Project acronym AsthmaVir
Project The roles of innate lymphoid cells and rhinovirus in asthma exacerbations
Researcher (PI) Hergen Spits
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.
Summary
Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.
Max ERC Funding
2 499 593 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym CALCEAM
Project Cooperative Acceptor Ligands for Catalysis with Earth-Abundant Metals
Researcher (PI) Marc-Etienne Moret
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Starting Grant (StG), PE5, ERC-2016-STG
Summary Homogeneous catalysis is of prime importance for the selective synthesis of high added value chemicals. Many of the currently available catalysts rely on noble metals (Ru, Os, Rh, Ir, Pd, Pt), which suffer from a high toxicity and environmental impact in addition to their high cost, calling for the development of new systems based on first-row transition metals (Mn, Fe, Co, Ni, Cu). The historical paradigm for catalyst design, i.e. one or more donor ligands giving electron density to stabilize a metal center and tune its reactivity, is currently being challenged by the development of acceptor ligands that mostly withdraw electron density from the metal center upon binding. In the last decade, such ligands – mostly based on boron and heavier main-group elements – have evolved from a structural curiosity to a powerful tool in designing new reactive units for homogeneous catalysis.
I will develop a novel class of ligands that use C=E (E=O, S, NR) multiple bonds anchored in close proximity to the metal by phosphine tethers. The electrophilic C=E multiple bond is designed to act as an acceptor moiety that adapts its binding mode to the electronic structure of reactive intermediates with the unique additional possibility of involving the lone pairs on heteroelement E in cooperative reactivity. Building on preliminary results showing that a C=O bond can function as a hemilabile ligand in a catalytic cycle, I will undertake a systematic, experimental and theoretical investigation of the structure and reactivity of M–C–E three membered rings formed by side-on coordination of C=E bonds to a first-row metal. Their ability to facilitate multi-electron transformations (oxidative addition, atom/group transfer reactions) will be investigated. In particular, hemilability of the C=E bond is expected to facilitate challenging C–C bond forming reactions mediated by Fe and Ni. This approach will demonstrate a new conceptual tool for the design of efficient base-metal catalysts.
Summary
Homogeneous catalysis is of prime importance for the selective synthesis of high added value chemicals. Many of the currently available catalysts rely on noble metals (Ru, Os, Rh, Ir, Pd, Pt), which suffer from a high toxicity and environmental impact in addition to their high cost, calling for the development of new systems based on first-row transition metals (Mn, Fe, Co, Ni, Cu). The historical paradigm for catalyst design, i.e. one or more donor ligands giving electron density to stabilize a metal center and tune its reactivity, is currently being challenged by the development of acceptor ligands that mostly withdraw electron density from the metal center upon binding. In the last decade, such ligands – mostly based on boron and heavier main-group elements – have evolved from a structural curiosity to a powerful tool in designing new reactive units for homogeneous catalysis.
I will develop a novel class of ligands that use C=E (E=O, S, NR) multiple bonds anchored in close proximity to the metal by phosphine tethers. The electrophilic C=E multiple bond is designed to act as an acceptor moiety that adapts its binding mode to the electronic structure of reactive intermediates with the unique additional possibility of involving the lone pairs on heteroelement E in cooperative reactivity. Building on preliminary results showing that a C=O bond can function as a hemilabile ligand in a catalytic cycle, I will undertake a systematic, experimental and theoretical investigation of the structure and reactivity of M–C–E three membered rings formed by side-on coordination of C=E bonds to a first-row metal. Their ability to facilitate multi-electron transformations (oxidative addition, atom/group transfer reactions) will be investigated. In particular, hemilability of the C=E bond is expected to facilitate challenging C–C bond forming reactions mediated by Fe and Ni. This approach will demonstrate a new conceptual tool for the design of efficient base-metal catalysts.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym DIRECTDELIVERY
Project Controlled fusion of liposomes and cells: a new pathway for direct drug delivery
Researcher (PI) Alexander Kros
Host Institution (HI) UNIVERSITEIT LEIDEN
Call Details Starting Grant (StG), PE5, ERC-2009-StG
Summary Inspired by the natural membrane fusion machinery, the aim of this research line is to design a synthetic analogue in order to: 1) Understand the process of the peptide-controlled fusion of two membranes at the atomic, molecular and mesoscopic level. 2) Developing a new generic method for the controlled delivery of any (bio)molecule directly into the cytoplasm of a cell thereby omitting endocytotic pathways. This new paradigm opens many new applications in the fields of functional proteomics, genomics and siRNA-technology. Studying, imitating and dissecting processes from Nature and applying the underlying principles has been highly successful approach for many years and opened up new lines of research and applications which were previously unimagineable. Examples are the aptamer and antibody technology. I will use this learning-from-Nature approach to design synthetic analogues of the membrane fusion machinery to create new functions and/or applications which are currently non-existent. Membrane fusion is a key process in all living cells as it facilitates the transport of molecules between and within cells. A primary mechanism by which molecules are conveyed to the appropriate location is to encapsulate them in liposomes that deliver the cargo by fusing with the lipid membrane of the target cell or compartment. I will use synthetic analogues of the membrane fusion machinery to induce the controlled fusion between 1) specific liposomes and 2) liposome-cell. This approach opens up a new paradigm for the direct introduction of (bio)molecule into the cytoplasm of living cells omitting the endocytotic pathways for which the applications are only limited by one s imagination.
Summary
Inspired by the natural membrane fusion machinery, the aim of this research line is to design a synthetic analogue in order to: 1) Understand the process of the peptide-controlled fusion of two membranes at the atomic, molecular and mesoscopic level. 2) Developing a new generic method for the controlled delivery of any (bio)molecule directly into the cytoplasm of a cell thereby omitting endocytotic pathways. This new paradigm opens many new applications in the fields of functional proteomics, genomics and siRNA-technology. Studying, imitating and dissecting processes from Nature and applying the underlying principles has been highly successful approach for many years and opened up new lines of research and applications which were previously unimagineable. Examples are the aptamer and antibody technology. I will use this learning-from-Nature approach to design synthetic analogues of the membrane fusion machinery to create new functions and/or applications which are currently non-existent. Membrane fusion is a key process in all living cells as it facilitates the transport of molecules between and within cells. A primary mechanism by which molecules are conveyed to the appropriate location is to encapsulate them in liposomes that deliver the cargo by fusing with the lipid membrane of the target cell or compartment. I will use synthetic analogues of the membrane fusion machinery to induce the controlled fusion between 1) specific liposomes and 2) liposome-cell. This approach opens up a new paradigm for the direct introduction of (bio)molecule into the cytoplasm of living cells omitting the endocytotic pathways for which the applications are only limited by one s imagination.
Max ERC Funding
1 392 262 €
Duration
Start date: 2009-10-01, End date: 2014-09-30
Project acronym ENCOPOL
Project Encoding information into polymers
Researcher (PI) Roeland NOLTE
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Advanced Grant (AdG), PE5, ERC-2016-ADG
Summary The amount of information trafficking internet nowadays is enormous and will increase further in the near future. It can be expected that in the next decennia the current technologies to store and process data will no longer suffice and that other strategies to handle information have to be developed. One approach is to explore chemical routes, which nature has also followed during evolution: our brain can store and handle very large amounts of data and process them in a way silicon-based computers cannot do. Although brain-like chemical computers are still far beyond reach, it is of interest to explore how atom and molecule-based systems that can write, read, and store information might be designed and constructed. In this proposal we aim at developing a new technology to write, store, and read information, i.e. on a single polymer chain with the help of a molecular machine that is inspired by the hypothetical device (Turing machine) proposed by the British mathematician Alan Turing in 1936 as the general basis for the operation of a computer. The molecular machine is composed of a chiral catalytic cage compound (tape-head) that moves unidirectionally along a chiral polymer chain (tape) while writing a binary code in the form of (R)- (symbol 0) and (S)- (symbol 1) epoxide functions. This writing process is controlled by light or electrons. The information on the tape will be read by single molecule spectroscopy using a reading device that is also based on a chiral cage compound. It moves along the encoded tape and produces left- or right-handed polarized fluorescence light depending on whether it reads a 0 (R-epoxide) or 1 (S-epoxide). As part of this project we will also make the first steps towards chemical computing by arranging two circular tapes (one left-handed and the other one right-handed), each with an attached writing head, in a teller set-up, which allows them to be addressed separately with light according to a set of instructions (Minsky machine).
Summary
The amount of information trafficking internet nowadays is enormous and will increase further in the near future. It can be expected that in the next decennia the current technologies to store and process data will no longer suffice and that other strategies to handle information have to be developed. One approach is to explore chemical routes, which nature has also followed during evolution: our brain can store and handle very large amounts of data and process them in a way silicon-based computers cannot do. Although brain-like chemical computers are still far beyond reach, it is of interest to explore how atom and molecule-based systems that can write, read, and store information might be designed and constructed. In this proposal we aim at developing a new technology to write, store, and read information, i.e. on a single polymer chain with the help of a molecular machine that is inspired by the hypothetical device (Turing machine) proposed by the British mathematician Alan Turing in 1936 as the general basis for the operation of a computer. The molecular machine is composed of a chiral catalytic cage compound (tape-head) that moves unidirectionally along a chiral polymer chain (tape) while writing a binary code in the form of (R)- (symbol 0) and (S)- (symbol 1) epoxide functions. This writing process is controlled by light or electrons. The information on the tape will be read by single molecule spectroscopy using a reading device that is also based on a chiral cage compound. It moves along the encoded tape and produces left- or right-handed polarized fluorescence light depending on whether it reads a 0 (R-epoxide) or 1 (S-epoxide). As part of this project we will also make the first steps towards chemical computing by arranging two circular tapes (one left-handed and the other one right-handed), each with an attached writing head, in a teller set-up, which allows them to be addressed separately with light according to a set of instructions (Minsky machine).
Max ERC Funding
2 498 076 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
Project acronym GLYCONTROL
Project Understanding and Controlling Glycosylation Reactions
Researcher (PI) Jeroen Dirk Cornelis CODÉE
Host Institution (HI) UNIVERSITEIT LEIDEN
Call Details Consolidator Grant (CoG), PE5, ERC-2016-COG
Summary This proposal aims to understand and control glycosylation reactions. In a glycosylation reaction a “donor” glycoside and an “acceptor” (the nucleophile) are united to form an oligosaccharide. Although it is the central reaction in carbohydrate chemistry, our understanding of this reaction, in terms of stereoselectivity and productivity is still limited. The structural variation in the building blocks leads to a complex continuum of SN2-SN1 mechanisms that operates and it is currently impossible to predict where in the continuum the reaction exactly takes place. This proposal provides fundamental insight into the outcome of glycosylations by studying both the activated donor glycoside and the acceptor nucleophile. Activation of a donor glycoside leads to different reactive intermediates, covalent anomeric species (most often triflates) and oxocarbenium ion-like species. The relative reactivity of these species is quantified to generate novel reactivity charts. The covalent species are studied by innovative competition experiments, kinetic studies and NMR spectroscopy. The (fleeting) oxocarbenium ion-like intermediates are probed by a computational approach and by “super-acid NMR” studies in which stable glycosyl cations are generated and studied in super-acid media. The reactivity of glycosyl acceptors is systematically studied in a set of SN2 or SN1-type glycosylations. Using kinetic studies and competition reactions charts of acceptor nucleophilicity are compiled. The reactivity of the donors and acceptors is matched using a family of tailor made “reactivity modulators”, spanning a broad reactivity window bridging the reactivity gap between the building blocks leading to predictable glycosylations. The developed methodology is employed in automated solid phase syntheses of libraries of oligosaccharides featuring multiple cis-glycosidic linkages. The proposal is a major step forward in the development of a general glycosylation procedure.
Summary
This proposal aims to understand and control glycosylation reactions. In a glycosylation reaction a “donor” glycoside and an “acceptor” (the nucleophile) are united to form an oligosaccharide. Although it is the central reaction in carbohydrate chemistry, our understanding of this reaction, in terms of stereoselectivity and productivity is still limited. The structural variation in the building blocks leads to a complex continuum of SN2-SN1 mechanisms that operates and it is currently impossible to predict where in the continuum the reaction exactly takes place. This proposal provides fundamental insight into the outcome of glycosylations by studying both the activated donor glycoside and the acceptor nucleophile. Activation of a donor glycoside leads to different reactive intermediates, covalent anomeric species (most often triflates) and oxocarbenium ion-like species. The relative reactivity of these species is quantified to generate novel reactivity charts. The covalent species are studied by innovative competition experiments, kinetic studies and NMR spectroscopy. The (fleeting) oxocarbenium ion-like intermediates are probed by a computational approach and by “super-acid NMR” studies in which stable glycosyl cations are generated and studied in super-acid media. The reactivity of glycosyl acceptors is systematically studied in a set of SN2 or SN1-type glycosylations. Using kinetic studies and competition reactions charts of acceptor nucleophilicity are compiled. The reactivity of the donors and acceptors is matched using a family of tailor made “reactivity modulators”, spanning a broad reactivity window bridging the reactivity gap between the building blocks leading to predictable glycosylations. The developed methodology is employed in automated solid phase syntheses of libraries of oligosaccharides featuring multiple cis-glycosidic linkages. The proposal is a major step forward in the development of a general glycosylation procedure.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym HELENA
Project Heavy-Element Nanowires
Researcher (PI) Erik Petrus Antonius Maria Bakkers
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Consolidator Grant (CoG), PE5, ERC-2013-CoG
Summary "Nanowires are a powerful and versatile platform for a broad range of applications. Among all semiconductors, the heavy-elements materials exhibit the highest electron mobilities, strongest spin-orbit coupling and best thermoelectric properties. Nonetheless, heavy-element nanowires have been unexplored. With this proposal we unite the unique advantages of design freedom of nanowires with the special properties of heavy-element semiconductors. We specifically reveal the potential of heavy-element nanowires in the areas of thermoelectrics, and topological insulators. Using our strong track record in this area, we will pioneer the synthesis of this new class of materials and study their intrinsic materials properties. Starting point are nanowires of InSb and PbTe grown using the vapor-liquid-solid mechanism. Our aims are 1) to obtain highest-possible electron mobilities for these bottom-up fabricated materials by investigating new materials combinations of different semiconductor classes to effectively passivate the nanowire surface and we will eliminate impurities; 2) to investigate and optimize thermoelectric properties by developing advanced superlattice and core/shell nanowire structures where electronic and phononic transport is decoupled; and 3) to fabricate high-quality planar nanowire networks, which enable four-point electronic transport measurements and allow precisely determining carrier concentration and mobility. Besides the fundamentally interesting materials science, the heavy-element nanowires will have major impact on the fields of renewable energy, new (quasi) particles and quantum information processing. Recently, the first signatures of Majorana fermions have been observed in our InSb nanowires. With the proposed nanowire networks the special properties of this recently discovered particle can be tested for the first time."
Summary
"Nanowires are a powerful and versatile platform for a broad range of applications. Among all semiconductors, the heavy-elements materials exhibit the highest electron mobilities, strongest spin-orbit coupling and best thermoelectric properties. Nonetheless, heavy-element nanowires have been unexplored. With this proposal we unite the unique advantages of design freedom of nanowires with the special properties of heavy-element semiconductors. We specifically reveal the potential of heavy-element nanowires in the areas of thermoelectrics, and topological insulators. Using our strong track record in this area, we will pioneer the synthesis of this new class of materials and study their intrinsic materials properties. Starting point are nanowires of InSb and PbTe grown using the vapor-liquid-solid mechanism. Our aims are 1) to obtain highest-possible electron mobilities for these bottom-up fabricated materials by investigating new materials combinations of different semiconductor classes to effectively passivate the nanowire surface and we will eliminate impurities; 2) to investigate and optimize thermoelectric properties by developing advanced superlattice and core/shell nanowire structures where electronic and phononic transport is decoupled; and 3) to fabricate high-quality planar nanowire networks, which enable four-point electronic transport measurements and allow precisely determining carrier concentration and mobility. Besides the fundamentally interesting materials science, the heavy-element nanowires will have major impact on the fields of renewable energy, new (quasi) particles and quantum information processing. Recently, the first signatures of Majorana fermions have been observed in our InSb nanowires. With the proposed nanowire networks the special properties of this recently discovered particle can be tested for the first time."
Max ERC Funding
2 698 447 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
Project acronym InflaMet
Project Mechanistic insights into the impact of tumor-associated neutrophils on metastatic breast cancer
Researcher (PI) Karina Elizabeth De Visser
Host Institution (HI) STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Call Details Consolidator Grant (CoG), LS6, ERC-2013-CoG
Summary Metastatic disease is still largely unexplored, poorly understood and incurable. Accumulating evidence indicates that cells and mediators of the immune system can facilitate metastasis. Neutrophil accumulation in cancer patients has been associated with metastasis formation. In mouse tumor models, neutrophils have been reported to be pro- or anti- metastatic, but the underlying mechanisms involved in either function remain largely elusive. This proposal outlines a research program aimed at resolving the pro-metastatic role of neutrophils in breast cancer, as our preliminary data indicate that neutrophils proactively mediate breast cancer metastasis. Using a state-of-the art spontaneous breast cancer metastasis mouse model, we will mechanistically study how neutrophils facilitate metastasis formation and how mammary tumors provoke the metastasis-facilitating function of neutrophils. Building upon my previous studies and our current data, we will focus on the unexplored crosstalk between the adaptive immune system and neutrophils in facilitating spontaneous metastatic disease. These crucial questions will be addressed by undertaking a multidisciplinary approach, involving sophisticated mouse models for metastatic breast cancer, RNA sequencing on tumor-associated neutrophil populations, state-of-the-art mouse engineering, intravital imaging and in vivo neutrophil manipulations. Moreover, we will validate our findings from the mouse metastasis model in human breast cancer samples. We will determine the metastasis predicting power of the identified murine pro-metastatic neutrophil-specific pathways by immunohistochemistry and multi-parameter immunofluorescence on breast cancer samples and blood of untreated patients of which clinical follow-up is available. Thus, we will identify novel molecular pathways that can be targeted to selectively inhibit the pro-metastatic activity of the immune system.
Summary
Metastatic disease is still largely unexplored, poorly understood and incurable. Accumulating evidence indicates that cells and mediators of the immune system can facilitate metastasis. Neutrophil accumulation in cancer patients has been associated with metastasis formation. In mouse tumor models, neutrophils have been reported to be pro- or anti- metastatic, but the underlying mechanisms involved in either function remain largely elusive. This proposal outlines a research program aimed at resolving the pro-metastatic role of neutrophils in breast cancer, as our preliminary data indicate that neutrophils proactively mediate breast cancer metastasis. Using a state-of-the art spontaneous breast cancer metastasis mouse model, we will mechanistically study how neutrophils facilitate metastasis formation and how mammary tumors provoke the metastasis-facilitating function of neutrophils. Building upon my previous studies and our current data, we will focus on the unexplored crosstalk between the adaptive immune system and neutrophils in facilitating spontaneous metastatic disease. These crucial questions will be addressed by undertaking a multidisciplinary approach, involving sophisticated mouse models for metastatic breast cancer, RNA sequencing on tumor-associated neutrophil populations, state-of-the-art mouse engineering, intravital imaging and in vivo neutrophil manipulations. Moreover, we will validate our findings from the mouse metastasis model in human breast cancer samples. We will determine the metastasis predicting power of the identified murine pro-metastatic neutrophil-specific pathways by immunohistochemistry and multi-parameter immunofluorescence on breast cancer samples and blood of untreated patients of which clinical follow-up is available. Thus, we will identify novel molecular pathways that can be targeted to selectively inhibit the pro-metastatic activity of the immune system.
Max ERC Funding
1 999 360 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym INTERCOM
Project Communication between immune cells via release of RNA-carrying vesicles: Lessons from viruses
Researcher (PI) Esther Neline Marielle Nolte
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Starting Grant (StG), LS6, ERC-2013-StG
Summary "Communication between immune cells is crucial for regulating the magnitude and quality of immune responses. A newly uncovered means of intercellular communication involves transfer of small cell-derived vesicles. I recently discovered that vesicles released by immune cells are enriched for small noncoding RNAs, which may act as regulatory RNAs that can influence gene expression in vesicle-targeted cells. Furthermore, remarkable parallels emerged between RNAs abundantly present in cell-derived vesicles and a group of host RNAs specifically incorporated into retroviruses. These shared RNAs may underlie the formation or function of both cell-derived vesicles and retroviruses. Until now, mechanisms behind selective incorporation of small RNAs into cell-derived vesicles and their function in vesicle-targeted cells are poorly understood.
Aim of INTERCOM: To resolve how the exchange of small RNAs via cell-derived vesicles contributes to intercellular communication between immune cells. Key objectives: 1. To determine the diversity and plasticity of the RNA content of vesicle subpopulations released by immune cells. 2. To explain functional differences between immune cell vesicle populations based on their RNA contents. 3. To determine the function of structural RNAs shared by immune cell-derived vesicles and retroviruses.
Tools in virology research will be used in combination with several high-end technologies, which were uniquely adapted in my lab for vesicle-related research. These include a high-resolution flow cytometric method suited to analyze individual nano-sized vesicles, RNA deep sequencing with previously developed data analysis methods, and super-resolution microscopic imaging.
The proposed work advances our understanding of communication processes in the immune system. This knowledge can be applied in defining vesicle RNA-based biomarkers for immune-related diseases and in designing genetically engineered cell-derived vesicles for therapeutic application."
Summary
"Communication between immune cells is crucial for regulating the magnitude and quality of immune responses. A newly uncovered means of intercellular communication involves transfer of small cell-derived vesicles. I recently discovered that vesicles released by immune cells are enriched for small noncoding RNAs, which may act as regulatory RNAs that can influence gene expression in vesicle-targeted cells. Furthermore, remarkable parallels emerged between RNAs abundantly present in cell-derived vesicles and a group of host RNAs specifically incorporated into retroviruses. These shared RNAs may underlie the formation or function of both cell-derived vesicles and retroviruses. Until now, mechanisms behind selective incorporation of small RNAs into cell-derived vesicles and their function in vesicle-targeted cells are poorly understood.
Aim of INTERCOM: To resolve how the exchange of small RNAs via cell-derived vesicles contributes to intercellular communication between immune cells. Key objectives: 1. To determine the diversity and plasticity of the RNA content of vesicle subpopulations released by immune cells. 2. To explain functional differences between immune cell vesicle populations based on their RNA contents. 3. To determine the function of structural RNAs shared by immune cell-derived vesicles and retroviruses.
Tools in virology research will be used in combination with several high-end technologies, which were uniquely adapted in my lab for vesicle-related research. These include a high-resolution flow cytometric method suited to analyze individual nano-sized vesicles, RNA deep sequencing with previously developed data analysis methods, and super-resolution microscopic imaging.
The proposed work advances our understanding of communication processes in the immune system. This knowledge can be applied in defining vesicle RNA-based biomarkers for immune-related diseases and in designing genetically engineered cell-derived vesicles for therapeutic application."
Max ERC Funding
1 499 806 €
Duration
Start date: 2013-11-01, End date: 2018-10-31
Project acronym MHC CLASS II-OMICS
Project Towards understanding and manipulation of MHC class II antigen presentation
Researcher (PI) Jacobus Jozef Cornelis Neefjes
Host Institution (HI) STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Call Details Advanced Grant (AdG), LS6, ERC-2009-AdG
Summary MHC class II molecules are crucial for specific immune responses. In a complicated series of cell biological events, they catch a peptide in the endosomal route for presentation at the plasma membrane to the immune system. At present some 20 factors have been identified as involved in the process of MHC class II antigen presentation that are potential targets for manipulating these responses as MHC class II molecules are involved in most auto-immune diseases. Defining further targets for manipulating MHC class II responses would have implications for various disease states when these can be inhibited by chemical compounds or biologicals. We have performed a genome-wide FACS-based siRNA screen for molecules affecting MHC class II expression and peptide loading. After 100.000 individual 2-color FACS analyses, we identified 276 proteins that can be functionally sub-clustered for expression and for cell biological effects. We now propose to study the cell biology of these 276 hits to elucidate the molecular and cell biological mechanisms of MHC class II antigen presentation (the MHC class II-ome). As a first step, the 276 hits are sub-clustered for effects on MHC class II transcription or cell biology. These sub-clusters may correspond to networks. We propose to validate and extend these networks by experiments by a team of scientists concentrating on the various aspects of the cell biology of MHC class II antigen presentation. A parallel chemical compound screen will be performed to identify compounds affecting MHC class II antigen presentation. By cross-correlating the biological phenotypes of compounds with those of siRNA silencing, novel target-lead combinations will be defined by reciprocal chemical genetics. Our experiments should result in a global understanding of MHC class II antigen presentation. In addition, it should reveal target-lead combinations for manipulation of MHC class II antigen presentation in infection, auto-immune disease and transplantation.
Summary
MHC class II molecules are crucial for specific immune responses. In a complicated series of cell biological events, they catch a peptide in the endosomal route for presentation at the plasma membrane to the immune system. At present some 20 factors have been identified as involved in the process of MHC class II antigen presentation that are potential targets for manipulating these responses as MHC class II molecules are involved in most auto-immune diseases. Defining further targets for manipulating MHC class II responses would have implications for various disease states when these can be inhibited by chemical compounds or biologicals. We have performed a genome-wide FACS-based siRNA screen for molecules affecting MHC class II expression and peptide loading. After 100.000 individual 2-color FACS analyses, we identified 276 proteins that can be functionally sub-clustered for expression and for cell biological effects. We now propose to study the cell biology of these 276 hits to elucidate the molecular and cell biological mechanisms of MHC class II antigen presentation (the MHC class II-ome). As a first step, the 276 hits are sub-clustered for effects on MHC class II transcription or cell biology. These sub-clusters may correspond to networks. We propose to validate and extend these networks by experiments by a team of scientists concentrating on the various aspects of the cell biology of MHC class II antigen presentation. A parallel chemical compound screen will be performed to identify compounds affecting MHC class II antigen presentation. By cross-correlating the biological phenotypes of compounds with those of siRNA silencing, novel target-lead combinations will be defined by reciprocal chemical genetics. Our experiments should result in a global understanding of MHC class II antigen presentation. In addition, it should reveal target-lead combinations for manipulation of MHC class II antigen presentation in infection, auto-immune disease and transplantation.
Max ERC Funding
2 112 300 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym NANOENABLEDPV
Project Novel Photovoltaics Enabled by Nanoscience
Researcher (PI) Erik Christian Garnett
Host Institution (HI) STICHTING NEDERLANDSE WETENSCHAPPELIJK ONDERZOEK INSTITUTEN
Call Details Starting Grant (StG), PE5, ERC-2013-StG
Summary The “NanoEnabledPV” research program will exploit the fundamental benefits of nanomaterials and address their challenges to make low-cost solar cells a reality. NanoEnabledPV contains three focus areas necessary to reach our goal:
1) “Nano surface doping” – surface-controlled nanomaterial properties. We will explore using charged surface oxides and surface ligands with dipole moments as a novel doping mechanism. We will make the first nanowire solar cell using a surface “p-n” junction. The lessons learned from single nanowire studies will be extended to make large-scale, high efficiency metal-insulator-semiconductor solar cells.
2) “Solar highways” – metal nanowire core-semiconductor shell photovoltaics. We will examine the optical and electrical properties of silver and copper nanowires coated with various semiconductor shells for the first time. This novel device structure can achieve complete absorption using 10 times thinner semiconductor layers compared to standard thin-film structures and also enables facile charge extraction via the metal core.
3) “Nanophotography” – hierarchical synthesis and assembly based on optical resonances in nanostructures. We will develop a new type of mask-free photolithography in solution with resolution far below the diffraction limit. This will enable rational, large-scale synthesis of ordered hierarchical structures that can be assembled into complex 3-D networks.
Together, these programs that sit at the intersection of physics, chemistry, materials science and engineering will provide the active light-absorbing materials needed for next generation solar energy conversion schemes, a deep understanding of how they work at the nanoscale and methods for integrating them into macroscale devices. We are requesting 1.5 Million Euros over a period of 5 years that will be used to hire 2 PhD students, 2 postdoctoral researchers and buy the equipment needed to build a unique nanowire solar cell fabrication and analysis lab.
Summary
The “NanoEnabledPV” research program will exploit the fundamental benefits of nanomaterials and address their challenges to make low-cost solar cells a reality. NanoEnabledPV contains three focus areas necessary to reach our goal:
1) “Nano surface doping” – surface-controlled nanomaterial properties. We will explore using charged surface oxides and surface ligands with dipole moments as a novel doping mechanism. We will make the first nanowire solar cell using a surface “p-n” junction. The lessons learned from single nanowire studies will be extended to make large-scale, high efficiency metal-insulator-semiconductor solar cells.
2) “Solar highways” – metal nanowire core-semiconductor shell photovoltaics. We will examine the optical and electrical properties of silver and copper nanowires coated with various semiconductor shells for the first time. This novel device structure can achieve complete absorption using 10 times thinner semiconductor layers compared to standard thin-film structures and also enables facile charge extraction via the metal core.
3) “Nanophotography” – hierarchical synthesis and assembly based on optical resonances in nanostructures. We will develop a new type of mask-free photolithography in solution with resolution far below the diffraction limit. This will enable rational, large-scale synthesis of ordered hierarchical structures that can be assembled into complex 3-D networks.
Together, these programs that sit at the intersection of physics, chemistry, materials science and engineering will provide the active light-absorbing materials needed for next generation solar energy conversion schemes, a deep understanding of how they work at the nanoscale and methods for integrating them into macroscale devices. We are requesting 1.5 Million Euros over a period of 5 years that will be used to hire 2 PhD students, 2 postdoctoral researchers and buy the equipment needed to build a unique nanowire solar cell fabrication and analysis lab.
Max ERC Funding
1 499 310 €
Duration
Start date: 2013-08-01, End date: 2018-07-31