Project acronym B-INNATE
Project Innate signaling networks in B cell antibody production: new targets for vaccine development
Researcher (PI) Andrea Cerutti
Host Institution (HI) FUNDACIO INSTITUT MAR D INVESTIGACIONS MEDIQUES IMIM
Call Details Advanced Grant (AdG), LS6, ERC-2011-ADG_20110310
Summary The long-term goal of this proposal is to explore a novel immune pathway that involves an unexpected interplay between marginal zone (MZ) B cells and neutrophils. MZ B cells are strategically positioned at the interface between the immune system and the circulation and rapidly produce protective antibodies to blood-borne pathogens through a T cell-independent pathway that remains poorly understood. We recently found that the human spleen contains a novel subset of B cell helper neutrophils (NBH cells) with a phenotype and gene expression profile distinct from those of conventional circulating neutrophils (NC cells). In this proposal, we hypothesize that NC cells undergo splenic reprogramming into NBH cells through an IL-10-dependent pathway involving perifollicular sinusoidal endothelial cells. We contend that these unique endothelial cells release NC cell-attracting chemokines and IL-10 upon sensing blood-borne bacteria through Toll-like receptors. We also argue that IL-10 from sinusoidal endothelial cells stimulates NC cells to differentiate into NBH cells equipped with powerful MZ B cell-stimulating activity. The following three aims will be pursued. Aim 1 is to determine the mechanisms by which splenic sinusoidal endothelial cells induce reprogramming of NC cells into NBH cells upon sensing bacteria through Toll-like receptors. Aim 2 is to elucidate the mechanisms by which NBH cells induce IgM production, IgG and IgA class switching, and plasma cell differentiation in MZ B cells. Aim 3 is to evaluate the mechanisms by which NBH cells induce V(D)J gene somatic hypermutation and high-affinity antibody production in MZ B cells. These studies will uncover previously unknown facets of the immunological function of neutrophils by taking advantage of unique cells and tissues from patients with rare primary immunodeficiencies and by making use of selected mouse models. Results from these studies may also lead to the identification of novel vaccine strategies.
Summary
The long-term goal of this proposal is to explore a novel immune pathway that involves an unexpected interplay between marginal zone (MZ) B cells and neutrophils. MZ B cells are strategically positioned at the interface between the immune system and the circulation and rapidly produce protective antibodies to blood-borne pathogens through a T cell-independent pathway that remains poorly understood. We recently found that the human spleen contains a novel subset of B cell helper neutrophils (NBH cells) with a phenotype and gene expression profile distinct from those of conventional circulating neutrophils (NC cells). In this proposal, we hypothesize that NC cells undergo splenic reprogramming into NBH cells through an IL-10-dependent pathway involving perifollicular sinusoidal endothelial cells. We contend that these unique endothelial cells release NC cell-attracting chemokines and IL-10 upon sensing blood-borne bacteria through Toll-like receptors. We also argue that IL-10 from sinusoidal endothelial cells stimulates NC cells to differentiate into NBH cells equipped with powerful MZ B cell-stimulating activity. The following three aims will be pursued. Aim 1 is to determine the mechanisms by which splenic sinusoidal endothelial cells induce reprogramming of NC cells into NBH cells upon sensing bacteria through Toll-like receptors. Aim 2 is to elucidate the mechanisms by which NBH cells induce IgM production, IgG and IgA class switching, and plasma cell differentiation in MZ B cells. Aim 3 is to evaluate the mechanisms by which NBH cells induce V(D)J gene somatic hypermutation and high-affinity antibody production in MZ B cells. These studies will uncover previously unknown facets of the immunological function of neutrophils by taking advantage of unique cells and tissues from patients with rare primary immunodeficiencies and by making use of selected mouse models. Results from these studies may also lead to the identification of novel vaccine strategies.
Max ERC Funding
2 214 035 €
Duration
Start date: 2012-04-01, End date: 2017-09-30
Project acronym BACCO
Project Bias and Clustering Calculations Optimised: Maximising discovery with galaxy surveys
Researcher (PI) Raúl Esteban ANGULO de la Fuente
Host Institution (HI) FUNDACION CENTRO DE ESTUDIOS DE FISICA DEL COSMOS DE ARAGON
Call Details Starting Grant (StG), PE9, ERC-2016-STG
Summary A new generation of galaxy surveys will soon start measuring the spatial distribution of millions of galaxies over a broad range of redshifts, offering an imminent opportunity to discover new physics. A detailed comparison of these measurements with theoretical models of galaxy clustering may reveal a new fundamental particle, a breakdown of General Relativity, or a hint on the nature of cosmic acceleration. Despite a large progress in the analytic treatment of structure formation in recent years, traditional clustering models still suffer from large uncertainties. This limits cosmological analyses to a very restricted range of scales and statistics, which will be one of the main obstacles to reach a comprehensive exploitation of future surveys.
Here I propose to develop a novel simulation--based approach to predict galaxy clustering. Combining recent advances in computational cosmology, from cosmological N--body calculations to physically-motivated galaxy formation models, I will develop a unified framework to directly predict the position and velocity of individual dark matter structures and galaxies as function of cosmological and astrophysical parameters. In this formulation, galaxy clustering will be a prediction of a set of physical assumptions in a given cosmological setting. The new theoretical framework will be flexible, accurate and fast: it will provide predictions for any clustering statistic, down to scales 100 times smaller than in state-of-the-art perturbation--theory--based models, and in less than 1 minute of CPU time. These advances will enable major improvements in future cosmological constraints, which will significantly increase the overall power of future surveys maximising our potential to discover new physics.
Summary
A new generation of galaxy surveys will soon start measuring the spatial distribution of millions of galaxies over a broad range of redshifts, offering an imminent opportunity to discover new physics. A detailed comparison of these measurements with theoretical models of galaxy clustering may reveal a new fundamental particle, a breakdown of General Relativity, or a hint on the nature of cosmic acceleration. Despite a large progress in the analytic treatment of structure formation in recent years, traditional clustering models still suffer from large uncertainties. This limits cosmological analyses to a very restricted range of scales and statistics, which will be one of the main obstacles to reach a comprehensive exploitation of future surveys.
Here I propose to develop a novel simulation--based approach to predict galaxy clustering. Combining recent advances in computational cosmology, from cosmological N--body calculations to physically-motivated galaxy formation models, I will develop a unified framework to directly predict the position and velocity of individual dark matter structures and galaxies as function of cosmological and astrophysical parameters. In this formulation, galaxy clustering will be a prediction of a set of physical assumptions in a given cosmological setting. The new theoretical framework will be flexible, accurate and fast: it will provide predictions for any clustering statistic, down to scales 100 times smaller than in state-of-the-art perturbation--theory--based models, and in less than 1 minute of CPU time. These advances will enable major improvements in future cosmological constraints, which will significantly increase the overall power of future surveys maximising our potential to discover new physics.
Max ERC Funding
1 484 240 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym BacRafts
Project Architecture of bacterial lipid rafts; inhibition of virulence and antibiotic resistance using raft-disassembling small molecules
Researcher (PI) Daniel López Serrano
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Call Details Starting Grant (StG), LS6, ERC-2013-StG
Summary Membranes of eukaryotic cells organize signal transduction proteins into microdomains or lipid rafts whose integrity is essential for numerous cellular processes. Lipid rafts has been considered a fundamental step to define the cellular complexity of eukaryotes, assuming that bacteria do not require such a sophisticated organization of their signaling networks. However, I have discovered that bacteria organize many signaling pathways in membrane microdomains similar to the eukaryotic lipid rafts. Perturbation of bacterial lipid rafts leads to a potent and simultaneous impairment of all raft-harbored signaling pathways. Consequently, the disassembly of lipid rafts in pathogens like Staphylococcus aureus generates a simultaneous inhibition of numerous infection-related processes that can be further explored to control bacterial infections. This unexpected sophistication in membrane organization is unprecedented in bacteria and hence, this proposal will explore the molecular basis of the assembly of bacterial lipid rafts and their role in the infection-related processes. These questions will be addressed in three main goals: First, I will elucidate the molecular components and the mechanism of assembly of bacterial lipid rafts using S. aureus as model organism. Second, I will dissect the molecular basis that links the functionality of the infection-related processes to the integrity of bacterial lipid rafts. Third, my collection of anti-raft small molecules that are able to disrupt lipid rafts will be tested as antimicrobial agents to prevent hospital-acquired infections, abrogate pre-existing infections and develop bacteria-free materials that can be used in clinical settings. I will use a number of molecular approaches in combination with cutting-edge techniques in flow cytometry, cell-imaging and transcriptomics to clarify the architecture and functionality of lipid rafts and demonstrate the feasibility of targeting lipid a new strategy for anti-microbial therapy.
Summary
Membranes of eukaryotic cells organize signal transduction proteins into microdomains or lipid rafts whose integrity is essential for numerous cellular processes. Lipid rafts has been considered a fundamental step to define the cellular complexity of eukaryotes, assuming that bacteria do not require such a sophisticated organization of their signaling networks. However, I have discovered that bacteria organize many signaling pathways in membrane microdomains similar to the eukaryotic lipid rafts. Perturbation of bacterial lipid rafts leads to a potent and simultaneous impairment of all raft-harbored signaling pathways. Consequently, the disassembly of lipid rafts in pathogens like Staphylococcus aureus generates a simultaneous inhibition of numerous infection-related processes that can be further explored to control bacterial infections. This unexpected sophistication in membrane organization is unprecedented in bacteria and hence, this proposal will explore the molecular basis of the assembly of bacterial lipid rafts and their role in the infection-related processes. These questions will be addressed in three main goals: First, I will elucidate the molecular components and the mechanism of assembly of bacterial lipid rafts using S. aureus as model organism. Second, I will dissect the molecular basis that links the functionality of the infection-related processes to the integrity of bacterial lipid rafts. Third, my collection of anti-raft small molecules that are able to disrupt lipid rafts will be tested as antimicrobial agents to prevent hospital-acquired infections, abrogate pre-existing infections and develop bacteria-free materials that can be used in clinical settings. I will use a number of molecular approaches in combination with cutting-edge techniques in flow cytometry, cell-imaging and transcriptomics to clarify the architecture and functionality of lipid rafts and demonstrate the feasibility of targeting lipid a new strategy for anti-microbial therapy.
Max ERC Funding
1 493 126 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym BePreSysE
Project Beyond Precision Cosmology: dealing with Systematic Errors
Researcher (PI) Licia VERDE
Host Institution (HI) UNIVERSITAT DE BARCELONA
Call Details Consolidator Grant (CoG), PE9, ERC-2016-COG
Summary Over the past 20 years cosmology has made the transition to a precision science: the standard cosmological model has been established and its parameters are now measured with unprecedented precision. But precision is not enough: accuracy is also crucial. Accuracy accounts for systematic errors which can be both on the observational and on the theory/modelling side (and everywhere in between). While there is a well-defined and developed framework for treating statistical errors, there is no established approach for systematic errors. The next decade will see the era of large surveys; a large coordinated effort of the scientific community in the field is on-going to map the cosmos producing an exponentially growing amount of data. This will shrink the statistical errors, making mitigation and control of systematics of the utmost importance. While there are isolated and targeted efforts to quantify systematic errors and propagate them through all the way to the final results, there is no well-established, self-consistent methodology. To go beyond precision cosmology and reap the benefits of the forthcoming observational program, a systematic approach to systematics is needed. Systematics should be interpreted in the most general sense as shifts between the recovered measured values and true values of physical quantities. I propose to develop a comprehensive approach to tackle systematic errors with the goal to uncover and quantify otherwise unknown differences between the interpretation of a measurement and reality. This will require to fully develop, combine and systematize all approaches proposed so far (many pioneered by the PI), develop new ones to fill the gaps, study and explore their interplay and finally test and validate the procedure. Beyond Precision Cosmology: Dealing with Systematic Errors (BePreSysE) will develop a framework to deal with systematics in forthcoming Cosmological surveys which, could, in principle, be applied beyond Cosmology.
Summary
Over the past 20 years cosmology has made the transition to a precision science: the standard cosmological model has been established and its parameters are now measured with unprecedented precision. But precision is not enough: accuracy is also crucial. Accuracy accounts for systematic errors which can be both on the observational and on the theory/modelling side (and everywhere in between). While there is a well-defined and developed framework for treating statistical errors, there is no established approach for systematic errors. The next decade will see the era of large surveys; a large coordinated effort of the scientific community in the field is on-going to map the cosmos producing an exponentially growing amount of data. This will shrink the statistical errors, making mitigation and control of systematics of the utmost importance. While there are isolated and targeted efforts to quantify systematic errors and propagate them through all the way to the final results, there is no well-established, self-consistent methodology. To go beyond precision cosmology and reap the benefits of the forthcoming observational program, a systematic approach to systematics is needed. Systematics should be interpreted in the most general sense as shifts between the recovered measured values and true values of physical quantities. I propose to develop a comprehensive approach to tackle systematic errors with the goal to uncover and quantify otherwise unknown differences between the interpretation of a measurement and reality. This will require to fully develop, combine and systematize all approaches proposed so far (many pioneered by the PI), develop new ones to fill the gaps, study and explore their interplay and finally test and validate the procedure. Beyond Precision Cosmology: Dealing with Systematic Errors (BePreSysE) will develop a framework to deal with systematics in forthcoming Cosmological surveys which, could, in principle, be applied beyond Cosmology.
Max ERC Funding
1 835 220 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym BLAST
Project Eclipsing binary stars as cutting edge laboratories for astrophysics of stellar
structure, stellar evolution and planet formation
Researcher (PI) Maciej Konacki
Host Institution (HI) CENTRUM ASTRONOMICZNE IM. MIKOLAJAKOPERNIKA POLSKIEJ AKADEMII NAUK
Call Details Starting Grant (StG), PE9, ERC-2010-StG_20091028
Summary Spectroscopic binary stars (SB2s) and in particular spectroscopic eclipsing binaries are one of the most useful objects in astrophysics. Their photometric and spectroscopic observations allow one to determine basic parameters of stars and carry out a wide range of tests of stellar structure, evolution and dynamics. Perhaps somewhat surprisingly, they can also contribute to our understanding of the formation and evolution of (extrasolar) planets. We will study eclipsing binary stars by combining the classic - stellar astronomy - and the modern - extrasolar planets - subjects into a cutting edge project.
We propose to search for and subsequently characterize circumbinary planets around ~350 eclipsing SB2s using our own novel cutting edge radial velocity technique for binary stars and a modern version of the photometry based eclipse timing of eclipsing binary stars employing 0.5-m robotic telescopes. We will also derive basic parameters of up to ~700 stars (~350 binaries) with an unprecedented precision. In particular for about 50% of our sample we expect to deliver masses of the components with an accuracy ~10-100 times better than the current state of the art.
Our project will provide unique constraints for the theories of planet formation and evolution and an unprecedented in quality set of the basic parameters of stars to test the theories of the stellar structure and evolution.
Summary
Spectroscopic binary stars (SB2s) and in particular spectroscopic eclipsing binaries are one of the most useful objects in astrophysics. Their photometric and spectroscopic observations allow one to determine basic parameters of stars and carry out a wide range of tests of stellar structure, evolution and dynamics. Perhaps somewhat surprisingly, they can also contribute to our understanding of the formation and evolution of (extrasolar) planets. We will study eclipsing binary stars by combining the classic - stellar astronomy - and the modern - extrasolar planets - subjects into a cutting edge project.
We propose to search for and subsequently characterize circumbinary planets around ~350 eclipsing SB2s using our own novel cutting edge radial velocity technique for binary stars and a modern version of the photometry based eclipse timing of eclipsing binary stars employing 0.5-m robotic telescopes. We will also derive basic parameters of up to ~700 stars (~350 binaries) with an unprecedented precision. In particular for about 50% of our sample we expect to deliver masses of the components with an accuracy ~10-100 times better than the current state of the art.
Our project will provide unique constraints for the theories of planet formation and evolution and an unprecedented in quality set of the basic parameters of stars to test the theories of the stellar structure and evolution.
Max ERC Funding
1 500 000 €
Duration
Start date: 2010-12-01, End date: 2016-11-30
Project acronym CAMAP
Project CAMAP: Computer Aided Modeling for Astrophysical Plasmas
Researcher (PI) Miguel-Ángel Aloy-Torás
Host Institution (HI) UNIVERSITAT DE VALENCIA
Call Details Starting Grant (StG), PE9, ERC-2010-StG_20091028
Summary This project will be aimed at obtaining a deeper insight into the physical processes taking place in astrophysical magnetized plasmas. To study these scenarios I will employ different numerical codes as virtual tools that enable me to experiment on computers (virtual labs) with distinct initial and boundary conditions. Among the kind of sources I am interested to consider, I outline the following: Gamma-Ray Bursts (GRBs), extragalactic jets from Active Galactic Nuclei (AGN), magnetars and collapsing stellar cores. A number of important questions are still open regarding the fundamental properties of these astrophysical sources (e.g., collimation, acceleration mechanism, composition, high-energy emission, gravitational wave signature). Additionally, there are analytical issues on the formalism in relativistic dynamics not resolved yet, e.g., the covariant extension of resistive magnetohydrodynamics (MHD). All these problems are so complex that only a computational approach is feasible. I plan to study them by means of relativistic and Newtonian MHD numerical simulations. A principal focus of the project will be to assess the relevance of magnetic fields in the generation, collimation and ulterior propagation of relativistic jets from the GRB progenitors and from AGNs. More generally, I will pursue the goal of understanding the process of amplification of seed magnetic fields until they become dynamically relevant, e.g., using semi-global and local simulations of representative boxes of collapsed stellar cores. A big emphasis will be put on including all the relevant microphysics (e.g. neutrino physics), non-ideal effects (particularly, reconnection physics) and energy transport due to neutrinos and photons to account for the relevant processes in the former systems. A milestone of this project will be to end up with a numerical tool that enables us to deal with General Relativistic Radiation Magnetohydrodynamics problems in Astrophysics.
Summary
This project will be aimed at obtaining a deeper insight into the physical processes taking place in astrophysical magnetized plasmas. To study these scenarios I will employ different numerical codes as virtual tools that enable me to experiment on computers (virtual labs) with distinct initial and boundary conditions. Among the kind of sources I am interested to consider, I outline the following: Gamma-Ray Bursts (GRBs), extragalactic jets from Active Galactic Nuclei (AGN), magnetars and collapsing stellar cores. A number of important questions are still open regarding the fundamental properties of these astrophysical sources (e.g., collimation, acceleration mechanism, composition, high-energy emission, gravitational wave signature). Additionally, there are analytical issues on the formalism in relativistic dynamics not resolved yet, e.g., the covariant extension of resistive magnetohydrodynamics (MHD). All these problems are so complex that only a computational approach is feasible. I plan to study them by means of relativistic and Newtonian MHD numerical simulations. A principal focus of the project will be to assess the relevance of magnetic fields in the generation, collimation and ulterior propagation of relativistic jets from the GRB progenitors and from AGNs. More generally, I will pursue the goal of understanding the process of amplification of seed magnetic fields until they become dynamically relevant, e.g., using semi-global and local simulations of representative boxes of collapsed stellar cores. A big emphasis will be put on including all the relevant microphysics (e.g. neutrino physics), non-ideal effects (particularly, reconnection physics) and energy transport due to neutrinos and photons to account for the relevant processes in the former systems. A milestone of this project will be to end up with a numerical tool that enables us to deal with General Relativistic Radiation Magnetohydrodynamics problems in Astrophysics.
Max ERC Funding
1 497 000 €
Duration
Start date: 2011-03-01, End date: 2017-02-28
Project acronym CepBin
Project A sub-percent distance scale from binaries and Cepheids
Researcher (PI) Grzegorz PIETRZYNSKI
Host Institution (HI) CENTRUM ASTRONOMICZNE IM. MIKOLAJAKOPERNIKA POLSKIEJ AKADEMII NAUK
Call Details Advanced Grant (AdG), PE9, ERC-2015-AdG
Summary We propose to carry out a project which will produce a decisive step towards improving the accuracy of the Hubble constant as determined from the Cepheid-SN Ia method to 1%, by using 28 extremely rare eclipsing binary systems in the LMC which offer the potential to determine their distances to 1%. To achieve this accuracy we will reduce the main error in the binary method by interferometric angular diameter measurements of a sample of red clump stars which resemble the stars in our binary systems. We will check on our calibration with similar binary systems close enough to determine their orbits from interferometry. We already showed the feasibility of our method which yielded the best-ever distance determination to the LMC of 2.2% from 8 such binary systems. With 28 systems and the improved angular diameter calibration we will push the LMC distance uncertainty down to 1% which will allow to set the zero point of the Cepheid PL relation with the same accuracy using the large available LMC Cepheid sample. We will determine the metallicity effect on Cepheid luminosities by a) determining a 2% distance to the more metal-poor SMC with our binary method, and by b) measuring the distances to LMC and SMC with an improved Baade-Wesselink (BW) method. We will achieve this improvement by analyzing 9 unique Cepheids in eclipsing binaries in the LMC our group has discovered which allow factor- of-ten improvements in the determination of all basic physical parameters of Cepheids. These studies will also increase our confidence in the Cepheid-based H0 determination. Our project bears strong synergy to the Gaia mission by providing the best checks on possible systematic uncertainties on Gaia parallaxes with 200 binary systems whose distances we will measure to 1-2%. We will provide two unique tools for 1-3 % distance determinations to individual objects in a volume of 1 Mpc, being competitive to Gaia already at a distance of 1 kpc from the Sun.
Summary
We propose to carry out a project which will produce a decisive step towards improving the accuracy of the Hubble constant as determined from the Cepheid-SN Ia method to 1%, by using 28 extremely rare eclipsing binary systems in the LMC which offer the potential to determine their distances to 1%. To achieve this accuracy we will reduce the main error in the binary method by interferometric angular diameter measurements of a sample of red clump stars which resemble the stars in our binary systems. We will check on our calibration with similar binary systems close enough to determine their orbits from interferometry. We already showed the feasibility of our method which yielded the best-ever distance determination to the LMC of 2.2% from 8 such binary systems. With 28 systems and the improved angular diameter calibration we will push the LMC distance uncertainty down to 1% which will allow to set the zero point of the Cepheid PL relation with the same accuracy using the large available LMC Cepheid sample. We will determine the metallicity effect on Cepheid luminosities by a) determining a 2% distance to the more metal-poor SMC with our binary method, and by b) measuring the distances to LMC and SMC with an improved Baade-Wesselink (BW) method. We will achieve this improvement by analyzing 9 unique Cepheids in eclipsing binaries in the LMC our group has discovered which allow factor- of-ten improvements in the determination of all basic physical parameters of Cepheids. These studies will also increase our confidence in the Cepheid-based H0 determination. Our project bears strong synergy to the Gaia mission by providing the best checks on possible systematic uncertainties on Gaia parallaxes with 200 binary systems whose distances we will measure to 1-2%. We will provide two unique tools for 1-3 % distance determinations to individual objects in a volume of 1 Mpc, being competitive to Gaia already at a distance of 1 kpc from the Sun.
Max ERC Funding
2 360 500 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
Project acronym CLR SENSING NECROSIS
Project Immune Functions of Myeloid Syk-coupled C-type Lectin Receptors Sensing Necrosis
Researcher (PI) David Sancho Madrid
Host Institution (HI) CENTRO NACIONAL DE INVESTIGACIONESCARDIOVASCULARES CARLOS III (F.S.P.)
Call Details Starting Grant (StG), LS6, ERC-2010-StG_20091118
Summary Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity in infection-free situations, such as autoimmunity or therapy-induced tumour rejection. Recently, we and others have identified the myeloid C-type lectin receptors (CLRs) CLEC9A (DNGR-1), in DC, and Mincle, in macrophages, as receptors for necrotic cells that can signal via the Syk kinase. Previous studies on similar Syk-coupled CLRs showed that Dectin-1 and Dectin-2 can induce innate and adaptive immune responses. We thus hypothesise that recognition of cell death by myeloid Syk-coupled CLRs is at the root of immune pathologies associated with accumulation of dead cells. The overall objective of this proposal is to investigate necrosis sensing by myeloid cells as a trigger of immunity and to study the underlying molecular mechanisms. Our first goal is to characterise signalling and gene induction via CLEC9A as a model necrosis receptor in DCs. Second, we will investigate the role of myeloid Syk-coupled necrosis-sensing CLRs in animal models of atherosclerosis, lupus and immunity to chemotherapy-treated tumours. Our preliminary data suggest that additional receptors can couple necrosis recognition to the Syk pathway in DC; thus, our third aim is to identify novel myeloid Syk-coupled receptors for necrotic cells. Characterisation of the outcomes of sensing necrosis by myeloid Syk-coupled receptors and their effect on the proposed pathologies promises to identify new mechanisms and targets for the treatment of these diseases.
Summary
Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity in infection-free situations, such as autoimmunity or therapy-induced tumour rejection. Recently, we and others have identified the myeloid C-type lectin receptors (CLRs) CLEC9A (DNGR-1), in DC, and Mincle, in macrophages, as receptors for necrotic cells that can signal via the Syk kinase. Previous studies on similar Syk-coupled CLRs showed that Dectin-1 and Dectin-2 can induce innate and adaptive immune responses. We thus hypothesise that recognition of cell death by myeloid Syk-coupled CLRs is at the root of immune pathologies associated with accumulation of dead cells. The overall objective of this proposal is to investigate necrosis sensing by myeloid cells as a trigger of immunity and to study the underlying molecular mechanisms. Our first goal is to characterise signalling and gene induction via CLEC9A as a model necrosis receptor in DCs. Second, we will investigate the role of myeloid Syk-coupled necrosis-sensing CLRs in animal models of atherosclerosis, lupus and immunity to chemotherapy-treated tumours. Our preliminary data suggest that additional receptors can couple necrosis recognition to the Syk pathway in DC; thus, our third aim is to identify novel myeloid Syk-coupled receptors for necrotic cells. Characterisation of the outcomes of sensing necrosis by myeloid Syk-coupled receptors and their effect on the proposed pathologies promises to identify new mechanisms and targets for the treatment of these diseases.
Max ERC Funding
1 297 671 €
Duration
Start date: 2010-12-01, End date: 2016-08-31
Project acronym CRC PROGRAMME
Project Dissecting the roles of the beta-catenin and Tcf genetic programmes during colorectal cancer progression
Researcher (PI) Eduard Batlle Gomez
Host Institution (HI) FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Call Details Starting Grant (StG), LS6, ERC-2007-StG
Summary Most colorectal cancers (CRCs) are initiated by activating mutations in components of the Wnt signalling pathway. Physiological Wnt signals are required for the specification and maintenance of the stem and progenitor cell compartments of the intestinal crypts. We demonstrated that early colorectal lesions exhibit a constitutive Wnt target gene programme, which is very similar to that of normal intestinal stem and progenitor cells. We originally proposed that colorectal adenomas behave as clusters of intestinal cells locked into a constitutive crypt progenitor phenotype. Given the prevalence of Wnt signalling mutations in CRC, an outstanding endeavour is the characterization of the similarities and differences in the instructions dictated by beta-catenin and Tcf to normal intestinal cells vs. CRC cells. Here, we propose to systematically compare and catalogue the beta-catenin/Tcf genetic programmes in intestinal progenitor/stem cells, intestinal adenomas and late CRCs. Transcriptomic analysis of isolated normal progenitor cells and tumor cell populations combined with bioinformatic analysis of gene regulatory networks will allow us to workout the hierarchical interactions downstream of beta-catenin and Tcf. Moreover, functional analysis of key beta-catenin/Tcf target genes using genetically modified mice models will help us to pinpoint which Wnt-controlled functions are essential for tumor maintenance and progression in vivo. Moreover, we seek to understand the tumor suppressor role of EphB2 and EphB3 receptors, two beta-catenin/Tcf target genes in normal crypts and benign colorectal adenomas, that block cancer progression by compartmentalizing tumor cells at the onset of CRC. Overall, our results will shed light on the relationship between stem/progenitor cells and cancer and hold potential for the future development of both therapeutic and diagnostic tools.
Summary
Most colorectal cancers (CRCs) are initiated by activating mutations in components of the Wnt signalling pathway. Physiological Wnt signals are required for the specification and maintenance of the stem and progenitor cell compartments of the intestinal crypts. We demonstrated that early colorectal lesions exhibit a constitutive Wnt target gene programme, which is very similar to that of normal intestinal stem and progenitor cells. We originally proposed that colorectal adenomas behave as clusters of intestinal cells locked into a constitutive crypt progenitor phenotype. Given the prevalence of Wnt signalling mutations in CRC, an outstanding endeavour is the characterization of the similarities and differences in the instructions dictated by beta-catenin and Tcf to normal intestinal cells vs. CRC cells. Here, we propose to systematically compare and catalogue the beta-catenin/Tcf genetic programmes in intestinal progenitor/stem cells, intestinal adenomas and late CRCs. Transcriptomic analysis of isolated normal progenitor cells and tumor cell populations combined with bioinformatic analysis of gene regulatory networks will allow us to workout the hierarchical interactions downstream of beta-catenin and Tcf. Moreover, functional analysis of key beta-catenin/Tcf target genes using genetically modified mice models will help us to pinpoint which Wnt-controlled functions are essential for tumor maintenance and progression in vivo. Moreover, we seek to understand the tumor suppressor role of EphB2 and EphB3 receptors, two beta-catenin/Tcf target genes in normal crypts and benign colorectal adenomas, that block cancer progression by compartmentalizing tumor cells at the onset of CRC. Overall, our results will shed light on the relationship between stem/progenitor cells and cancer and hold potential for the future development of both therapeutic and diagnostic tools.
Max ERC Funding
1 602 817 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym Danger ATP
Project Regulation of inflammatory response by extracellular ATP and P2X7 receptor signalling: through and beyond the inflammasome
Researcher (PI) Pablo Pelegrin Vivancos
Host Institution (HI) FUNDACION PARA LA FORMACION E INVESTIGACION SANITARIAS DE LA REGION DE MURCIA
Call Details Consolidator Grant (CoG), LS6, ERC-2013-CoG
Summary Inflammatory diseases affect over 80 million people worldwide and accompany many diseases of industrialized countries, being the majority of them infection-free conditions. There are few efficient anti-inflammatory drugs to treat chronic inflammation and thus, there is an urgent need to validate novel targets. We now know that innate immunity is the main coordinator and driver of inflammation. Recently, we and others have shown that the activation of purinergic P2X7 receptors (P2X7R) in immune cells is a novel and increasingly validated pathway to initiate inflammation through the activation of the NLRP3 inflammasome and the release of IL-1β and IL-18 cytokines. However, how NLRP3 sense P2X7R activation is not fully understood. Furthermore, extracellular ATP, the physiological P2X7R agonist, is a crucial danger signal released by injured cells, and one of the most important mediators of infection-free inflammation. We have also identified novel signalling roles for P2X7R independent on the NLRP3 inflammasome, including the release of proteases or inflammatory lipids. Therefore, P2X7R has generated increasing interest as a therapeutic target in inflammatory diseases, being drug like P2X7R antagonist in clinical trials to treat inflammatory diseases. However, it is often questioned the functionality of P2X7R in vivo, where it is thought that extracellular ATP levels are below the threshold to activate P2X7R. The overall significance of this proposal relays to elucidate how extracellular ATP controls host-defence in vivo, ultimately depicting P2X7R signalling through and beyond inflammasome activation. We foresee that our results will generate a leading innovative knowledge about in vivo extracellular ATP signalling during the host response to infection and sterile danger.
Summary
Inflammatory diseases affect over 80 million people worldwide and accompany many diseases of industrialized countries, being the majority of them infection-free conditions. There are few efficient anti-inflammatory drugs to treat chronic inflammation and thus, there is an urgent need to validate novel targets. We now know that innate immunity is the main coordinator and driver of inflammation. Recently, we and others have shown that the activation of purinergic P2X7 receptors (P2X7R) in immune cells is a novel and increasingly validated pathway to initiate inflammation through the activation of the NLRP3 inflammasome and the release of IL-1β and IL-18 cytokines. However, how NLRP3 sense P2X7R activation is not fully understood. Furthermore, extracellular ATP, the physiological P2X7R agonist, is a crucial danger signal released by injured cells, and one of the most important mediators of infection-free inflammation. We have also identified novel signalling roles for P2X7R independent on the NLRP3 inflammasome, including the release of proteases or inflammatory lipids. Therefore, P2X7R has generated increasing interest as a therapeutic target in inflammatory diseases, being drug like P2X7R antagonist in clinical trials to treat inflammatory diseases. However, it is often questioned the functionality of P2X7R in vivo, where it is thought that extracellular ATP levels are below the threshold to activate P2X7R. The overall significance of this proposal relays to elucidate how extracellular ATP controls host-defence in vivo, ultimately depicting P2X7R signalling through and beyond inflammasome activation. We foresee that our results will generate a leading innovative knowledge about in vivo extracellular ATP signalling during the host response to infection and sterile danger.
Max ERC Funding
1 794 948 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
