Project acronym CAAXPROCESSINGHUMDIS
Project CAAX Protein Processing in Human DIsease: From Cancer to Progeria
Researcher (PI) Martin Olof Bergö
Host Institution (HI) GOETEBORGS UNIVERSITET
Call Details Starting Grant (StG), LS6, ERC-2007-StG
Summary My objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.
Summary
My objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.
Max ERC Funding
1 689 600 €
Duration
Start date: 2008-06-01, End date: 2013-05-31
Project acronym CANALOHMICS
Project Biophysical networks underlying the robustness of neuronal excitability
Researcher (PI) Jean-Marc Goaillard
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Consolidator Grant (CoG), LS5, ERC-2013-CoG
Summary The mammalian nervous system is in some respect surprisingly robust to perturbations, as suggested by the virtually complete recovery of brain function after strokes or the pre-clinical asymptomatic phase of Parkinson’s disease. Ultimately though, cognitive and behavioral robustness relies on the ability of single neurons to cope with perturbations, and in particular to maintain a constant and reliable transfer of information.
So far, the main facet of robustness that has been studied at the neuronal level is homeostatic plasticity of electrical activity, which refers to the ability of neurons to stabilize their activity level in response to external perturbations. But neurons are also able to maintain their function when one of the major ion channels underlying their activity is deleted or mutated: the number of ion channel subtypes expressed by most excitable cells by far exceeds the minimal number of components necessary to achieve function, offering great potential for compensation when one of the channel’s function is altered. How ion channels are dynamically co-regulated to maintain the appropriate pattern of activity has yet to be determined.
In the current project, we will develop a systems-level approach to robustness of neuronal activity based on the combination of electrophysiology, microfluidic single-cell qPCR and computational modeling. We propose to i) characterize the electrical phenotype of dopaminergic neurons following different types of perturbations (ion channel KO, chronic pharmacological treatment), ii) measure the quantitatives changes in ion channel transcriptome (40 voltage-dependent ion channels) associated with these perturbations and iii) determine the mathematical relationships between quantitative changes in ion channel expression and electrical phenotype. Although focused on dopaminergic neurons, this project will provide a general framework that could be applied to any type of excitable cell to decipher its code of robustness.
Summary
The mammalian nervous system is in some respect surprisingly robust to perturbations, as suggested by the virtually complete recovery of brain function after strokes or the pre-clinical asymptomatic phase of Parkinson’s disease. Ultimately though, cognitive and behavioral robustness relies on the ability of single neurons to cope with perturbations, and in particular to maintain a constant and reliable transfer of information.
So far, the main facet of robustness that has been studied at the neuronal level is homeostatic plasticity of electrical activity, which refers to the ability of neurons to stabilize their activity level in response to external perturbations. But neurons are also able to maintain their function when one of the major ion channels underlying their activity is deleted or mutated: the number of ion channel subtypes expressed by most excitable cells by far exceeds the minimal number of components necessary to achieve function, offering great potential for compensation when one of the channel’s function is altered. How ion channels are dynamically co-regulated to maintain the appropriate pattern of activity has yet to be determined.
In the current project, we will develop a systems-level approach to robustness of neuronal activity based on the combination of electrophysiology, microfluidic single-cell qPCR and computational modeling. We propose to i) characterize the electrical phenotype of dopaminergic neurons following different types of perturbations (ion channel KO, chronic pharmacological treatment), ii) measure the quantitatives changes in ion channel transcriptome (40 voltage-dependent ion channels) associated with these perturbations and iii) determine the mathematical relationships between quantitative changes in ion channel expression and electrical phenotype. Although focused on dopaminergic neurons, this project will provide a general framework that could be applied to any type of excitable cell to decipher its code of robustness.
Max ERC Funding
1 972 797 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym CATCIR
Project Catalytic Carbene Insertion Reactions; Creating Diversity in (Material) Synthesis
Researcher (PI) Bastiaan (Bas) De Bruin
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), PE4, ERC-2007-StG
Summary With this proposal the PI capitalises on his recent breakthroughs in transition metal catalysed carbene (migratory) insertion reactions to build up a new research line for controlled catalytic preparation of a variety of new functionalised (co)polymers with expected special material properties. Metallo-carbenes are well-known intermediates in olefin cyclopropanation and olefin metathesis, but the PI recently discovered that their chemistry is far richer. He demonstrated for the first time that metallo-carbenoids can be used in transition metal catalysed insertion polymerisation to arrive at completely new types of stereoregular carbon-chain polymers functionalised at each carbon of the polymer backbone. Rhodium mediated polymerisation of carbenes provides the means to prepare new materials with yet unknown properties. It also provides a valuable alternative to prepare practically identical polymers as in the desirable (but still unachievable) highly stereo-selective (co)polymerisation of functionalised olefins, representing the ‘holey-grail’ in world-wide TM polymerisation catalysis research. The mechanism and scope of this remarkable new discovery will be investigated and new, improved catalysts will be developed for the preparation of novel materials based on homo- and copolymerisation of a variety of carbene precursors. Copolymerisation of carbenes and other reactive monomers will also be investigated and the properties of all new materials will be investigated. In addition the team will try to uncover new reactions in which carbene insertion reactions play a central role. DFT calculations suggest that the transition state (TS) of the new carbene polymerisation reaction is very similar to the TS’s of a variety of carbonyl insertion reactions. Based on this analogy, the team will investigate several new carbene insertion reactions, potentially leading to new, useful polymeric materials and new synthetic routes to prepare small functional organic molecules.
Summary
With this proposal the PI capitalises on his recent breakthroughs in transition metal catalysed carbene (migratory) insertion reactions to build up a new research line for controlled catalytic preparation of a variety of new functionalised (co)polymers with expected special material properties. Metallo-carbenes are well-known intermediates in olefin cyclopropanation and olefin metathesis, but the PI recently discovered that their chemistry is far richer. He demonstrated for the first time that metallo-carbenoids can be used in transition metal catalysed insertion polymerisation to arrive at completely new types of stereoregular carbon-chain polymers functionalised at each carbon of the polymer backbone. Rhodium mediated polymerisation of carbenes provides the means to prepare new materials with yet unknown properties. It also provides a valuable alternative to prepare practically identical polymers as in the desirable (but still unachievable) highly stereo-selective (co)polymerisation of functionalised olefins, representing the ‘holey-grail’ in world-wide TM polymerisation catalysis research. The mechanism and scope of this remarkable new discovery will be investigated and new, improved catalysts will be developed for the preparation of novel materials based on homo- and copolymerisation of a variety of carbene precursors. Copolymerisation of carbenes and other reactive monomers will also be investigated and the properties of all new materials will be investigated. In addition the team will try to uncover new reactions in which carbene insertion reactions play a central role. DFT calculations suggest that the transition state (TS) of the new carbene polymerisation reaction is very similar to the TS’s of a variety of carbonyl insertion reactions. Based on this analogy, the team will investigate several new carbene insertion reactions, potentially leading to new, useful polymeric materials and new synthetic routes to prepare small functional organic molecules.
Max ERC Funding
1 250 000 €
Duration
Start date: 2008-08-01, End date: 2013-07-31
Project acronym CCC
Project Cracking the Cerebellar Code
Researcher (PI) Christiaan Innocentius De Zeeuw
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary Spike trains transfer information to and from neurons. Most studies so far assume that the average firing rate or “rate coding” is the predominant way of information coding. However, spikes occur at millisecond precision, and their actual timing or “temporal coding” can in principle strongly increase the information content of spike trains. The two coding mechanisms are not mutually exclusive. Neurons may switch between rate and temporal coding, or use a combination of both coding mechanisms at the same time, which would increase the information content of spike trains even further. Here, we propose to investigate the hypothesis that temporal coding plays, next to rate coding, important and specific roles in cerebellar processing during learning. The cerebellum is ideal to study this timely topic, because it has a clear anatomy with well-organized modules and matrices, a well-described physiology of different types of neurons with distinguishable spiking activity, and a central role in various forms of tractable motor learning. Moreover, uniquely in the brain, the main types of neurons in the cerebellar system can be genetically manipulated in a cell-specific fashion, which will allow us to investigate the behavioural importance of both coding mechanisms following cell-specific interference and/or during cell-specific visual imaging. Thus, for this proposal we will create conditional mouse mutants that will be subjected to learning paradigms in which we can disentangle the contributions of rate coding and temporal coding using electrophysiological and optogenetic recordings and stimulation. Together, our experiments should elucidate how neurons in the brain communicate during natural learning behaviour and how one may be able to intervene in this process to affect or improve procedural learning skills.
Summary
Spike trains transfer information to and from neurons. Most studies so far assume that the average firing rate or “rate coding” is the predominant way of information coding. However, spikes occur at millisecond precision, and their actual timing or “temporal coding” can in principle strongly increase the information content of spike trains. The two coding mechanisms are not mutually exclusive. Neurons may switch between rate and temporal coding, or use a combination of both coding mechanisms at the same time, which would increase the information content of spike trains even further. Here, we propose to investigate the hypothesis that temporal coding plays, next to rate coding, important and specific roles in cerebellar processing during learning. The cerebellum is ideal to study this timely topic, because it has a clear anatomy with well-organized modules and matrices, a well-described physiology of different types of neurons with distinguishable spiking activity, and a central role in various forms of tractable motor learning. Moreover, uniquely in the brain, the main types of neurons in the cerebellar system can be genetically manipulated in a cell-specific fashion, which will allow us to investigate the behavioural importance of both coding mechanisms following cell-specific interference and/or during cell-specific visual imaging. Thus, for this proposal we will create conditional mouse mutants that will be subjected to learning paradigms in which we can disentangle the contributions of rate coding and temporal coding using electrophysiological and optogenetic recordings and stimulation. Together, our experiments should elucidate how neurons in the brain communicate during natural learning behaviour and how one may be able to intervene in this process to affect or improve procedural learning skills.
Max ERC Funding
2 499 600 €
Duration
Start date: 2012-04-01, End date: 2017-03-31
Project acronym CD4DNASP
Project Cell intrinsic control of CD4 T cell differentiation by cytosolic DNA sensing pathways
Researcher (PI) Lionel Jerome Apetoh
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS6, ERC-2015-STG
Summary This proposal aims to investigate the role of cytosolic DNA sensing pathways in CD4 T cell differentiation.
Cellular host defense to pathogens relies on the detection of pathogen-associated molecular patterns including deoxyribonucleic acid (DNA), which can be recognized by host myeloid cells through Toll-like receptor (TLR) 9 binding. Recent evidence however suggests that innate immune cells can also perceive cytoplasmic DNA from infectious or autologous origin through cytosolic DNA sensors triggering TLR9-independent signaling. Activation of cytosolic DNA sensor-dependent signaling pathways has been clearly shown to trigger innate immune responses to microbial and host DNA, but the contribution of cytosolic DNA sensors to the differentiation of CD4 T cells, an essential event for shaping adaptive immune responses, has not been documented. This proposal aims to fill this current knowledge gap.
We aim to decipher the molecular series of transcriptional events triggered by DNA in CD4 T cells that ultimately result in altered T cell differentiation. This aim will be addressed by combining in vitro and in vivo approaches such as advanced gene expression analysis of CD4 T cells and use of transgenic and gene-deficient mice. Structure activity relationship and biophysical studies will also be performed to unravel novel immunomodulators able to affect CD4 T cell differentiation.
Summary
This proposal aims to investigate the role of cytosolic DNA sensing pathways in CD4 T cell differentiation.
Cellular host defense to pathogens relies on the detection of pathogen-associated molecular patterns including deoxyribonucleic acid (DNA), which can be recognized by host myeloid cells through Toll-like receptor (TLR) 9 binding. Recent evidence however suggests that innate immune cells can also perceive cytoplasmic DNA from infectious or autologous origin through cytosolic DNA sensors triggering TLR9-independent signaling. Activation of cytosolic DNA sensor-dependent signaling pathways has been clearly shown to trigger innate immune responses to microbial and host DNA, but the contribution of cytosolic DNA sensors to the differentiation of CD4 T cells, an essential event for shaping adaptive immune responses, has not been documented. This proposal aims to fill this current knowledge gap.
We aim to decipher the molecular series of transcriptional events triggered by DNA in CD4 T cells that ultimately result in altered T cell differentiation. This aim will be addressed by combining in vitro and in vivo approaches such as advanced gene expression analysis of CD4 T cells and use of transgenic and gene-deficient mice. Structure activity relationship and biophysical studies will also be performed to unravel novel immunomodulators able to affect CD4 T cell differentiation.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym CD8 T CELLS
Project Development and differentiation of CD8 T lymphocytes
Researcher (PI) Benedita Rocha
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Advanced Grant (AdG), LS6, ERC-2008-AdG
Summary CD8 T lymphocytes have a fundamental role in ensuring the control of different types of intracellular pathogens including bacteria, parasites and most viruses. This control may fail due to several reasons. The current aggressive anti-cancer therapies (or rarely certain congenital immune deficiencies) induce CD8 depletion. After bone-marrow transplantation, long time periods are required to ensure T cell reconstitution particularly in the adult. This long lag-time is due to the long-time periods required for hematopoietic precursors to generate T lymphocytes and to a thymus insufficiency in the adult. However, even when CD8 T cells are present CD8 immune responses are not always adequate. Certain chronic infections, as HIV, induce CD8 dysfunction and it is yet unclear how to generate efficient CD8 memory responses conferring adequate protection. To address these questions this project aims 1) To find strategies ensuring the rapid reconstitution of the peripheral and the gut CD8 T cell compartments a) by studying the mechanisms involved HSC division and T cell commitment; b) by isolating and characterizing progenitors we previously described that are T cell committed and able of an accelerated CD8 reconstitution c) by developing new strategies that may allow stable thymus transplantation and continuous thymus T cell generation. 2) To determine the mechanics associated to efficient CD8 memory generation a) by evaluating cellular modifications that ensure the efficient division and the remarkable accumulation and survival of CD8 T cells during the adequate immune responses as compared to inefficient responses b) by studying CD8 differentiation into effector and memory cells in both conditions. These studies will use original experiment mouse models we develop in the laboratory, that allow to address each of these aims. Besides state of the art methods, they will also apply unique very advanced approaches we introduced and are the sole laboratory to perform.
Summary
CD8 T lymphocytes have a fundamental role in ensuring the control of different types of intracellular pathogens including bacteria, parasites and most viruses. This control may fail due to several reasons. The current aggressive anti-cancer therapies (or rarely certain congenital immune deficiencies) induce CD8 depletion. After bone-marrow transplantation, long time periods are required to ensure T cell reconstitution particularly in the adult. This long lag-time is due to the long-time periods required for hematopoietic precursors to generate T lymphocytes and to a thymus insufficiency in the adult. However, even when CD8 T cells are present CD8 immune responses are not always adequate. Certain chronic infections, as HIV, induce CD8 dysfunction and it is yet unclear how to generate efficient CD8 memory responses conferring adequate protection. To address these questions this project aims 1) To find strategies ensuring the rapid reconstitution of the peripheral and the gut CD8 T cell compartments a) by studying the mechanisms involved HSC division and T cell commitment; b) by isolating and characterizing progenitors we previously described that are T cell committed and able of an accelerated CD8 reconstitution c) by developing new strategies that may allow stable thymus transplantation and continuous thymus T cell generation. 2) To determine the mechanics associated to efficient CD8 memory generation a) by evaluating cellular modifications that ensure the efficient division and the remarkable accumulation and survival of CD8 T cells during the adequate immune responses as compared to inefficient responses b) by studying CD8 differentiation into effector and memory cells in both conditions. These studies will use original experiment mouse models we develop in the laboratory, that allow to address each of these aims. Besides state of the art methods, they will also apply unique very advanced approaches we introduced and are the sole laboratory to perform.
Max ERC Funding
1 969 644 €
Duration
Start date: 2009-02-01, End date: 2014-05-31
Project acronym chemREPEAT
Project Structure and Dynamics of Low-Complexity Regions in Proteins: The Huntingtin Case
Researcher (PI) Pau Bernado Pereto
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Consolidator Grant (CoG), PE4, ERC-2014-CoG
Summary Proteins hosting regions highly enriched in one or few amino acids, the so-called Low-Complexity Regions (LCR), are very common in eukaryotes and play crucial roles in biology. Homorepeats, a subfamily of LCR that present stretches of the same amino acid, perform very specialized functions facilitated by the localized enrichment of the same physicochemical property. In contrast, numerous severe pathologies have been associated to abnormally long repetitions. Despite the relevance of homorepeats, their high-resolution characterization by traditional structural biology techniques is hampered by the degeneracy of the amino acid environments and their intrinsic flexibility. In chemREPEAT, I will develop strategies to incorporate isotopically labelled and unnatural amino acids at specific positions within homorepeats that will overcome present limitations. These labelled positions will be unique probes to investigate for first time the structure and dynamics of homorepeats at atomic level using complementary biophysical techniques. Computational tools will be specifically developed to derive three-dimensional conformational ensembles of homorepeats by synergistically integrating experimental data.
chemREPEAT strategies will be developed on huntingtin (Htt), the prototype of repetitive protein. Htt hosts a glutamine tract that is linked with Huntington’s disease (HD), a deadly neuropathology appearing in individuals with more than 35 consecutive Glutamine residues that represent a pathological threshold. The application of the developed approaches to several Htt constructions with different number of Glutamines will reveal the structural bases of the pathological threshold in HD and the role played by the regions flanking the Glutamine tract.
The strategies designed in chemREPEAT will expand present frontiers of structural biology to unveil the structure/function relationships for LCRs. This capacity will pave the way for a rational intervention in associated diseases.
Summary
Proteins hosting regions highly enriched in one or few amino acids, the so-called Low-Complexity Regions (LCR), are very common in eukaryotes and play crucial roles in biology. Homorepeats, a subfamily of LCR that present stretches of the same amino acid, perform very specialized functions facilitated by the localized enrichment of the same physicochemical property. In contrast, numerous severe pathologies have been associated to abnormally long repetitions. Despite the relevance of homorepeats, their high-resolution characterization by traditional structural biology techniques is hampered by the degeneracy of the amino acid environments and their intrinsic flexibility. In chemREPEAT, I will develop strategies to incorporate isotopically labelled and unnatural amino acids at specific positions within homorepeats that will overcome present limitations. These labelled positions will be unique probes to investigate for first time the structure and dynamics of homorepeats at atomic level using complementary biophysical techniques. Computational tools will be specifically developed to derive three-dimensional conformational ensembles of homorepeats by synergistically integrating experimental data.
chemREPEAT strategies will be developed on huntingtin (Htt), the prototype of repetitive protein. Htt hosts a glutamine tract that is linked with Huntington’s disease (HD), a deadly neuropathology appearing in individuals with more than 35 consecutive Glutamine residues that represent a pathological threshold. The application of the developed approaches to several Htt constructions with different number of Glutamines will reveal the structural bases of the pathological threshold in HD and the role played by the regions flanking the Glutamine tract.
The strategies designed in chemREPEAT will expand present frontiers of structural biology to unveil the structure/function relationships for LCRs. This capacity will pave the way for a rational intervention in associated diseases.
Max ERC Funding
1 999 844 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym CIMNAS
Project Corrosion Initiation Mechanisms at the Nanometric/Atomic Scale
Researcher (PI) Philippe MARCUS
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), PE4, ERC-2016-ADG
Summary The failure of metallic materials caused by corrosion strongly impacts our society with cost, safety, health and performance issues. The mechanisms of corrosion propagation are fairly well understood, and various means of mitigation are known even if research is still necessary to improve this knowledge or to develop corrosion protection for the application of new materials. The vision of CIMNAS is that a major breakthrough for corrosion protection lies in a deep understanding and control of the initiation stage triggering corrosion. Corrosion initiation takes place at the atomic/molecular scale or at a scale of a few nanometres (the nanoscale) on metal and alloy surfaces, metallic, oxidised or coated, and interacting with the corroding environment. The mission of CIMNAS is to challenge the difficulty of understanding corrosion initiation at the nanometric/atomic scale on such complex interfaces, ultimately aiming at designing more robust metallic surfaces via the understanding of corrosion mechanisms. The project is constructed on new ideas to achieve three knowledge breakthroughs, each answering a key question for the understanding of corrosion initiation on metal and alloy surfaces. It is envisioned that the model approach used and the achieved breakthroughs will open up a new horizon for research on corrosion initiation mechanisms at the nanoscale, and new opportunities for a knowledge-based design of novel corrosion protection technologies. Technologies presently at low TRL (Technology Readiness Level) will benefit from these breakthroughs. Resources will include a team of highly experienced and recognised researchers headed by the PI, a unique apparatus recently installed at the PI’s lab, integrating surface spectroscopy, microscopy, and electrochemistry for in situ measurements in a closed system, novel experimental approaches, and a strong complementarity of experiments and modelling.
Summary
The failure of metallic materials caused by corrosion strongly impacts our society with cost, safety, health and performance issues. The mechanisms of corrosion propagation are fairly well understood, and various means of mitigation are known even if research is still necessary to improve this knowledge or to develop corrosion protection for the application of new materials. The vision of CIMNAS is that a major breakthrough for corrosion protection lies in a deep understanding and control of the initiation stage triggering corrosion. Corrosion initiation takes place at the atomic/molecular scale or at a scale of a few nanometres (the nanoscale) on metal and alloy surfaces, metallic, oxidised or coated, and interacting with the corroding environment. The mission of CIMNAS is to challenge the difficulty of understanding corrosion initiation at the nanometric/atomic scale on such complex interfaces, ultimately aiming at designing more robust metallic surfaces via the understanding of corrosion mechanisms. The project is constructed on new ideas to achieve three knowledge breakthroughs, each answering a key question for the understanding of corrosion initiation on metal and alloy surfaces. It is envisioned that the model approach used and the achieved breakthroughs will open up a new horizon for research on corrosion initiation mechanisms at the nanoscale, and new opportunities for a knowledge-based design of novel corrosion protection technologies. Technologies presently at low TRL (Technology Readiness Level) will benefit from these breakthroughs. Resources will include a team of highly experienced and recognised researchers headed by the PI, a unique apparatus recently installed at the PI’s lab, integrating surface spectroscopy, microscopy, and electrochemistry for in situ measurements in a closed system, novel experimental approaches, and a strong complementarity of experiments and modelling.
Max ERC Funding
1 657 056 €
Duration
Start date: 2017-09-01, End date: 2021-08-31
Project acronym CIRCUMVENT
Project Closing in on Runx3 and CXCL4 to open novel avenues for therapeutic intervention in systemic sclerosis
Researcher (PI) Timothy Radstake
Host Institution (HI) UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Call Details Starting Grant (StG), LS6, ERC-2011-StG_20101109
Summary Systemic sclerosis (SSc) is an autoimmune disease that culminates in excessive extra-cellular matrix deposition (fibrosis) in skin and internal organs. SSc is a severe disease in which fibrotic events lead to organ failure such as renal failure, deterioration of lung function and development of pulmonary arterial hypertension (PAH). Together, these disease hallmarks culminate in profound disability and premature death.
Over the past three years several crucial observations by my group changed the landscape of our thinking about the ethiopathogenesis of this disease. First, plasmacytoid dendritic (pDCs) cells were found to be extremely frequent in the circulation of SSc patients (1000-fold) compared with healthy individuals. In addition, we observed that pDCs from SSc patients are largely dedicated to synthesize CXCL4 that was proven to be directly implicated in fibroblast biology and endothelial cell activation, two events recapitulating SSc. Finally, research aimed to decipher the underlying cause of this increased pDCs frequency led to the observation that Runx3, a transcription factor that controls the differentiation of DC subsets, was almost not expressed in pDC of SSc patients. Together, these observations led me to pose the “SSc immune postulate” in which the pathogenesis of SSc is explained by a multi-step process in which Runx3 and CXCL4 play a central role.
The project CIRCUMVENT is designed to provide proof of concept for the role of CXCL4 and RUNX3 in SSc. For this aim we will exploit a unique set of patient material (cell subsets, protein and DNA bank), various recently developed in vitro techniques (siRNA for pDCs, viral over expression of CXCL4/RUNX3) and apply three recently optimised experimental models (CXCL4 subcutaneous pump model, DC specific RUNX3 KO and the SCID/NOD/rag2 KO mice).
The project CIRCUMVENT aims to proof the direct role for Runx3 and CXCL4 that could provide the final step towards the development of novel therapeutic targets
Summary
Systemic sclerosis (SSc) is an autoimmune disease that culminates in excessive extra-cellular matrix deposition (fibrosis) in skin and internal organs. SSc is a severe disease in which fibrotic events lead to organ failure such as renal failure, deterioration of lung function and development of pulmonary arterial hypertension (PAH). Together, these disease hallmarks culminate in profound disability and premature death.
Over the past three years several crucial observations by my group changed the landscape of our thinking about the ethiopathogenesis of this disease. First, plasmacytoid dendritic (pDCs) cells were found to be extremely frequent in the circulation of SSc patients (1000-fold) compared with healthy individuals. In addition, we observed that pDCs from SSc patients are largely dedicated to synthesize CXCL4 that was proven to be directly implicated in fibroblast biology and endothelial cell activation, two events recapitulating SSc. Finally, research aimed to decipher the underlying cause of this increased pDCs frequency led to the observation that Runx3, a transcription factor that controls the differentiation of DC subsets, was almost not expressed in pDC of SSc patients. Together, these observations led me to pose the “SSc immune postulate” in which the pathogenesis of SSc is explained by a multi-step process in which Runx3 and CXCL4 play a central role.
The project CIRCUMVENT is designed to provide proof of concept for the role of CXCL4 and RUNX3 in SSc. For this aim we will exploit a unique set of patient material (cell subsets, protein and DNA bank), various recently developed in vitro techniques (siRNA for pDCs, viral over expression of CXCL4/RUNX3) and apply three recently optimised experimental models (CXCL4 subcutaneous pump model, DC specific RUNX3 KO and the SCID/NOD/rag2 KO mice).
The project CIRCUMVENT aims to proof the direct role for Runx3 and CXCL4 that could provide the final step towards the development of novel therapeutic targets
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-08-01, End date: 2017-07-31
Project acronym CMTaaRS
Project Defective protein translation as a pathogenic mechanism of peripheral neuropathy
Researcher (PI) Erik Jan Marthe STORKEBAUM
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Familial forms of neurodegenerative diseases are caused by mutations in a single gene. It is unknown whether distinct mutations in the same gene or in functionally related genes cause disease through similar or disparate mechanisms. Furthermore, the precise molecular mechanisms underlying virtually all neurodegenerative disorders are poorly understood, and effective treatments are typically lacking.
This is also the case for Charcot-Marie-Tooth (CMT) peripheral neuropathy caused by mutations in five distinct tRNA synthetase (aaRS) genes. We previously generated Drosophila CMT-aaRS models and used a novel method for cell-type-specific labeling of newly synthesized proteins in vivo to show that impaired protein translation may represent a common pathogenic mechanism.
In this proposal, I aim to determine whether translation is also inhibited in CMT-aaRS mouse models, and whether all mutations cause disease through gain-of-toxic-function, or alternatively, whether some mutations act through a dominant-negative mechanism. In addition, I will evaluate whether all CMT-aaRS mutant proteins inhibit translation, and I will test the hypothesis, raised by our unpublished preliminary data shown here, that a defect in the transfer of the (aminoacylated) tRNA from the mutant synthetase to elongation factor eEF1A is the molecular mechanism underlying CMT-aaRS. Finally, I will validate the identified molecular mechanism in CMT-aaRS mouse models, as the most disease-relevant mammalian model.
I expect to elucidate whether all CMT-aaRS mutations cause disease through a common molecular mechanism that involves inhibition of translation. This is of key importance from a therapeutic perspective, as a common pathogenic mechanism allows for a unified therapeutic approach. Furthermore, this proposal has the potential to unravel the detailed molecular mechanism underlying CMT-aaRS, what would constitute a breakthrough and a requirement for rational drug design for this incurable disease.
Summary
Familial forms of neurodegenerative diseases are caused by mutations in a single gene. It is unknown whether distinct mutations in the same gene or in functionally related genes cause disease through similar or disparate mechanisms. Furthermore, the precise molecular mechanisms underlying virtually all neurodegenerative disorders are poorly understood, and effective treatments are typically lacking.
This is also the case for Charcot-Marie-Tooth (CMT) peripheral neuropathy caused by mutations in five distinct tRNA synthetase (aaRS) genes. We previously generated Drosophila CMT-aaRS models and used a novel method for cell-type-specific labeling of newly synthesized proteins in vivo to show that impaired protein translation may represent a common pathogenic mechanism.
In this proposal, I aim to determine whether translation is also inhibited in CMT-aaRS mouse models, and whether all mutations cause disease through gain-of-toxic-function, or alternatively, whether some mutations act through a dominant-negative mechanism. In addition, I will evaluate whether all CMT-aaRS mutant proteins inhibit translation, and I will test the hypothesis, raised by our unpublished preliminary data shown here, that a defect in the transfer of the (aminoacylated) tRNA from the mutant synthetase to elongation factor eEF1A is the molecular mechanism underlying CMT-aaRS. Finally, I will validate the identified molecular mechanism in CMT-aaRS mouse models, as the most disease-relevant mammalian model.
I expect to elucidate whether all CMT-aaRS mutations cause disease through a common molecular mechanism that involves inhibition of translation. This is of key importance from a therapeutic perspective, as a common pathogenic mechanism allows for a unified therapeutic approach. Furthermore, this proposal has the potential to unravel the detailed molecular mechanism underlying CMT-aaRS, what would constitute a breakthrough and a requirement for rational drug design for this incurable disease.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
