Project acronym 2SEXES_1GENOME
Project Sex-specific genetic effects on fitness and human disease
Researcher (PI) Edward Hugh Morrow
Host Institution (HI) THE UNIVERSITY OF SUSSEX
Call Details Starting Grant (StG), LS8, ERC-2011-StG_20101109
Summary Darwin’s theory of natural selection rests on the principle that fitness variation in natural populations has a heritable component, on which selection acts, thereby leading to evolutionary change. A fundamental and so far unresolved question for the field of evolutionary biology is to identify the genetic loci responsible for this fitness variation, thereby coming closer to an understanding of how variation is maintained in the face of continual selection. One important complicating factor in the search for fitness related genes however is the existence of separate sexes – theoretical expectations and empirical data both suggest that sexually antagonistic genes are common. The phrase “two sexes, one genome” nicely sums up the problem; selection may favour alleles in one sex, even if they have detrimental effects on the fitness of the opposite sex, since it is their net effect across both sexes that determine the likelihood that alleles persist in a population. This theoretical framework raises an interesting, and so far entirely unexplored issue: that in one sex the functional performance of some alleles is predicted to be compromised and this effect may account for some common human diseases and conditions which show genotype-sex interactions. I propose to explore the genetic basis of sex-specific fitness in a model organism in both laboratory and natural conditions and to test whether those genes identified as having sexually antagonistic effects can help explain the incidence of human diseases that display sexual dimorphism in prevalence, age of onset or severity. This multidisciplinary project directly addresses some fundamental unresolved questions in evolutionary biology: the genetic basis and maintenance of fitness variation; the evolution of sexual dimorphism; and aims to provide novel insights into the genetic basis of some common human diseases.
Summary
Darwin’s theory of natural selection rests on the principle that fitness variation in natural populations has a heritable component, on which selection acts, thereby leading to evolutionary change. A fundamental and so far unresolved question for the field of evolutionary biology is to identify the genetic loci responsible for this fitness variation, thereby coming closer to an understanding of how variation is maintained in the face of continual selection. One important complicating factor in the search for fitness related genes however is the existence of separate sexes – theoretical expectations and empirical data both suggest that sexually antagonistic genes are common. The phrase “two sexes, one genome” nicely sums up the problem; selection may favour alleles in one sex, even if they have detrimental effects on the fitness of the opposite sex, since it is their net effect across both sexes that determine the likelihood that alleles persist in a population. This theoretical framework raises an interesting, and so far entirely unexplored issue: that in one sex the functional performance of some alleles is predicted to be compromised and this effect may account for some common human diseases and conditions which show genotype-sex interactions. I propose to explore the genetic basis of sex-specific fitness in a model organism in both laboratory and natural conditions and to test whether those genes identified as having sexually antagonistic effects can help explain the incidence of human diseases that display sexual dimorphism in prevalence, age of onset or severity. This multidisciplinary project directly addresses some fundamental unresolved questions in evolutionary biology: the genetic basis and maintenance of fitness variation; the evolution of sexual dimorphism; and aims to provide novel insights into the genetic basis of some common human diseases.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym 3D-E
Project 3D Engineered Environments for Regenerative Medicine
Researcher (PI) Ruth Elizabeth Cameron
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), PE8, ERC-2012-ADG_20120216
Summary "This proposal develops a unified, underpinning technology to create novel, complex and biomimetic 3D environments for the control of tissue growth. As director of Cambridge Centre for Medical Materials, I have recently been approached by medical colleagues to help to solve important problems in the separate therapeutic areas of breast cancer, cardiac disease and blood disorders. In each case, the solution lies in complex 3D engineered environments for cell culture. These colleagues make it clear that existing 3D scaffolds fail to provide the required complex orientational and spatial anisotropy, and are limited in their ability to impart appropriate biochemical and mechanical cues.
I have a strong track record in this area. A particular success has been the use of a freeze drying technology to make collagen based porous implants for the cartilage-bone interface in the knee, which has now been commercialised. The novelty of this proposal lies in the broadening of the established scientific base of this technology to enable biomacromolecular structures with:
(A) controlled and complex pore orientation to mimic many normal multi-oriented tissue structures
(B) compositional and positional control to match varying local biochemical environments,
(C) the attachment of novel peptides designed to control cell behaviour, and
(D) mechanical control at both a local and macroscopic level to provide mechanical cues for cells.
These will be complemented by the development of
(E) robust characterisation methodologies for the structures created.
These advances will then be employed in each of the medical areas above.
This approach is highly interdisciplinary. Existing working relationships with experts in each medical field will guarantee expertise and licensed facilities in the required biological disciplines. Funds for this proposal would therefore establish a rich hub of mutually beneficial research and opportunities for cross-disciplinary sharing of expertise."
Summary
"This proposal develops a unified, underpinning technology to create novel, complex and biomimetic 3D environments for the control of tissue growth. As director of Cambridge Centre for Medical Materials, I have recently been approached by medical colleagues to help to solve important problems in the separate therapeutic areas of breast cancer, cardiac disease and blood disorders. In each case, the solution lies in complex 3D engineered environments for cell culture. These colleagues make it clear that existing 3D scaffolds fail to provide the required complex orientational and spatial anisotropy, and are limited in their ability to impart appropriate biochemical and mechanical cues.
I have a strong track record in this area. A particular success has been the use of a freeze drying technology to make collagen based porous implants for the cartilage-bone interface in the knee, which has now been commercialised. The novelty of this proposal lies in the broadening of the established scientific base of this technology to enable biomacromolecular structures with:
(A) controlled and complex pore orientation to mimic many normal multi-oriented tissue structures
(B) compositional and positional control to match varying local biochemical environments,
(C) the attachment of novel peptides designed to control cell behaviour, and
(D) mechanical control at both a local and macroscopic level to provide mechanical cues for cells.
These will be complemented by the development of
(E) robust characterisation methodologies for the structures created.
These advances will then be employed in each of the medical areas above.
This approach is highly interdisciplinary. Existing working relationships with experts in each medical field will guarantee expertise and licensed facilities in the required biological disciplines. Funds for this proposal would therefore establish a rich hub of mutually beneficial research and opportunities for cross-disciplinary sharing of expertise."
Max ERC Funding
2 486 267 €
Duration
Start date: 2013-04-01, End date: 2018-03-31
Project acronym ACOULOMODE
Project Advanced coupling of low order combustor simulations with thermoacoustic modelling and controller design
Researcher (PI) Aimee Morgans
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Starting Grant (StG), PE8, ERC-2012-StG_20111012
Summary "Combustion is essential to the world’s energy generation and transport needs, and will remain so for the foreseeable future. Mitigating its impact on the climate and human health, by reducing its associated emissions, is thus a priority. One significant challenge for gas-turbine combustion is combustion instability, which is currently inhibiting reductions in NOx emissions (these damage human health via a deterioration in air quality). Combustion instability is caused by a two-way coupling between unsteady combustion and acoustic waves - the large pressure oscillations that result can cause substantial mechanical damage. Currently, the lack of fast, accurate modelling tools for combustion instability, and the lack of reliable ways of suppressing it are severely hindering reductions in NOx emissions.
This proposal aims to make step improvements in both fast, accurate modelling of combustion instability, and in developing reliable active control strategies for its suppression. It will achieve this by coupling low order combustor models (these are fast, simplified models for simulating combustion instability) with advances in analytical modelling, CFD simulation, reduced order modelling and control theory tools. In particular:
* important advances in accurately incorporating the effect of entropy waves (temperature variations resulting from unsteady combustion) and non-linear flame models will be made;
* new active control strategies for achieving reliable suppression of combustion instability, including from within limit cycle oscillations, will be developed;
* an open-source low order combustor modelling tool will be developed and widely disseminated, opening access to researchers worldwide and improving communications between the fields of thermoacoustics and control theory.
Thus the proposal aims to use analytical and computational methods to contribute to achieving low NOx gas-turbine combustion, without the penalty of damaging combustion instability."
Summary
"Combustion is essential to the world’s energy generation and transport needs, and will remain so for the foreseeable future. Mitigating its impact on the climate and human health, by reducing its associated emissions, is thus a priority. One significant challenge for gas-turbine combustion is combustion instability, which is currently inhibiting reductions in NOx emissions (these damage human health via a deterioration in air quality). Combustion instability is caused by a two-way coupling between unsteady combustion and acoustic waves - the large pressure oscillations that result can cause substantial mechanical damage. Currently, the lack of fast, accurate modelling tools for combustion instability, and the lack of reliable ways of suppressing it are severely hindering reductions in NOx emissions.
This proposal aims to make step improvements in both fast, accurate modelling of combustion instability, and in developing reliable active control strategies for its suppression. It will achieve this by coupling low order combustor models (these are fast, simplified models for simulating combustion instability) with advances in analytical modelling, CFD simulation, reduced order modelling and control theory tools. In particular:
* important advances in accurately incorporating the effect of entropy waves (temperature variations resulting from unsteady combustion) and non-linear flame models will be made;
* new active control strategies for achieving reliable suppression of combustion instability, including from within limit cycle oscillations, will be developed;
* an open-source low order combustor modelling tool will be developed and widely disseminated, opening access to researchers worldwide and improving communications between the fields of thermoacoustics and control theory.
Thus the proposal aims to use analytical and computational methods to contribute to achieving low NOx gas-turbine combustion, without the penalty of damaging combustion instability."
Max ERC Funding
1 489 309 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym BACKTOBACK
Project Engineering Solutions for Back Pain: Simulation of Patient Variance
Researcher (PI) Ruth Wilcox
Host Institution (HI) UNIVERSITY OF LEEDS
Call Details Starting Grant (StG), PE8, ERC-2012-StG_20111012
Summary Back pain affects eight out of ten adults during their lifetime. It a huge economic burden on society, estimated to cost as much as 1-2% of gross national product in several European countries. Treatments for back pain have lower levels of success and are not as technologically mature as those for other musculoskeletal disorders such as hip and knee replacement. This application proposes to tackle one of the major barriers to the development of better surgical treatments for back pain.
At present, new spinal devices are commonly assessed in isolation in the laboratory under standardised conditions that do not represent the variation across the patient population. Consequently many interventions have failed during clinical trials or have proved to have poor long term success rates.
Using a combination of computational and experimental models, a new testing methodology will be developed that will enable the variation between patients to be simulated for the first time. This will enable spinal implants and therapies to be more robustly evaluated across a virtual patient population prior to clinical trial. The tools developed will be used in collaboration with clinicians and basic scientists to develop and, crucially, optimise new treatments that reduce back pain whilst preserving the unique functions of the spine.
If successful, this approach could be translated to evaluate and optimise emerging minimally invasive treatments in other joints such as the hip and knee. Research in the spine could then, for the first time, lead rather than follow that undertaken in other branches of orthopaedics.
Summary
Back pain affects eight out of ten adults during their lifetime. It a huge economic burden on society, estimated to cost as much as 1-2% of gross national product in several European countries. Treatments for back pain have lower levels of success and are not as technologically mature as those for other musculoskeletal disorders such as hip and knee replacement. This application proposes to tackle one of the major barriers to the development of better surgical treatments for back pain.
At present, new spinal devices are commonly assessed in isolation in the laboratory under standardised conditions that do not represent the variation across the patient population. Consequently many interventions have failed during clinical trials or have proved to have poor long term success rates.
Using a combination of computational and experimental models, a new testing methodology will be developed that will enable the variation between patients to be simulated for the first time. This will enable spinal implants and therapies to be more robustly evaluated across a virtual patient population prior to clinical trial. The tools developed will be used in collaboration with clinicians and basic scientists to develop and, crucially, optimise new treatments that reduce back pain whilst preserving the unique functions of the spine.
If successful, this approach could be translated to evaluate and optimise emerging minimally invasive treatments in other joints such as the hip and knee. Research in the spine could then, for the first time, lead rather than follow that undertaken in other branches of orthopaedics.
Max ERC Funding
1 498 777 €
Duration
Start date: 2012-12-01, End date: 2018-11-30
Project acronym BALDWINIAN_BEETLES
Project "The origin of the fittest: canalization, plasticity and selection as a consequence of provisioning during development"
Researcher (PI) Rebecca Kilner
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Starting Grant (StG), LS8, ERC-2012-StG_20111109
Summary "A major outstanding challenge for evolutionary biology is to explain how novel adaptations arise. We propose to test whether developmental plasticity initiates evolutionary change in morphological, behavioural and social traits, using laboratory experiments, fieldwork and comparative analyses.
Using burying beetles Nicrophorus spp as our model experimental system, we shall:
1) Test whether variation in parental provisioning during development induces correlated phenotypic change in adult body size and a suite of life history traits; whether these phenotypic changes can be genetically accommodated under experimental evolution (the Baldwin Effect); and whether changes induced by experimental evolution mimic natural variation in adult body size and life history strategy among Nicrophorus species;
2) Test whether parental provisioning has a canalizing effect on the developmental environment, potentially storing up cryptic genetic variation which might then be released as random new phenotypes, if offspring are exposed to a new developmental environment;
3) Investigate whether developmental trade-offs, induced by under-provisioning from parents, provide the first step towards the evolution of a novel interspecific mutualism. Is a second species recruited in adulthood to carry out the function of a structure that was under-nourished during development?
4) Using comparative analyses of data from the literature on insects, frogs, birds and mammals, we shall test whether the evolution of parental provisioning in a given lineage is positively correlated with the number of species in the lineage.
Our proposal is original in focusing on developmental plasticity induced by variation in parental provisioning. Given the diverse and numerous species that provision their young, including several whose genomes have now been sequenced, this potentially opens up a rich new area for future work on the developmental mechanisms underlying evolutionary innovations."
Summary
"A major outstanding challenge for evolutionary biology is to explain how novel adaptations arise. We propose to test whether developmental plasticity initiates evolutionary change in morphological, behavioural and social traits, using laboratory experiments, fieldwork and comparative analyses.
Using burying beetles Nicrophorus spp as our model experimental system, we shall:
1) Test whether variation in parental provisioning during development induces correlated phenotypic change in adult body size and a suite of life history traits; whether these phenotypic changes can be genetically accommodated under experimental evolution (the Baldwin Effect); and whether changes induced by experimental evolution mimic natural variation in adult body size and life history strategy among Nicrophorus species;
2) Test whether parental provisioning has a canalizing effect on the developmental environment, potentially storing up cryptic genetic variation which might then be released as random new phenotypes, if offspring are exposed to a new developmental environment;
3) Investigate whether developmental trade-offs, induced by under-provisioning from parents, provide the first step towards the evolution of a novel interspecific mutualism. Is a second species recruited in adulthood to carry out the function of a structure that was under-nourished during development?
4) Using comparative analyses of data from the literature on insects, frogs, birds and mammals, we shall test whether the evolution of parental provisioning in a given lineage is positively correlated with the number of species in the lineage.
Our proposal is original in focusing on developmental plasticity induced by variation in parental provisioning. Given the diverse and numerous species that provision their young, including several whose genomes have now been sequenced, this potentially opens up a rich new area for future work on the developmental mechanisms underlying evolutionary innovations."
Max ERC Funding
1 499 914 €
Duration
Start date: 2012-11-01, End date: 2017-10-31
Project acronym BP-CarDiO
Project Investigating the therapeutic potential of manipulating the IGF-IGFBP1 axis in the prevention and treatment of cardiovascular disease, diabetes and obesity
Researcher (PI) Stephen Bentley Wheatcroft
Host Institution (HI) UNIVERSITY OF LEEDS
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary More than 30 million people are living with diabetes in the EU, with a prevalence expected to grow to over 10% of the adult population by the year 2030. Type 2 diabetes is a major cause of cardiovascular disease related death and disability, substantially increasing the risk of myocardial infarction, stroke and peripheral arterial disease. Recent landmark trials, showing that intensive glucose control does not improve cardiovascular outcomes and may increase mortality in some circumstances, provide a compelling rationale for intense research aimed at developing novel therapeutic strategies. Type 2 diabetes is underpinned by resistance to the effects of insulin, which I have shown in endothelial cells causes reduced bioavailability of the anti-atherosclerotic molecule nitric oxide and leads to accelerated atherosclerosis. The cellular effects of insulin are mirrored by insulin-like growth factor factor-1, the bioavailability of which at its receptor is in turn is regulated by a family of high affinity binding proteins (IGFBP). Epidemiological studies demonstrate and inverse association between one of these binding proteins, IGFBP1, and diabetes-related cardiovascular risk. I have recently demonstrated that IGFBP1 when expressed in mice can ameliorate insulin resistance, obesity and atherosclerosis. In endothelial cells, I showed that IGFBP1 upregulates the production of nitric oxide indepenedently of IGF. These findings suggest that IGFBP1 may be a ‘protective’ endogenous protein and that increasing circulating levels may be a therapeutic strategy to prevent development of diabetes and cardiovascular disease. In this proposal I will address this hypothesis by employing state of the art studies in cells and novel gene modified mice to unravel the molecular basis of the protective effects of IGFBP1 and to investigate the possibility of exploiting the IGF-IGFBP axis to prevent cardiovascular disease in the setting of diabetes and obesity.
Summary
More than 30 million people are living with diabetes in the EU, with a prevalence expected to grow to over 10% of the adult population by the year 2030. Type 2 diabetes is a major cause of cardiovascular disease related death and disability, substantially increasing the risk of myocardial infarction, stroke and peripheral arterial disease. Recent landmark trials, showing that intensive glucose control does not improve cardiovascular outcomes and may increase mortality in some circumstances, provide a compelling rationale for intense research aimed at developing novel therapeutic strategies. Type 2 diabetes is underpinned by resistance to the effects of insulin, which I have shown in endothelial cells causes reduced bioavailability of the anti-atherosclerotic molecule nitric oxide and leads to accelerated atherosclerosis. The cellular effects of insulin are mirrored by insulin-like growth factor factor-1, the bioavailability of which at its receptor is in turn is regulated by a family of high affinity binding proteins (IGFBP). Epidemiological studies demonstrate and inverse association between one of these binding proteins, IGFBP1, and diabetes-related cardiovascular risk. I have recently demonstrated that IGFBP1 when expressed in mice can ameliorate insulin resistance, obesity and atherosclerosis. In endothelial cells, I showed that IGFBP1 upregulates the production of nitric oxide indepenedently of IGF. These findings suggest that IGFBP1 may be a ‘protective’ endogenous protein and that increasing circulating levels may be a therapeutic strategy to prevent development of diabetes and cardiovascular disease. In this proposal I will address this hypothesis by employing state of the art studies in cells and novel gene modified mice to unravel the molecular basis of the protective effects of IGFBP1 and to investigate the possibility of exploiting the IGF-IGFBP axis to prevent cardiovascular disease in the setting of diabetes and obesity.
Max ERC Funding
1 493 543 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym BrainGutTalk
Project Brain-gut interactions in Drosophila melanogaster
Researcher (PI) Irene Miguel-Aliaga
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary The gastrointestinal tract is emerging as a key regulator of appetite and metabolism, but studies aimed at identifying the signals involved are faced with daunting neuroanatomical complexity: there are as many as 500 million neurons in the human gut. Drosophila should provide a simple and genetically amenable alternative, but both its autonomic nervous system and the signalling significance of its digestive tract have remained largely unexplored. My research programme will characterize the signals and neurons mediating the interaction between the nervous and digestive systems, and will establish their significance both in the maintenance of metabolic homeostasis and in response to nutritional challenges. To achieve these goals, we will capitalize on a multi-disciplinary approach that combines the genetic manipulation of defined neuronal lineages, a cell-biological approach to the study of enterocyte metabolism, and our recently developed physiological and behavioural readouts. Our work will provide new insights into the signals and mechanisms modulating internal metabolism and food intake: processes which, when deregulated, contribute to increasingly prevalent conditions such as diabetes, metabolic syndrome and obesity. Our recent finding of conserved mechanisms of autonomic control in the fruit fly makes us confident that the signals we identify will be relevant to mammalian systems.
Summary
The gastrointestinal tract is emerging as a key regulator of appetite and metabolism, but studies aimed at identifying the signals involved are faced with daunting neuroanatomical complexity: there are as many as 500 million neurons in the human gut. Drosophila should provide a simple and genetically amenable alternative, but both its autonomic nervous system and the signalling significance of its digestive tract have remained largely unexplored. My research programme will characterize the signals and neurons mediating the interaction between the nervous and digestive systems, and will establish their significance both in the maintenance of metabolic homeostasis and in response to nutritional challenges. To achieve these goals, we will capitalize on a multi-disciplinary approach that combines the genetic manipulation of defined neuronal lineages, a cell-biological approach to the study of enterocyte metabolism, and our recently developed physiological and behavioural readouts. Our work will provide new insights into the signals and mechanisms modulating internal metabolism and food intake: processes which, when deregulated, contribute to increasingly prevalent conditions such as diabetes, metabolic syndrome and obesity. Our recent finding of conserved mechanisms of autonomic control in the fruit fly makes us confident that the signals we identify will be relevant to mammalian systems.
Max ERC Funding
1 499 740 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym CANBUILD
Project Building a Human Tumour Microenvironment
Researcher (PI) Frances Rosemary Balkwill
Host Institution (HI) QUEEN MARY UNIVERSITY OF LONDON
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary Even at their earliest stages, human cancers are more than just cells with malignant potential. Cells and extracellular matrix components that normally support and protect the body are coerced into a tumour microenvironment that is central to disease progression. My hypothesis is that recent advances in tissue engineering, biomechanics and stem cell biology make it possible to engineer, for the first time, a complex 3D human tumour microenvironment in which individual cell lineages of malignant, haemopoietic and mesenchymal origin will communicate, evolve and grow in vitro. The ultimate aim is to build this cancerous tissue with autologous cells: there is an urgent need for models in which we can study the interaction of human immune cells with malignant cells from the same individual in an appropriate 3D biomechanical microenvironment.
To achieve the objectives of the CANBUILD project, I have assembled a multi-disciplinary team of collaborators with international standing in tumour microenvironment research, cancer treatment, tissue engineering, mechanobiology, stem cell research and 3D computer-assisted imaging.
The goal is to recreate the microenvironment of high-grade serous ovarian cancer metastases in the omentum. This is a major clinical problem, my lab has extensive knowledge of this microenvironment and we have already established simple 3D models of these metastases.
The research plan involves:
Deconstruction of this specific tumour microenvironment
Construction of artificial scaffold, optimising growth of cell lineages, assembly of the model
Comparison to fresh tissue
Investigating the role of individual cell lineages
Testing therapies that target the tumour microenvironment
My vision is that this project will revolutionise the practice of human malignant cell research, replacing misleading systems based on cancer cell monoculture on plastic surfaces and allowing us to better test new treatments that target the human tumour microenvironment.
Summary
Even at their earliest stages, human cancers are more than just cells with malignant potential. Cells and extracellular matrix components that normally support and protect the body are coerced into a tumour microenvironment that is central to disease progression. My hypothesis is that recent advances in tissue engineering, biomechanics and stem cell biology make it possible to engineer, for the first time, a complex 3D human tumour microenvironment in which individual cell lineages of malignant, haemopoietic and mesenchymal origin will communicate, evolve and grow in vitro. The ultimate aim is to build this cancerous tissue with autologous cells: there is an urgent need for models in which we can study the interaction of human immune cells with malignant cells from the same individual in an appropriate 3D biomechanical microenvironment.
To achieve the objectives of the CANBUILD project, I have assembled a multi-disciplinary team of collaborators with international standing in tumour microenvironment research, cancer treatment, tissue engineering, mechanobiology, stem cell research and 3D computer-assisted imaging.
The goal is to recreate the microenvironment of high-grade serous ovarian cancer metastases in the omentum. This is a major clinical problem, my lab has extensive knowledge of this microenvironment and we have already established simple 3D models of these metastases.
The research plan involves:
Deconstruction of this specific tumour microenvironment
Construction of artificial scaffold, optimising growth of cell lineages, assembly of the model
Comparison to fresh tissue
Investigating the role of individual cell lineages
Testing therapies that target the tumour microenvironment
My vision is that this project will revolutionise the practice of human malignant cell research, replacing misleading systems based on cancer cell monoculture on plastic surfaces and allowing us to better test new treatments that target the human tumour microenvironment.
Max ERC Funding
2 431 035 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
Project acronym CANCERPHAGY
Project Autophagy as a cancer treatment
Researcher (PI) Ivana Bjedov
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary Cancer is one of the most prevalent human killer diseases. Autophagy, a lysosome-mediated process that degrades cellular components and damaged organelles, has recently emerged as an important player in cancer. Indeed, autophagy inhibition promotes cancer initiation through generation of genomic instability and inflammation, whereas in contrast, autophagy activation is often required to sustain growth of advanced solid tumours in a nutrient-deprived hypoxic environment. Recent findings firmly demonstrate that modulating autophagy can potentially be exploited to suppress tumours and to avoid resistance in anti-cancer therapy. However, the interplay between cancer and autophagy is complex, and further in-depth investigation is urgently required. Therefore I propose to use the well-described cancer models in Drosophila, together with the autophagy mutants that I have developed, firstly to test how an autophagy-proficient/deficient host environment alters growth and dissemination of allografted tumours. Secondly, I will examine how modulation of autophagy within the tumour can impact on its growth. In order to alter independently tumour induction with autophagy inhibition/activation, I will make use of the two inducible expression systems currently only available for Drosophila. These experiments will be accompanied by detailed analysis of mitochondrial status, as well as protein damage and DNA lesions, which will shed light on the intricate mechanisms whereby autophagy affects cancer and will help indicate optimal time points for further analysis of the tumours by in-depth transcriptional, proteomic and metabolomic profiling. Collectively, this project proposal is designed to rapidly test various hypotheses for cancer prevention and treatment, to provide valuable insights for further validation in higher organisms, and to identify new potential drug targets for cancer research.
Summary
Cancer is one of the most prevalent human killer diseases. Autophagy, a lysosome-mediated process that degrades cellular components and damaged organelles, has recently emerged as an important player in cancer. Indeed, autophagy inhibition promotes cancer initiation through generation of genomic instability and inflammation, whereas in contrast, autophagy activation is often required to sustain growth of advanced solid tumours in a nutrient-deprived hypoxic environment. Recent findings firmly demonstrate that modulating autophagy can potentially be exploited to suppress tumours and to avoid resistance in anti-cancer therapy. However, the interplay between cancer and autophagy is complex, and further in-depth investigation is urgently required. Therefore I propose to use the well-described cancer models in Drosophila, together with the autophagy mutants that I have developed, firstly to test how an autophagy-proficient/deficient host environment alters growth and dissemination of allografted tumours. Secondly, I will examine how modulation of autophagy within the tumour can impact on its growth. In order to alter independently tumour induction with autophagy inhibition/activation, I will make use of the two inducible expression systems currently only available for Drosophila. These experiments will be accompanied by detailed analysis of mitochondrial status, as well as protein damage and DNA lesions, which will shed light on the intricate mechanisms whereby autophagy affects cancer and will help indicate optimal time points for further analysis of the tumours by in-depth transcriptional, proteomic and metabolomic profiling. Collectively, this project proposal is designed to rapidly test various hypotheses for cancer prevention and treatment, to provide valuable insights for further validation in higher organisms, and to identify new potential drug targets for cancer research.
Max ERC Funding
1 453 219 €
Duration
Start date: 2012-10-01, End date: 2018-09-30
Project acronym CDREG
Project Carbon dioxide regulation of Earth’s ecological weathering engine: from microorganisms to ecosystems
Researcher (PI) David Beerling
Host Institution (HI) THE UNIVERSITY OF SHEFFIELD
Call Details Advanced Grant (AdG), LS8, ERC-2012-ADG_20120314
Summary CDREG develops the major new Earth system science research hypothesis that tectonic-related variations in Earth’s atmospheric CO2 concentration ([CO2]a) drive negative ecological feedbacks on terrestrial silicate weathering rates that stabilise further [CO2]a change and regulate climate. This paradigm-changing hypothesis integrates ecological and abiotic controls on silicate weathering to understand how terrestrial ecosystems have shaped past Earth system dynamics. The proposed ecological feedbacks are mechanistically linked to the extent and activities of forested ecosystems and their symbiotic fungal partners as the primary engines of biological weathering.
CDREG’s core hypothesis establishes an exciting cross-disciplinary Research Programme that offers novel opportunities for major breakthroughs implemented through four linked hypothesis-driven work packages (WPs) employing experimental, geochemical and numerical modelling approaches. WP1 quantitatively characterises [CO2]a-driven tree/grass-fungal mineral weathering by coupling metabolic profiling with advanced nanometre scale surface metrological techniques for investigating hyphal-mineral interactions. WP2 quantifies the role [CO2]a-drought interactions on savanna tree mortality and C4 grass survivorship, plus symbiotic fungal-driven mineral weathering. WP3 exploits the past 8 Ma of marine sediment archives to investigate the links between forest to savanna transition, terrestrial weathering, fire, and climate in Africa. WP4 integrates findings from WP1-3 into a new Earth system modelling framework to rigorously investigate the biogeochemical feedbacks of [CO2]a-regulated ecological weathering on [CO2]a via marine carbonate deposition and organic C burial.
The ultimate goal is to provide a new synthesis in which the role of [CO2]a in regulating the ecological weathering engine across scales from root-associated microorganisms to terrestrial ecosystems is mechanistically understood and assessed.
Summary
CDREG develops the major new Earth system science research hypothesis that tectonic-related variations in Earth’s atmospheric CO2 concentration ([CO2]a) drive negative ecological feedbacks on terrestrial silicate weathering rates that stabilise further [CO2]a change and regulate climate. This paradigm-changing hypothesis integrates ecological and abiotic controls on silicate weathering to understand how terrestrial ecosystems have shaped past Earth system dynamics. The proposed ecological feedbacks are mechanistically linked to the extent and activities of forested ecosystems and their symbiotic fungal partners as the primary engines of biological weathering.
CDREG’s core hypothesis establishes an exciting cross-disciplinary Research Programme that offers novel opportunities for major breakthroughs implemented through four linked hypothesis-driven work packages (WPs) employing experimental, geochemical and numerical modelling approaches. WP1 quantitatively characterises [CO2]a-driven tree/grass-fungal mineral weathering by coupling metabolic profiling with advanced nanometre scale surface metrological techniques for investigating hyphal-mineral interactions. WP2 quantifies the role [CO2]a-drought interactions on savanna tree mortality and C4 grass survivorship, plus symbiotic fungal-driven mineral weathering. WP3 exploits the past 8 Ma of marine sediment archives to investigate the links between forest to savanna transition, terrestrial weathering, fire, and climate in Africa. WP4 integrates findings from WP1-3 into a new Earth system modelling framework to rigorously investigate the biogeochemical feedbacks of [CO2]a-regulated ecological weathering on [CO2]a via marine carbonate deposition and organic C burial.
The ultimate goal is to provide a new synthesis in which the role of [CO2]a in regulating the ecological weathering engine across scales from root-associated microorganisms to terrestrial ecosystems is mechanistically understood and assessed.
Max ERC Funding
2 271 980 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
