financial crises. I will link the magnitude of price drops of given equities in crisis times to the institutional and geographical characteristics of their holders. Fourth, I will extend the methodology developed to analyze external adjustment to the issue of fiscal adjustment and twin deficits.
Summary
This project develops new theories and constructs new datasets to understand the determinants of net and gross foreign assets, the trade balance and the exchange rate. It also quantifies their respective roles in the dynamics of countries’ external deficits. In previous work, I constructed a database of US foreign assets and liabilities to analyse the sustainability of US current account deficits. I propose to build on this work along four related lines. First, I will generalize the analysis to other countries, contrasting the external balance sheets of large financially developed economies (US, UK) with those of small open economies (Canada, Australia). I will compare the historical role of the UK as a world banker to the current position of the US in the international monetary system. I will construct disaggregated databases of foreign assets at market value for these countries. Second, I will develop new theories of portfolio investment where international wealth transfers and predictable excess returns play a key role. These elements are rarely incorporated in open economy models but are essential for realism. I will develop and calibrate a new class of portfolio balance models compatible with the macroeconomic stylized facts on capital flows to study how countries’ capacity to accumulate foreign debt depends on changes in portfolio preferences (e.g. erosion of home bias). Third, I will use a disaggregated database of international investment positions of institutional investors to test for portfolio rebalancing at the microeconomic level. This exceptional database should also provide insights on the international propagation of financial crises. I will link the magnitude of price drops of given equities in crisis times to the institutional and geographical characteristics of their holders. Fourth, I will extend the methodology developed to analyze external adjustment to the issue of fiscal adjustment and twin deficits.
Max ERC Funding
1 340 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
