Project acronym AGRIWESTMED
Project Origins and spread of agriculture in the south-western Mediterranean region
Researcher (PI) Maria Leonor Peña Chocarro
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Call Details Advanced Grant (AdG), SH6, ERC-2008-AdG
Summary This project focuses on one of the most fascinating events of the long history of the human species: the origins and spread of agriculture. Research over the past 40 years has provided an invaluable dataset on crop domestication and the spread of agriculture into Europe. However, despite the enormous advances in research there are important areas that remain almost unexplored, some of immense interest. This is the case of the western Mediterranean region from where our knowledge is still limited (Iberian Peninsula) or almost inexistent (northern Morocco). The last few years have witnessed a considerable increase in archaeobotany and the effort of a group of Spanish researchers working together in different aspects of agriculture has started to produce the first results. My proposal will approach the study of the arrival of agriculture to the western Mediterranean by exploring different interrelated research areas. The project involves the
application of different techniques (analysis of charred plant remains, pollen and non-pollen microfossils, phytoliths, micro-wear analyses, isotopes, soil micromorphology, genetics, and ethnoarchaeology) which will help to define the emergence and spread of agriculture in the area, its likely place of origin, its main technological attributes as well as the range crop husbandry practices carried out. The interaction between the different approaches and the methodologies involved will allow achieving a greater understanding of the type of agriculture that characterized the first farming communities in the most south-western part of Europe.
Summary
This project focuses on one of the most fascinating events of the long history of the human species: the origins and spread of agriculture. Research over the past 40 years has provided an invaluable dataset on crop domestication and the spread of agriculture into Europe. However, despite the enormous advances in research there are important areas that remain almost unexplored, some of immense interest. This is the case of the western Mediterranean region from where our knowledge is still limited (Iberian Peninsula) or almost inexistent (northern Morocco). The last few years have witnessed a considerable increase in archaeobotany and the effort of a group of Spanish researchers working together in different aspects of agriculture has started to produce the first results. My proposal will approach the study of the arrival of agriculture to the western Mediterranean by exploring different interrelated research areas. The project involves the
application of different techniques (analysis of charred plant remains, pollen and non-pollen microfossils, phytoliths, micro-wear analyses, isotopes, soil micromorphology, genetics, and ethnoarchaeology) which will help to define the emergence and spread of agriculture in the area, its likely place of origin, its main technological attributes as well as the range crop husbandry practices carried out. The interaction between the different approaches and the methodologies involved will allow achieving a greater understanding of the type of agriculture that characterized the first farming communities in the most south-western part of Europe.
Max ERC Funding
1 545 169 €
Duration
Start date: 2009-04-01, End date: 2013-03-31
Project acronym AP-1-FUN
Project AP-1 (Fos/Jun) Functions in Physiology and Disease
Researcher (PI) Erwin F. Wagner
Host Institution (HI) FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Our research interests lie in breaking new ground in studying mechanism-based functions of AP-1 (Fos/Jun) in vivo with the aim of obtaining a more global perspective on AP-1 in human physiology and disease/cancer. The unresolved issues regarding the AP-1 subunit composition will be tackled biochemically and genetically in various cell types including bone, liver and skin, the primary organs affected by altered AP-1 activity. I plan to utilize the knowledge gained on AP-1 functions in the mouse and transfer it to human disease. The opportunities here lie in exploiting the knowledge of AP-1 target genes and utilizing this information to interfere with pathways involved in normal physiology and disease/cancer. The past investigations revealed that the functions of AP-1 are an essential node at the crossroads between life and death in different cellular systems. I plan to further exploit our findings and concentrate on utilising better mouse models to define these connections. The emphasis will be on identifying molecular signatures and potential treatments in models for cancer, inflammatory and fibrotic diseases. Exploring genetically modified stem cell-based therapies in murine and human cells is an ongoing challenge I would like to meet in the forthcoming years at the CNIO. In addition, the mouse models will be used for mechanism-driven therapeutic strategies and these studies will be undertaken in collaboration with the Experimental Therapeutics Division and the service units such as the tumor bank. The project proposal is divided into 6 Goals (see also Figure 1): Some are a logical continuation based on previous work with completely new aspects (Goal 1-2), some focussing on in depth molecular analyses of disease models with innovative and unconventional concepts, such as for inflammation and cancer, psoriasis and fibrosis (Goal 3-5). A final section is devoted to mouse and human ES cells and their impact for regenerative medicine in bone diseases and cancer.
Summary
Our research interests lie in breaking new ground in studying mechanism-based functions of AP-1 (Fos/Jun) in vivo with the aim of obtaining a more global perspective on AP-1 in human physiology and disease/cancer. The unresolved issues regarding the AP-1 subunit composition will be tackled biochemically and genetically in various cell types including bone, liver and skin, the primary organs affected by altered AP-1 activity. I plan to utilize the knowledge gained on AP-1 functions in the mouse and transfer it to human disease. The opportunities here lie in exploiting the knowledge of AP-1 target genes and utilizing this information to interfere with pathways involved in normal physiology and disease/cancer. The past investigations revealed that the functions of AP-1 are an essential node at the crossroads between life and death in different cellular systems. I plan to further exploit our findings and concentrate on utilising better mouse models to define these connections. The emphasis will be on identifying molecular signatures and potential treatments in models for cancer, inflammatory and fibrotic diseases. Exploring genetically modified stem cell-based therapies in murine and human cells is an ongoing challenge I would like to meet in the forthcoming years at the CNIO. In addition, the mouse models will be used for mechanism-driven therapeutic strategies and these studies will be undertaken in collaboration with the Experimental Therapeutics Division and the service units such as the tumor bank. The project proposal is divided into 6 Goals (see also Figure 1): Some are a logical continuation based on previous work with completely new aspects (Goal 1-2), some focussing on in depth molecular analyses of disease models with innovative and unconventional concepts, such as for inflammation and cancer, psoriasis and fibrosis (Goal 3-5). A final section is devoted to mouse and human ES cells and their impact for regenerative medicine in bone diseases and cancer.
Max ERC Funding
2 500 000 €
Duration
Start date: 2009-11-01, End date: 2015-10-31
Project acronym ATMNUCLE
Project Atmospheric nucleation: from molecular to global scale
Researcher (PI) Markku Tapio Kulmala
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Advanced Grant (AdG), PE10, ERC-2008-AdG
Summary Atmospheric aerosol particles and trace gases affect the quality of our life in many ways (e.g. health effects, changes in climate and hydrological cycle). Trace gases and atmospheric aerosols are tightly connected via physical, chemical, meteorological and biological processes occurring in the atmosphere and at the atmosphere-biosphere interface. One important phenomenon is atmospheric aerosol formation, which involves the production of nanometer-size particles by nucleation and their growth to detectable sizes. The main scientific objectives of this project are 1) to quantify the mechanisms responsible for atmospheric new particle formation and 2) to find out how important this process is for the behaviour of the global aerosol system and, ultimately, for the whole climate system. Our scientific plan is designed as a research chain that aims to advance our understanding of climate and air quality through a series of connected activities. We start from molecular simulations and laboratory measurements to understand nucleation and aerosol thermodynamic processes. We measure nanoparticles and atmospheric clusters at 15-20 sites all around the world using state of the art instrumentation and study feedbacks and interactions between climate and biosphere. With these atmospheric boundary layer studies we form a link to regional-scale processes and further to global-scale phenomena. In order to be able to simulate global climate and air quality, the most recent progress on this chain of processes must be compiled, integrated and implemented in Climate Change and Air Quality numerical models via novel parameterizations.
Summary
Atmospheric aerosol particles and trace gases affect the quality of our life in many ways (e.g. health effects, changes in climate and hydrological cycle). Trace gases and atmospheric aerosols are tightly connected via physical, chemical, meteorological and biological processes occurring in the atmosphere and at the atmosphere-biosphere interface. One important phenomenon is atmospheric aerosol formation, which involves the production of nanometer-size particles by nucleation and their growth to detectable sizes. The main scientific objectives of this project are 1) to quantify the mechanisms responsible for atmospheric new particle formation and 2) to find out how important this process is for the behaviour of the global aerosol system and, ultimately, for the whole climate system. Our scientific plan is designed as a research chain that aims to advance our understanding of climate and air quality through a series of connected activities. We start from molecular simulations and laboratory measurements to understand nucleation and aerosol thermodynamic processes. We measure nanoparticles and atmospheric clusters at 15-20 sites all around the world using state of the art instrumentation and study feedbacks and interactions between climate and biosphere. With these atmospheric boundary layer studies we form a link to regional-scale processes and further to global-scale phenomena. In order to be able to simulate global climate and air quality, the most recent progress on this chain of processes must be compiled, integrated and implemented in Climate Change and Air Quality numerical models via novel parameterizations.
Max ERC Funding
2 000 000 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym BIOFORCE
Project Simultaneous multi-pathway engineering in crop plants through combinatorial genetic transformation: Creating nutritionally biofortified cereal grains for food security
Researcher (PI) Paul Christou
Host Institution (HI) UNIVERSIDAD DE LLEIDA
Call Details Advanced Grant (AdG), LS9, ERC-2008-AdG
Summary BIOFORCE has a highly ambitious applied objective: to create transgenic cereal plants that will provide a near-complete micronutrient complement (vitamins A, C, E, folate and essential minerals Ca, Fe, Se and Zn) for malnourished people in the developing world, as well as built-in resistance to insects and parasitic weeds. This in itself represents a striking advance over current efforts to address food insecurity using applied biotechnology in the developing world. We will also address fundamental mechanistic aspects of multi-gene/pathway engineering through transcriptome and metabolome profiling. Fundamental science and applied objectives will be achieved through the application of an exciting novel technology (combinatorial genetic transformation) developed and patented by my research group. This allows the simultaneous transfer of an unlimited number of transgenes into plants followed by library-based selection of plants with appropriate genotypes and phenotypes. All transgenes integrate into one locus ensuring expression stability over multiple generations. This proposal represents a new line of research in my laboratory, founded on incremental advances in the elucidation of transgene integration mechanisms in plants over the past two and a half decades. In addition to scientific issues, BIOFORCE address challenges such as intellectual property, regulatory and biosafety issues and crucially how the fruits of our work will be taken up through philanthropic initiatives in the developing world while creating exploitable opportunities elsewhere. BIOFORCE is comprehensive and it provides a complete package that stands to make an unprecedented contribution to food security in the developing world, while at the same time generating new knowledge to streamline and simplify multiplex gene transfer and the simultaneous modification of multiple complex plant metabolic pathways
Summary
BIOFORCE has a highly ambitious applied objective: to create transgenic cereal plants that will provide a near-complete micronutrient complement (vitamins A, C, E, folate and essential minerals Ca, Fe, Se and Zn) for malnourished people in the developing world, as well as built-in resistance to insects and parasitic weeds. This in itself represents a striking advance over current efforts to address food insecurity using applied biotechnology in the developing world. We will also address fundamental mechanistic aspects of multi-gene/pathway engineering through transcriptome and metabolome profiling. Fundamental science and applied objectives will be achieved through the application of an exciting novel technology (combinatorial genetic transformation) developed and patented by my research group. This allows the simultaneous transfer of an unlimited number of transgenes into plants followed by library-based selection of plants with appropriate genotypes and phenotypes. All transgenes integrate into one locus ensuring expression stability over multiple generations. This proposal represents a new line of research in my laboratory, founded on incremental advances in the elucidation of transgene integration mechanisms in plants over the past two and a half decades. In addition to scientific issues, BIOFORCE address challenges such as intellectual property, regulatory and biosafety issues and crucially how the fruits of our work will be taken up through philanthropic initiatives in the developing world while creating exploitable opportunities elsewhere. BIOFORCE is comprehensive and it provides a complete package that stands to make an unprecedented contribution to food security in the developing world, while at the same time generating new knowledge to streamline and simplify multiplex gene transfer and the simultaneous modification of multiple complex plant metabolic pathways
Max ERC Funding
2 290 046 €
Duration
Start date: 2009-04-01, End date: 2014-03-31
Project acronym BIOMOL. SIMULATION
Project Development of multi-scale molecular models, force fields and computer software for biomolecular simulation
Researcher (PI) Willem Frederik Van Gunsteren
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Advanced Grant (AdG), PE4, ERC-2008-AdG
Summary During the past decades the PI has helped shape the research field of computer simulation of biomolecular systems at the atomic level. He has carried out one of the first molecular dynamics (MD) simulations of proteins, and has since then contributed many different methodological improvements and developed one of the major atomic-level force fields for simulations of proteins, carbohydrates, nucleotides and lipids. Methodology and force field have been implemented in a set of programs called GROMOS (GROningen MOlecular Simulation package), which is currently used in hundreds of academic and industrial research groups from over 50 countries on all continents. It is proposed to develop a next generation of molecular models, force fields, multi-scaling simulation methodology and software for biomolecular simulations which is at least an order of magnitude more accurate in terms of energetics, and which is 1000 times more efficient through the use of coarse-grained molecular models than the currently available software and models.
Summary
During the past decades the PI has helped shape the research field of computer simulation of biomolecular systems at the atomic level. He has carried out one of the first molecular dynamics (MD) simulations of proteins, and has since then contributed many different methodological improvements and developed one of the major atomic-level force fields for simulations of proteins, carbohydrates, nucleotides and lipids. Methodology and force field have been implemented in a set of programs called GROMOS (GROningen MOlecular Simulation package), which is currently used in hundreds of academic and industrial research groups from over 50 countries on all continents. It is proposed to develop a next generation of molecular models, force fields, multi-scaling simulation methodology and software for biomolecular simulations which is at least an order of magnitude more accurate in terms of energetics, and which is 1000 times more efficient through the use of coarse-grained molecular models than the currently available software and models.
Max ERC Funding
1 320 000 €
Duration
Start date: 2008-11-01, End date: 2014-09-30
Project acronym BRAIN2BRAIN
Project Towards two-person neuroscience
Researcher (PI) Riitta Kyllikki Hari
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.
Summary
Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.
Max ERC Funding
2 489 643 €
Duration
Start date: 2009-01-01, End date: 2014-12-31
Project acronym BSMOXFORD
Project Physics Beyond the Standard Model at the LHC and with Atom Interferometers
Researcher (PI) Savas Dimopoulos
Host Institution (HI) EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH
Call Details Advanced Grant (AdG), PE2, ERC-2008-AdG
Summary Elementary particle physics is entering a spectacular new era in which experiments at the Large Hadron Collider (LHC) at CERN will soon start probing some of the deepest questions in physics, such as: Why is gravity so weak? Do elementary particles have substructure? What is the origin of mass? Are there new dimensions? Can we produce black holes in the lab? Could there be other universes with different physical laws? While the LHC pushes the energy frontier, the unprecedented precision of Atom Interferometry, has pointed me to a new tool for fundamental physics. These experiments based on the quantum interference of atoms can test General Relativity on the surface of the Earth, detect gravity waves, and test short-distance gravity, charge quantization, and quantum mechanics with unprecedented precision in the next decade. This ERC Advanced grant proposal is aimed at setting up a world-leading European center for development of a deeper theory of fundamental physics. The next 10 years is the optimal time for such studies to benefit from the wealth of new data that will emerge from the LHC, astrophysical observations and atom interferometry. This is a once-in-a-generation opportunity for making ground-breaking progress, and will open up many new research horizons.
Summary
Elementary particle physics is entering a spectacular new era in which experiments at the Large Hadron Collider (LHC) at CERN will soon start probing some of the deepest questions in physics, such as: Why is gravity so weak? Do elementary particles have substructure? What is the origin of mass? Are there new dimensions? Can we produce black holes in the lab? Could there be other universes with different physical laws? While the LHC pushes the energy frontier, the unprecedented precision of Atom Interferometry, has pointed me to a new tool for fundamental physics. These experiments based on the quantum interference of atoms can test General Relativity on the surface of the Earth, detect gravity waves, and test short-distance gravity, charge quantization, and quantum mechanics with unprecedented precision in the next decade. This ERC Advanced grant proposal is aimed at setting up a world-leading European center for development of a deeper theory of fundamental physics. The next 10 years is the optimal time for such studies to benefit from the wealth of new data that will emerge from the LHC, astrophysical observations and atom interferometry. This is a once-in-a-generation opportunity for making ground-breaking progress, and will open up many new research horizons.
Max ERC Funding
2 200 000 €
Duration
Start date: 2009-05-01, End date: 2014-04-30
Project acronym CANCER&AGEING
Project COMMOM MECHANISMS UNDERLYING CANCER AND AGEING
Researcher (PI) Manuel Serrano
Host Institution (HI) FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Call Details Advanced Grant (AdG), LS1, ERC-2008-AdG
Summary "In recent years, we have made significant contributions to the understanding of the tumour suppressors p53, p16INK4a, and ARF, particularly in relation with cellular senescence and aging. The current project is motivated by two hypothesis: 1) that the INK4/ARF locus is a sensor of epigenetic damage and this is at the basis of its activation by oncogenes and aging; and, 2) that the accumulation of cellular damage and stress is at the basis of both cancer and aging, and consequently ""anti-damage genes"", such as tumour suppressors, simultaneously counteract both cancer and aging. With regard to the INK4/ARF locus, the project includes: 1.1) the generation of null mice for the Regulatory Domain (RD) thought to be essential for the proper regulation of the locus; 1.2) the study of the INK4/ARF anti-sense transcription and its importance for the assembly of Polycomb repressive complexes; 1.3) the generation of mice carrying the human INK4/ARF locus to analyze, among other aspects, whether the known differences between the human and murine loci are ""locus autonomous""; and, 1.4) to analyze the INK4/ARF locus in the process of epigenetic reprogramming both from ES cells to differentiated cells and, conversely, from differentiated cells to induced-pluripotent stem (iPS) cells. With regard to the impact of ""anti-damage genes"" on cancer and aging, the project includes: 2.1) the analysis of the aging of super-INK4/ARF mice and super-p53 mice; 2.2) we have generated super-PTEN mice and we will examine whether PTEN not only confers cancer resistance but also anti-aging activity; and, finally, 2.3) we have generated super-SIRT1 mice, which is among the best-characterized anti-aging genes in non-mammalian model systems (where it is named Sir2) involved in protection from metabolic damage, and we will study the cancer and aging of these mice. Together, this project will significantly advance our understanding of the molecular mechanisms underlying cancer and aging."
Summary
"In recent years, we have made significant contributions to the understanding of the tumour suppressors p53, p16INK4a, and ARF, particularly in relation with cellular senescence and aging. The current project is motivated by two hypothesis: 1) that the INK4/ARF locus is a sensor of epigenetic damage and this is at the basis of its activation by oncogenes and aging; and, 2) that the accumulation of cellular damage and stress is at the basis of both cancer and aging, and consequently ""anti-damage genes"", such as tumour suppressors, simultaneously counteract both cancer and aging. With regard to the INK4/ARF locus, the project includes: 1.1) the generation of null mice for the Regulatory Domain (RD) thought to be essential for the proper regulation of the locus; 1.2) the study of the INK4/ARF anti-sense transcription and its importance for the assembly of Polycomb repressive complexes; 1.3) the generation of mice carrying the human INK4/ARF locus to analyze, among other aspects, whether the known differences between the human and murine loci are ""locus autonomous""; and, 1.4) to analyze the INK4/ARF locus in the process of epigenetic reprogramming both from ES cells to differentiated cells and, conversely, from differentiated cells to induced-pluripotent stem (iPS) cells. With regard to the impact of ""anti-damage genes"" on cancer and aging, the project includes: 2.1) the analysis of the aging of super-INK4/ARF mice and super-p53 mice; 2.2) we have generated super-PTEN mice and we will examine whether PTEN not only confers cancer resistance but also anti-aging activity; and, finally, 2.3) we have generated super-SIRT1 mice, which is among the best-characterized anti-aging genes in non-mammalian model systems (where it is named Sir2) involved in protection from metabolic damage, and we will study the cancer and aging of these mice. Together, this project will significantly advance our understanding of the molecular mechanisms underlying cancer and aging."
Max ERC Funding
2 000 000 €
Duration
Start date: 2009-04-01, End date: 2015-03-31
Project acronym CELLDOCTOR
Project Quantitative understanding of a living system and its engineering as a cellular organelle
Researcher (PI) Luis Serrano
Host Institution (HI) FUNDACIO CENTRE DE REGULACIO GENOMICA
Call Details Advanced Grant (AdG), LS2, ERC-2008-AdG
Summary The idea of harnessing living organisms for treating human diseases is not new but, so far, the majority of the living vectors used in human therapy are viruses which have the disadvantage of the limited number of genes and networks that can contain. Bacteria allow the cloning of complex networks and the possibility of making a large plethora of compounds, naturally or through careful redesign. One of the main limitations for the use of bacteria to treat human diseases is their complexity, the existence of a cell wall that difficult the communication with the target cells, the lack of control over its growth and the immune response that will elicit on its target. Ideally one would like to have a very small bacterium (of a mitochondria size), with no cell wall, which could be grown in Vitro, be genetically manipulated, for which we will have enough data to allow a complete understanding of its behaviour and which could live as a human cell parasite. Such a microorganism could in principle be used as a living vector in which genes of interests, or networks producing organic molecules of medical relevance, could be introduced under in Vitro conditions and then inoculated on extracted human cells or in the organism, and then become a new organelle in the host. Then, it could produce and secrete into the host proteins which will be needed to correct a genetic disease, or drugs needed by the patient. To do that, we need to understand in excruciating detail the Biology of the target bacterium and how to interface with the host cell cycle (Systems biology aspect). Then we need to have engineering tools (network design, protein design, simulations) to modify the target bacterium to behave like an organelle once inside the cell (Synthetic biology aspect). M.pneumoniae could be such a bacterium. It is one of the smallest free-living bacterium known (680 genes), has no cell wall, can be cultivated in Vitro, can be genetically manipulated and can enter inside human cells.
Summary
The idea of harnessing living organisms for treating human diseases is not new but, so far, the majority of the living vectors used in human therapy are viruses which have the disadvantage of the limited number of genes and networks that can contain. Bacteria allow the cloning of complex networks and the possibility of making a large plethora of compounds, naturally or through careful redesign. One of the main limitations for the use of bacteria to treat human diseases is their complexity, the existence of a cell wall that difficult the communication with the target cells, the lack of control over its growth and the immune response that will elicit on its target. Ideally one would like to have a very small bacterium (of a mitochondria size), with no cell wall, which could be grown in Vitro, be genetically manipulated, for which we will have enough data to allow a complete understanding of its behaviour and which could live as a human cell parasite. Such a microorganism could in principle be used as a living vector in which genes of interests, or networks producing organic molecules of medical relevance, could be introduced under in Vitro conditions and then inoculated on extracted human cells or in the organism, and then become a new organelle in the host. Then, it could produce and secrete into the host proteins which will be needed to correct a genetic disease, or drugs needed by the patient. To do that, we need to understand in excruciating detail the Biology of the target bacterium and how to interface with the host cell cycle (Systems biology aspect). Then we need to have engineering tools (network design, protein design, simulations) to modify the target bacterium to behave like an organelle once inside the cell (Synthetic biology aspect). M.pneumoniae could be such a bacterium. It is one of the smallest free-living bacterium known (680 genes), has no cell wall, can be cultivated in Vitro, can be genetically manipulated and can enter inside human cells.
Max ERC Funding
2 400 000 €
Duration
Start date: 2009-03-01, End date: 2015-02-28
Project acronym CENDUP
Project Decoding the mechanisms of centrosome duplication
Researcher (PI) Pierre Gönczy
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Advanced Grant (AdG), LS3, ERC-2008-AdG
Summary Centrosome duplication entails the formation of a single procentriole next to each centriole once per cell cycle. The mechanisms governing procentriole formation are poorly understood and constitute a fundamental open question in cell biology. We will launch an innovative multidisciplinary research program to gain significant insight into these mechanisms using C. elegans and human cells. This research program is also expected to have a significant impact by contributing important novel assays to the field. Six specific aims will be pursued: 1) SAS-6 as a ZYG-1 substrate: mechanisms of procentriole formation in C. elegans. We will test in vivo the consequence of SAS-6 phosphorylation by ZYG-1. 2) Biochemical and structural analysis of SAS-6-containing macromolecular complexes (SAMACs). We will isolate and characterize SAMACs from C. elegans embryos and human cells, and analyze their structure using single-particle electron microscopy. 3) Novel cell-free assay for procentriole formation in human cells. We will develop such an assay and use it to test whether SAMACs can direct procentriole formation and whether candidate proteins are needed at centrioles or in the cytoplasm. 4) Mapping interactions between centriolar proteins in live human cells. We will use chemical methods developed by our collaborators to probe interactions between HsSAS-6 and centriolar proteins in a time- and space-resolved manner. 5) Functional genomic and chemical genetic screens in human cells. We will conduct high-throughput fluorescence-based screens in human cells to identify novel genes required for procentriole formation and small molecule inhibitors of this process. 6) Mechanisms underlying differential centriolar maintenance in the germline. In C. elegans, we will characterize how the sas-1 locus is required for centriole maintenance during spermatogenesis, as well as analyze centriole elimination during oogenesis and identify components needed for this process
Summary
Centrosome duplication entails the formation of a single procentriole next to each centriole once per cell cycle. The mechanisms governing procentriole formation are poorly understood and constitute a fundamental open question in cell biology. We will launch an innovative multidisciplinary research program to gain significant insight into these mechanisms using C. elegans and human cells. This research program is also expected to have a significant impact by contributing important novel assays to the field. Six specific aims will be pursued: 1) SAS-6 as a ZYG-1 substrate: mechanisms of procentriole formation in C. elegans. We will test in vivo the consequence of SAS-6 phosphorylation by ZYG-1. 2) Biochemical and structural analysis of SAS-6-containing macromolecular complexes (SAMACs). We will isolate and characterize SAMACs from C. elegans embryos and human cells, and analyze their structure using single-particle electron microscopy. 3) Novel cell-free assay for procentriole formation in human cells. We will develop such an assay and use it to test whether SAMACs can direct procentriole formation and whether candidate proteins are needed at centrioles or in the cytoplasm. 4) Mapping interactions between centriolar proteins in live human cells. We will use chemical methods developed by our collaborators to probe interactions between HsSAS-6 and centriolar proteins in a time- and space-resolved manner. 5) Functional genomic and chemical genetic screens in human cells. We will conduct high-throughput fluorescence-based screens in human cells to identify novel genes required for procentriole formation and small molecule inhibitors of this process. 6) Mechanisms underlying differential centriolar maintenance in the germline. In C. elegans, we will characterize how the sas-1 locus is required for centriole maintenance during spermatogenesis, as well as analyze centriole elimination during oogenesis and identify components needed for this process
Max ERC Funding
2 004 155 €
Duration
Start date: 2009-04-01, End date: 2014-03-31
