Project acronym COMOTION
Project Controlling the Motion of Complex Molecules and Particles
Researcher (PI) Jochen Küpper
Host Institution (HI) STIFTUNG DEUTSCHES ELEKTRONEN-SYNCHROTRON DESY
Call Details Consolidator Grant (CoG), PE4, ERC-2013-CoG
Summary "The main objective of COMOTION is to enable novel experiments for the investigation of the intrinsic properties of large molecules, including biological samples like proteins, viruses, and small cells
-X-ray free-electron lasers have enabled the observation of near-atomic-resolution structures in diffraction- before-destruction experiments, for instance, of isolated mimiviruses and of proteins from microscopic crystals. The goal to record molecular movies with spatial and temporal atomic-resolution (femtoseconds and picometers) of individual molecules is near.
-The investigation of ultrafast, sub-femtosecond electron dynamics in small molecules is providing first results. Its extension to large molecules promises the unraveling of charge migration and energy transport in complex (bio)molecules.
-Matter-wave experiments of large molecules, with currently up to some hundred atoms, are testing the limits of quantum mechanics, particle-wave duality, and coherence. These metrology experiments also allow the precise measurement of molecular properties.
The principal obstacle for these and similar experiments in molecular sciences is the controlled production of samples of identical molecules in the gas phase. We will develop novel concepts and technologies for the manipulation of complex molecules, ranging from amino acids to proteins, viruses, nano-objects, and small cells: We will implement new methods to inject complex molecules into vacuum, to rapidly cool them, and to manipulate the motion of these cold gas-phase samples using combinations of external electric and electromagnetic fields. These external-field handles enable the spatial separation of molecules according to size, shape, and isomer.
The generated controlled samples are ideally suited for the envisioned precision experiments. We will exploit them to record atomic-resolution molecular movies using the European XFEL, as well as to investigate the limits of quantum mechanics using matter-wave interferometry."
Summary
"The main objective of COMOTION is to enable novel experiments for the investigation of the intrinsic properties of large molecules, including biological samples like proteins, viruses, and small cells
-X-ray free-electron lasers have enabled the observation of near-atomic-resolution structures in diffraction- before-destruction experiments, for instance, of isolated mimiviruses and of proteins from microscopic crystals. The goal to record molecular movies with spatial and temporal atomic-resolution (femtoseconds and picometers) of individual molecules is near.
-The investigation of ultrafast, sub-femtosecond electron dynamics in small molecules is providing first results. Its extension to large molecules promises the unraveling of charge migration and energy transport in complex (bio)molecules.
-Matter-wave experiments of large molecules, with currently up to some hundred atoms, are testing the limits of quantum mechanics, particle-wave duality, and coherence. These metrology experiments also allow the precise measurement of molecular properties.
The principal obstacle for these and similar experiments in molecular sciences is the controlled production of samples of identical molecules in the gas phase. We will develop novel concepts and technologies for the manipulation of complex molecules, ranging from amino acids to proteins, viruses, nano-objects, and small cells: We will implement new methods to inject complex molecules into vacuum, to rapidly cool them, and to manipulate the motion of these cold gas-phase samples using combinations of external electric and electromagnetic fields. These external-field handles enable the spatial separation of molecules according to size, shape, and isomer.
The generated controlled samples are ideally suited for the envisioned precision experiments. We will exploit them to record atomic-resolution molecular movies using the European XFEL, as well as to investigate the limits of quantum mechanics using matter-wave interferometry."
Max ERC Funding
1 982 500 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
Project acronym COMP-MICR-CROW-MEM
Project Computational Microscopy of Crowded Membranes
Researcher (PI) Siewert Jan Marrink
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Call Details Advanced Grant (AdG), PE4, ERC-2014-ADG
Summary Cell membranes form a highly complex and heterogeneous mixture of membrane proteins and lipids. Understanding the protein-lipid interplay that gives rise to the lateral organisation principles of cell membranes is essential for life and health. Thus, investigations of these crowded membranes is emerging as a new and exceptionally exciting frontier at the crossroads of biology, life sciences, physics, and chemistry.
However, our current understanding of the detailed organisation of cellular membranes remains rather elusive. Characterisation of the structural heterogeneity in-vivo remains very challenging, owing to the lack of experimental methods suitable for studying these fluctuating nanoscale assemblies of lipids and proteins with the required spatio-temporal resolution. In recent years, computer simulations have become a unique investigatory tool for understanding the driving forces governing the lateral organisation of cellular membrane components and this “computational microscopy” has become indispensible as a complement to traditional microscopy methods.
In this ERC project I will, using advanced computational microscopy, study the interaction of lipids and proteins in complex, crowded, membrane patches, to enable the driving forces of membrane protein sorting and clustering to be unravelled at conditions closely mimicking real cellular membranes. The specific objectives are:
• To develop a novel computational microscopy framework for simulating biomolecular processes at multiple resolutions.
• To use this new computational microscopy framework to investigate the driving forces of membrane protein sorting and clustering.
• To provide a molecular view of realistic, crowded, biological membranes composed of hundreds of different lipids and proteins.
The outcomes will enable subsequent studies of many different types of cell membranes based on forthcoming lipidomics studies and progress in structural characterisation of membrane proteins.
Summary
Cell membranes form a highly complex and heterogeneous mixture of membrane proteins and lipids. Understanding the protein-lipid interplay that gives rise to the lateral organisation principles of cell membranes is essential for life and health. Thus, investigations of these crowded membranes is emerging as a new and exceptionally exciting frontier at the crossroads of biology, life sciences, physics, and chemistry.
However, our current understanding of the detailed organisation of cellular membranes remains rather elusive. Characterisation of the structural heterogeneity in-vivo remains very challenging, owing to the lack of experimental methods suitable for studying these fluctuating nanoscale assemblies of lipids and proteins with the required spatio-temporal resolution. In recent years, computer simulations have become a unique investigatory tool for understanding the driving forces governing the lateral organisation of cellular membrane components and this “computational microscopy” has become indispensible as a complement to traditional microscopy methods.
In this ERC project I will, using advanced computational microscopy, study the interaction of lipids and proteins in complex, crowded, membrane patches, to enable the driving forces of membrane protein sorting and clustering to be unravelled at conditions closely mimicking real cellular membranes. The specific objectives are:
• To develop a novel computational microscopy framework for simulating biomolecular processes at multiple resolutions.
• To use this new computational microscopy framework to investigate the driving forces of membrane protein sorting and clustering.
• To provide a molecular view of realistic, crowded, biological membranes composed of hundreds of different lipids and proteins.
The outcomes will enable subsequent studies of many different types of cell membranes based on forthcoming lipidomics studies and progress in structural characterisation of membrane proteins.
Max ERC Funding
2 396 585 €
Duration
Start date: 2015-11-01, End date: 2020-10-31
Project acronym complexNMR
Project Structural Dynamics of Protein Complexes by Solid-State NMR
Researcher (PI) Józef Romuald Lewandowski
Host Institution (HI) THE UNIVERSITY OF WARWICK
Call Details Starting Grant (StG), PE4, ERC-2014-STG
Summary Multidrug resistant bacteria that render worthless the current arsenal of antibiotics are a growing global problem. This grave challenge could be tackled by polyketide synthases (PKSs), which are gigantic modular enzymatic assembly lines for natural products. PKSs could be developed for industry to produce chemically difficult to synthesize drugs, but cannot be harnessed until we understand how they work on the molecular level. However, such understanding is missing because we cannot easily investigate large complexes with current structural biology and modeling methods. A key puzzle is how the function of these multicomponent systems emerges from atomic-scale interactions of their parts. Solving this puzzle requires a holistic approach involving measuring and modeling the relevant interacting parts together.
Our goal is to develop a multidisciplinary approach rooted in solid and solution state NMR that will make possible studies of complexes from PKSs. The two main challenges for the NMR of PKSs are increasing sensitivity and resolution. Recent innovations from our lab allow application of solid-state to study large complexes in 2–10 nanomole quantities. Building on this approach, with a protein-antibody complex as a test case, we will develop new NMR methods that will enable a study of structure and motions of domains in complexes. We will probe, for the first time, the structural dynamics of PKSs of enacyloxin and gladiolin, which are antibiotics against life-threatening multidrug resistant hospital-acquired Acinetobacter baumannii infections and tuberculosis. These studies will guide rational engineering of the PKSs to enable synthetic biology approaches to produce new antibiotics.
If successful, this project will go beyond the state of the art by: enabling studies of unknown proteins in large complexes and providing unique insights into novel mechanisms for controlling biosynthesis in PKSs, turning them into truly programmable synthetic biology devices.
Summary
Multidrug resistant bacteria that render worthless the current arsenal of antibiotics are a growing global problem. This grave challenge could be tackled by polyketide synthases (PKSs), which are gigantic modular enzymatic assembly lines for natural products. PKSs could be developed for industry to produce chemically difficult to synthesize drugs, but cannot be harnessed until we understand how they work on the molecular level. However, such understanding is missing because we cannot easily investigate large complexes with current structural biology and modeling methods. A key puzzle is how the function of these multicomponent systems emerges from atomic-scale interactions of their parts. Solving this puzzle requires a holistic approach involving measuring and modeling the relevant interacting parts together.
Our goal is to develop a multidisciplinary approach rooted in solid and solution state NMR that will make possible studies of complexes from PKSs. The two main challenges for the NMR of PKSs are increasing sensitivity and resolution. Recent innovations from our lab allow application of solid-state to study large complexes in 2–10 nanomole quantities. Building on this approach, with a protein-antibody complex as a test case, we will develop new NMR methods that will enable a study of structure and motions of domains in complexes. We will probe, for the first time, the structural dynamics of PKSs of enacyloxin and gladiolin, which are antibiotics against life-threatening multidrug resistant hospital-acquired Acinetobacter baumannii infections and tuberculosis. These studies will guide rational engineering of the PKSs to enable synthetic biology approaches to produce new antibiotics.
If successful, this project will go beyond the state of the art by: enabling studies of unknown proteins in large complexes and providing unique insights into novel mechanisms for controlling biosynthesis in PKSs, turning them into truly programmable synthetic biology devices.
Max ERC Funding
1 999 044 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym CONCERT
Project Description of information transfer across macromolecules by concerted conformational changes
Researcher (PI) Xavier Salvatella Giralt
Host Institution (HI) FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Call Details Consolidator Grant (CoG), PE4, ERC-2014-CoG
Summary Signal transduction in biology relies on the transfer of information across biomolecules by concerted conformational changes that cannot currently be characterized experimentally at high resolution. In CONCERT we will develop a method based on the use of nuclear magnetic resonance spectroscopy in solution that will provide very detailed descriptions of such changes by using the information about structural heterogeneity contained in a parameter that is exquisitely sensitive to molecular shape called residual dipolar coupling measured in steric alignment. To show how this new method will allow the study of information transfer we will determine conformational ensembles that will report on the intra and inter-domain concerted conformational changes that activate the androgen receptor, a large allosteric multi-domain protein that regulates the male phenotype and is a therapeutic target for castration resistant prostate cancer, the condition suffered by prostate cancer patients that have become refractory to hormone therapy, the first line of treatment for this disease. To complement the structural information obtained by nuclear magnetic resonance and, especially, measure the rate of information transfer across the androgen receptor we will carry out in a collaborative fashion high precision single molecule Förster resonance energy transfer and fluorescence correlation spectroscopy experiments on AR constructs labelled with fluorescent dyes. In summary we will develop a method that will make it possible to describe some of the most fascinating biological phenomena, such as allostery and signal transduction, and will, in the long term, be an instrument for the discovery of drugs to treat castration resistant prostate cancer, a late stage of prostate cancer that is incurable and kills ca. 70.000 European men every year.
Summary
Signal transduction in biology relies on the transfer of information across biomolecules by concerted conformational changes that cannot currently be characterized experimentally at high resolution. In CONCERT we will develop a method based on the use of nuclear magnetic resonance spectroscopy in solution that will provide very detailed descriptions of such changes by using the information about structural heterogeneity contained in a parameter that is exquisitely sensitive to molecular shape called residual dipolar coupling measured in steric alignment. To show how this new method will allow the study of information transfer we will determine conformational ensembles that will report on the intra and inter-domain concerted conformational changes that activate the androgen receptor, a large allosteric multi-domain protein that regulates the male phenotype and is a therapeutic target for castration resistant prostate cancer, the condition suffered by prostate cancer patients that have become refractory to hormone therapy, the first line of treatment for this disease. To complement the structural information obtained by nuclear magnetic resonance and, especially, measure the rate of information transfer across the androgen receptor we will carry out in a collaborative fashion high precision single molecule Förster resonance energy transfer and fluorescence correlation spectroscopy experiments on AR constructs labelled with fluorescent dyes. In summary we will develop a method that will make it possible to describe some of the most fascinating biological phenomena, such as allostery and signal transduction, and will, in the long term, be an instrument for the discovery of drugs to treat castration resistant prostate cancer, a late stage of prostate cancer that is incurable and kills ca. 70.000 European men every year.
Max ERC Funding
1 950 000 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym CONNECTINGEUROPE
Project Digital Crossings in Europe: Gender, Diaspora and Belonging
Researcher (PI) Sandra Ponzanesi
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Consolidator Grant (CoG), SH5, ERC-2014-CoG
Summary Many immigrants enter Europe both legally and illegally every year. This creates multiple challenges for the Union, including the gender and ethnic segregation of migrant groups, especially women. While it strives for an inclusive and integrated society as envisioned by the EU motto ‘Unity in Diversity’, it is still often perceived more as ‘Fortress Europe.’ This project focuses on the ‘connected migrant’, studying how virtual communities of migrants, or digital diasporas, convey issues of technology, migration, globalisation, alienation and belonging capturing the lives of migrants in their interaction with multiple worlds and media.
More specifically, it will investigate whether digital technologies enhance European integration or foster gender and ethnic segregation, and, if so, how. Using a multi-layered and cutting-edge approach that draws from the humanities, social science and new media studies (i.e. internet studies and mobile media), this research considers: 1. How migration and digital technologies enable digital diasporas (Somali, Turkish, Romanian) and the impact these have on identity, gender and belonging in European urban centres; 2. How these entanglements are connected to and perceived from outside Europe by focusing on transnational ties; and 3. How digital connections create new possibilities for cosmopolitan outlooks, rearticulating Europe’s motto of ‘Unity in Diversity.’
The outcomes of this work will be innovative at three levels. a) Empirically, the project gathers, maps and critically grounds online behaviour by migrant women from a European comparative perspective. b) Methodologically, it breaks new ground by developing new methods of analysis for digital diasporas contributing to the development of ‘postcolonial’ digital humanities. c) Conceptually, it integrates colonial and migrant relations into the idea of Europe, elaborating on the notion of cosmopolitan belonging through virtual connectivity.
Summary
Many immigrants enter Europe both legally and illegally every year. This creates multiple challenges for the Union, including the gender and ethnic segregation of migrant groups, especially women. While it strives for an inclusive and integrated society as envisioned by the EU motto ‘Unity in Diversity’, it is still often perceived more as ‘Fortress Europe.’ This project focuses on the ‘connected migrant’, studying how virtual communities of migrants, or digital diasporas, convey issues of technology, migration, globalisation, alienation and belonging capturing the lives of migrants in their interaction with multiple worlds and media.
More specifically, it will investigate whether digital technologies enhance European integration or foster gender and ethnic segregation, and, if so, how. Using a multi-layered and cutting-edge approach that draws from the humanities, social science and new media studies (i.e. internet studies and mobile media), this research considers: 1. How migration and digital technologies enable digital diasporas (Somali, Turkish, Romanian) and the impact these have on identity, gender and belonging in European urban centres; 2. How these entanglements are connected to and perceived from outside Europe by focusing on transnational ties; and 3. How digital connections create new possibilities for cosmopolitan outlooks, rearticulating Europe’s motto of ‘Unity in Diversity.’
The outcomes of this work will be innovative at three levels. a) Empirically, the project gathers, maps and critically grounds online behaviour by migrant women from a European comparative perspective. b) Methodologically, it breaks new ground by developing new methods of analysis for digital diasporas contributing to the development of ‘postcolonial’ digital humanities. c) Conceptually, it integrates colonial and migrant relations into the idea of Europe, elaborating on the notion of cosmopolitan belonging through virtual connectivity.
Max ERC Funding
1 992 809 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym corr-DFT
Project Improving the accuracy and reliability of electronic structure calculations: New exchange-correlation functionals from a rigorous expansion at infinite coupling strength
Researcher (PI) Paola Gori-Giorgi
Host Institution (HI) STICHTING VU
Call Details Consolidator Grant (CoG), PE4, ERC-2014-CoG
Summary By virtue of its computational efficiency, Kohn-Sham (KS) density functional theory (DFT) is the method of choice for the electronic structure calculations in computational chemistry and solid-state physics. Despite its enormous successes, KS DFT’s predictive power and overall usefulness are still hampered by inadequate approximations for near-degenerate and strongly-correlated systems. Crucial examples are transition metal complexes (key for catalysis), stretched chemical bonds (key to predict chemical reactions), technologically advanced functional materials, and manmade nanostructures.
I aim to address these fundamental issues, by constructing a novel framework for electronic structure calculations at all correlation regimes. This new approach is based on recent formal developments from my group, which reproduce key features of strong correlation within KS DFT, without any artificial symmetry breaking. My results on the exact infinite-coupling-strength expansion of KS DFT will be used to endow that theory with many-body properties from the ground up, thereby removing its intrinsic bias for weak correlation regimes.
This requires novel combinations of ideas from three research communities: chemists and physicists that develop approximations for KS DFT, condensed matter physicists that work on strongly-correlated systems using lattice hamiltonians, and mathematicians working on mass transportation theory. The strong-correlation limit of DFT enables these links by defining a natural framework for extending lattice-based results to the real space continuum. On the other hand, this limit has a mathematical structure formally equivalent to the optimal transport problem of mathematics, enabling adaptation of methods and algorithms.
The new approximations will be implemented with the assistance of an industrial partner and validated on representative benchmark chemical and physical systems.
Summary
By virtue of its computational efficiency, Kohn-Sham (KS) density functional theory (DFT) is the method of choice for the electronic structure calculations in computational chemistry and solid-state physics. Despite its enormous successes, KS DFT’s predictive power and overall usefulness are still hampered by inadequate approximations for near-degenerate and strongly-correlated systems. Crucial examples are transition metal complexes (key for catalysis), stretched chemical bonds (key to predict chemical reactions), technologically advanced functional materials, and manmade nanostructures.
I aim to address these fundamental issues, by constructing a novel framework for electronic structure calculations at all correlation regimes. This new approach is based on recent formal developments from my group, which reproduce key features of strong correlation within KS DFT, without any artificial symmetry breaking. My results on the exact infinite-coupling-strength expansion of KS DFT will be used to endow that theory with many-body properties from the ground up, thereby removing its intrinsic bias for weak correlation regimes.
This requires novel combinations of ideas from three research communities: chemists and physicists that develop approximations for KS DFT, condensed matter physicists that work on strongly-correlated systems using lattice hamiltonians, and mathematicians working on mass transportation theory. The strong-correlation limit of DFT enables these links by defining a natural framework for extending lattice-based results to the real space continuum. On the other hand, this limit has a mathematical structure formally equivalent to the optimal transport problem of mathematics, enabling adaptation of methods and algorithms.
The new approximations will be implemented with the assistance of an industrial partner and validated on representative benchmark chemical and physical systems.
Max ERC Funding
1 999 891 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
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 CrIC
Project Molecular basis of the cross-talk between chronic inflammation and cancer
Researcher (PI) Nadine Laguette
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS6, ERC-2014-STG
Summary Cancer related inflammation (CRI) is a well-established hallmark of cancer. We recently demonstrated that the DNA damage repair SLX4 complex suppresses spontaneous and human immunodeficiency virus (HIV)-dependent pro-inflammatory cytokine production, revealing a role for this DNA repair complex in controlling innate immune responses. Bi-allelic mutations in SLX4 are involved in the onset of Fanconi Anemia (FA), a syndrome characterized, besides heightened cancer susceptibility, by severe defects of the immune system, resulting from increased pro-inflammatory cytokine levels and progressive bone marrow failure. Within this proposal, using SLX4-deficiency as a working model, I aim at investigating the molecular process underlying CRI. Based on our previous observation that the SLX4 complex binds to HIV-derived reverse-transcripts and promotes their degradation, my working hypothesis is that CRI results from the accumulation of endogenous pathological nucleic acids that are recognized by the innate immune system in the absence of SLX4. The present project should unveil the relationship between repression of pro-inflammatory cytokine production by proteins involved in DNA repair, DNA damage, and CRI, thereby opening unforeseen perspectives in the treatment of cancer patients.
Summary
Cancer related inflammation (CRI) is a well-established hallmark of cancer. We recently demonstrated that the DNA damage repair SLX4 complex suppresses spontaneous and human immunodeficiency virus (HIV)-dependent pro-inflammatory cytokine production, revealing a role for this DNA repair complex in controlling innate immune responses. Bi-allelic mutations in SLX4 are involved in the onset of Fanconi Anemia (FA), a syndrome characterized, besides heightened cancer susceptibility, by severe defects of the immune system, resulting from increased pro-inflammatory cytokine levels and progressive bone marrow failure. Within this proposal, using SLX4-deficiency as a working model, I aim at investigating the molecular process underlying CRI. Based on our previous observation that the SLX4 complex binds to HIV-derived reverse-transcripts and promotes their degradation, my working hypothesis is that CRI results from the accumulation of endogenous pathological nucleic acids that are recognized by the innate immune system in the absence of SLX4. The present project should unveil the relationship between repression of pro-inflammatory cytokine production by proteins involved in DNA repair, DNA damage, and CRI, thereby opening unforeseen perspectives in the treatment of cancer patients.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym CRYVISIL
Project Crystalline and vitreous silica films and their interconversion
Researcher (PI) Hans-Joachim Freund
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Advanced Grant (AdG), PE4, ERC-2014-ADG
Summary Silicon is the most abundant element in the earth’s crust. Its oxide, silica (SiO2) is the basis for most minerals of the earth’s crust, and also for a number of technological applications ranging from window glass, via electronics to catalysis. The structure of crystalline materials such as quartz or silica-based minerals is well understood due to the application of scattering techniques such as x-ray or neutron diffraction, for example, which allow accurate structure determinations. Silica, however, also forms glasses, which are amorphous or vitreous. Its structure is not well understood. In fact, diffraction techniques have only been able to deliver pair correlation functions, which reveal the density of a material around a given atom, but do not allow a detailed reconstruction of the atomic structure as in the case of crystalline materials. Until recently, a real space image of a silica glass with atomic resolution had not been recorded. Using scanning probe techniques applied to a thin silica film grown atomically flat on a metal substrate, it has been possible to reveal, for the first time, an atomically resolved image of vitreous silica. Both, a crystalline as well as a vitreous phase have been imaged. With this system, it is now possible to address the transition from a vitreous state to a crystal-line in real space by developing a scanning probe microscope that allows the study of its structure over a wide range of temperatures ranging from cryogenic temperatures to 1500 K. It is the purpose of this grant application to build such a device and apply it to the crystal-glass transition and the study of vibrational properties. This instrument may also be used to address a number of scientific problems related to other glass-formers, such as borates and the influence of silica modifications by atom doping, for example.
Summary
Silicon is the most abundant element in the earth’s crust. Its oxide, silica (SiO2) is the basis for most minerals of the earth’s crust, and also for a number of technological applications ranging from window glass, via electronics to catalysis. The structure of crystalline materials such as quartz or silica-based minerals is well understood due to the application of scattering techniques such as x-ray or neutron diffraction, for example, which allow accurate structure determinations. Silica, however, also forms glasses, which are amorphous or vitreous. Its structure is not well understood. In fact, diffraction techniques have only been able to deliver pair correlation functions, which reveal the density of a material around a given atom, but do not allow a detailed reconstruction of the atomic structure as in the case of crystalline materials. Until recently, a real space image of a silica glass with atomic resolution had not been recorded. Using scanning probe techniques applied to a thin silica film grown atomically flat on a metal substrate, it has been possible to reveal, for the first time, an atomically resolved image of vitreous silica. Both, a crystalline as well as a vitreous phase have been imaged. With this system, it is now possible to address the transition from a vitreous state to a crystal-line in real space by developing a scanning probe microscope that allows the study of its structure over a wide range of temperatures ranging from cryogenic temperatures to 1500 K. It is the purpose of this grant application to build such a device and apply it to the crystal-glass transition and the study of vibrational properties. This instrument may also be used to address a number of scientific problems related to other glass-formers, such as borates and the influence of silica modifications by atom doping, for example.
Max ERC Funding
2 484 375 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym Cu4Energy
Project Biomimetic Copper Complexes for Energy Conversion Reactions
Researcher (PI) Dennis Gerardus Hendrikus Hetterscheid
Host Institution (HI) UNIVERSITEIT LEIDEN
Call Details Starting Grant (StG), PE4, ERC-2014-STG
Summary Water oxidation (WO) and oxygen reduction (OR) are crucial reactions to produce and to consume solar fuels. It is important that WO and OR occur with very high catalytic rates with only a very small thermodynamic driving force (i.e. a small overpotential). In these terms, natural catalysts perform significantly better than the artificial systems. Especially the copper enzyme Laccase operates fast at a low overpotential. In principle one could use the same design principles used in the enzymatic systems to produce artificial catalysts for OR and WO. It is envisioned that for the most ideal OR and WO catalysts:
1. All redox reactions within the catalytic cycle should occur as close as possible to the thermodynamic potential where OR and WO become accessible.
2. Equilibria that are not coupled to redox reactions need to be biased for product formation.
3. Proton shuttles are necessary to manage proton transfer concerted with electron-transfer and electron-transfer coupled to O–O bond cleavage or O–O bond formation.
In this proposal molecular copper catalysts for OR and WO are studied by means of a combined electrochemical and computational approach, taking in account the design principles above. Experiments will be carried out wherein the structure of the catalyst is linked to the observed catalytic activity and the potential energy surface of the catalytic cycle. The proposal is in particular focused on the rate-determining step of the catalytic reaction, as improvements here will directly lead to enhanced catalytic rates. A functional model system of Laccase will be designed to study the rate limiting proton-and-electron-coupled O–O bond scission reaction, which is the rate limiting step in OR by Laccase.
The aim of the proposal is to significantly increase of fundamental understanding of the design principles for molecular OR and WO catalysts and to deliver new and very active molecular copper catalysts for OR and WO at the end of the project.
Summary
Water oxidation (WO) and oxygen reduction (OR) are crucial reactions to produce and to consume solar fuels. It is important that WO and OR occur with very high catalytic rates with only a very small thermodynamic driving force (i.e. a small overpotential). In these terms, natural catalysts perform significantly better than the artificial systems. Especially the copper enzyme Laccase operates fast at a low overpotential. In principle one could use the same design principles used in the enzymatic systems to produce artificial catalysts for OR and WO. It is envisioned that for the most ideal OR and WO catalysts:
1. All redox reactions within the catalytic cycle should occur as close as possible to the thermodynamic potential where OR and WO become accessible.
2. Equilibria that are not coupled to redox reactions need to be biased for product formation.
3. Proton shuttles are necessary to manage proton transfer concerted with electron-transfer and electron-transfer coupled to O–O bond cleavage or O–O bond formation.
In this proposal molecular copper catalysts for OR and WO are studied by means of a combined electrochemical and computational approach, taking in account the design principles above. Experiments will be carried out wherein the structure of the catalyst is linked to the observed catalytic activity and the potential energy surface of the catalytic cycle. The proposal is in particular focused on the rate-determining step of the catalytic reaction, as improvements here will directly lead to enhanced catalytic rates. A functional model system of Laccase will be designed to study the rate limiting proton-and-electron-coupled O–O bond scission reaction, which is the rate limiting step in OR by Laccase.
The aim of the proposal is to significantly increase of fundamental understanding of the design principles for molecular OR and WO catalysts and to deliver new and very active molecular copper catalysts for OR and WO at the end of the project.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
