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 CANCER INVASION
Project Deciphering and targeting the invasive nature of Diffuse Intrinsic Pontine Glioma
Researcher (PI) Anne RIOS
Host Institution (HI) PRINSES MAXIMA CENTRUM VOOR KINDERONCOLOGIE BV
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary Introduction: The ability of a cancer cell to invade into the surrounding tissue is the main feature of malignant cancer progression. Diffuse Intrinsic Pontine Glioma (DIPG) is a paediatric high-grade brain tumour with no chance of survival due to its highly invasive nature.
Goal: By combining state-of-the-art imaging and transcriptomics, we aim to identify and target the key mechanisms driving the highly invasive growth of DIPG.
Technology advances: Two unique single cell resolution imaging techniques that we have recently developed will be implemented: Large-scale Single-cell Resolution 3D imaging (LSR-3D) that allows visualization of complete tumour specimens and intravital microscopy using a cranial imaging window that allows imaging of tumour cell behaviour in living mice. In addition, we will apply a technique of live imaging Patch-seq to perform behaviour studies together with single cell RNA profiling.
Expected results: Using a glioma murine model in which the disease is induced in neonates and a new embryonic model based on in utero electroporation, we expect to gain knowledge on the progression of DIPG in maturing brain. LSR-3D imaging on human and murine specimens will provide insight into the cellular tumour composition and its integration in the neuroglial network. With intravital imaging, we will characterize invasive cancer cell behaviour and functional connections with healthy brain cells. In combination with Patch-seq, we will identify transcriptional program(s) specific to invasive behaviour. Altogether, we expect to identify novel key players in cancer invasion and assess their potential to prevent DIPG progression.
Future perspective: With the studies proposed, we will gain fundamental insights into the cancer cell invasion mechanisms that govern DIPG which may provide new potential therapeutic target(s) for this dismal disease. Overall, the knowledge and advanced technologies obtained here will be of great value for the tumour biology field.
Summary
Introduction: The ability of a cancer cell to invade into the surrounding tissue is the main feature of malignant cancer progression. Diffuse Intrinsic Pontine Glioma (DIPG) is a paediatric high-grade brain tumour with no chance of survival due to its highly invasive nature.
Goal: By combining state-of-the-art imaging and transcriptomics, we aim to identify and target the key mechanisms driving the highly invasive growth of DIPG.
Technology advances: Two unique single cell resolution imaging techniques that we have recently developed will be implemented: Large-scale Single-cell Resolution 3D imaging (LSR-3D) that allows visualization of complete tumour specimens and intravital microscopy using a cranial imaging window that allows imaging of tumour cell behaviour in living mice. In addition, we will apply a technique of live imaging Patch-seq to perform behaviour studies together with single cell RNA profiling.
Expected results: Using a glioma murine model in which the disease is induced in neonates and a new embryonic model based on in utero electroporation, we expect to gain knowledge on the progression of DIPG in maturing brain. LSR-3D imaging on human and murine specimens will provide insight into the cellular tumour composition and its integration in the neuroglial network. With intravital imaging, we will characterize invasive cancer cell behaviour and functional connections with healthy brain cells. In combination with Patch-seq, we will identify transcriptional program(s) specific to invasive behaviour. Altogether, we expect to identify novel key players in cancer invasion and assess their potential to prevent DIPG progression.
Future perspective: With the studies proposed, we will gain fundamental insights into the cancer cell invasion mechanisms that govern DIPG which may provide new potential therapeutic target(s) for this dismal disease. Overall, the knowledge and advanced technologies obtained here will be of great value for the tumour biology field.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym CRCStemCellDynamics
Project Molecular Subtype Specific Stem Cell Dynamics in Developing and Established Colorectal Cancers
Researcher (PI) Louis Vermeulen
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary Annually 1.2 million new cases of colorectal cancer (CRC) are seen worldwide and over 50% of patients die of the disease making it a leading cause of cancer-related mortality. A crucial contributing factor to these disappointing figures is that CRC is a heterogeneous disease and tumours differ extensively in the clinical presentation and response to therapy. Recent unsupervised classification studies highlight that only a proportion of this heterogeneity can be explained by the variation in commonly found (epi-)genetic aberrations. Hence the origins of CRC heterogeneity remain poorly understood.
The central hypothesis of this research project is that the cell of origin contributes to the phenotype and functional properties of the pre-malignant clone and the resulting malignancy. To study this concept I will generate cell of origin- and mutation-specific molecular profiles of oncogenic clones and relate those to human CRC samples. Furthermore, I will quantitatively investigate how mutations and the cell of origin act in concert to determine the functional characteristics of the pre-malignant clone that ultimately develops into an invasive intestinal tumour. These studies are paralleled by the investigation of stem cell dynamics within established human CRCs by means of a novel marker independent lineage tracing strategy in combination with mathematical analysis techniques. This will provide critical and quantitative information on the relevance of the cancer stem cell concept in CRC and on the degree of inter-tumour variation with respect to the frequency and functional features of stem-like cells within individual CRCs and molecular subtypes of the disease.
I am convinced that a better and quantitative understanding of the dynamical properties of stem cells during tumour development and within established CRCs will be pivotal for an improved classification, prevention and treatment of CRC.
Summary
Annually 1.2 million new cases of colorectal cancer (CRC) are seen worldwide and over 50% of patients die of the disease making it a leading cause of cancer-related mortality. A crucial contributing factor to these disappointing figures is that CRC is a heterogeneous disease and tumours differ extensively in the clinical presentation and response to therapy. Recent unsupervised classification studies highlight that only a proportion of this heterogeneity can be explained by the variation in commonly found (epi-)genetic aberrations. Hence the origins of CRC heterogeneity remain poorly understood.
The central hypothesis of this research project is that the cell of origin contributes to the phenotype and functional properties of the pre-malignant clone and the resulting malignancy. To study this concept I will generate cell of origin- and mutation-specific molecular profiles of oncogenic clones and relate those to human CRC samples. Furthermore, I will quantitatively investigate how mutations and the cell of origin act in concert to determine the functional characteristics of the pre-malignant clone that ultimately develops into an invasive intestinal tumour. These studies are paralleled by the investigation of stem cell dynamics within established human CRCs by means of a novel marker independent lineage tracing strategy in combination with mathematical analysis techniques. This will provide critical and quantitative information on the relevance of the cancer stem cell concept in CRC and on the degree of inter-tumour variation with respect to the frequency and functional features of stem-like cells within individual CRCs and molecular subtypes of the disease.
I am convinced that a better and quantitative understanding of the dynamical properties of stem cells during tumour development and within established CRCs will be pivotal for an improved classification, prevention and treatment of CRC.
Max ERC Funding
1 499 875 €
Duration
Start date: 2015-04-01, End date: 2021-03-31
Project acronym Crosstag
Project Unravelling cross-presentation pathways using a chemical biology approach
Researcher (PI) Sander Van kasteren
Host Institution (HI) UNIVERSITEIT LEIDEN
Call Details Starting Grant (StG), PE5, ERC-2014-STG
Summary Immune therapies are therefore currently being pursued to reinvigorate the immune reaction against tumours. This is not trivial, as the right type of immune cells must be activated against a tumour-specific antigen. One method to achieve this is by targeting tumour antigens to certain cross-presentation-promoting receptors on antigen presenting cells. The most intriguing of these is the mannose receptor (MR) as the method by which it does this is unknown.
This glycoprotein-binding receptor appears to have two functions on APCs: general uptake-enhancement and, in certain isolated cases, cross-presentation-enhancment. What ligand parameters are important in causing cross-presentation enhancement is not known. Current tools, such as anti-MR antibodies and randomly glycosylated ligands fail to selectively enhance cross-presentation. The main aim of this proposal is to determine what structural parameters of the glycoprotein antigen result in enhanced cross-presentation upon MR-ligation.
I will synthesise a library of biologically traceable single glycoform ligands - with controlled variation in glycan nature, stoichiometry and positioning - for the MR and study differences in uptake, routing and antigen presentation.
A 2nd aim is to uncover what happens to the antigen after uptake by the MR. I.e. whether changes in antigen routing and proteolysis are responsible for enhanced cross presentation of different glycoforms. A 3rd aim is to develop a new method to study the kinetics of surface appearance of epitopes without T-cell reagents to quantify differences between glycoforms.
With this approach I aim to gain new insight into methods for enhancing cross-presentation resulting in improved immune therapies against cancer. My background in carbohydrate and protein modification chemistry will provide the toolkit to synthesise the relevant reagents and my background in immunology will ensure the successful immunological validation of the synthetic single glycoforms.
Summary
Immune therapies are therefore currently being pursued to reinvigorate the immune reaction against tumours. This is not trivial, as the right type of immune cells must be activated against a tumour-specific antigen. One method to achieve this is by targeting tumour antigens to certain cross-presentation-promoting receptors on antigen presenting cells. The most intriguing of these is the mannose receptor (MR) as the method by which it does this is unknown.
This glycoprotein-binding receptor appears to have two functions on APCs: general uptake-enhancement and, in certain isolated cases, cross-presentation-enhancment. What ligand parameters are important in causing cross-presentation enhancement is not known. Current tools, such as anti-MR antibodies and randomly glycosylated ligands fail to selectively enhance cross-presentation. The main aim of this proposal is to determine what structural parameters of the glycoprotein antigen result in enhanced cross-presentation upon MR-ligation.
I will synthesise a library of biologically traceable single glycoform ligands - with controlled variation in glycan nature, stoichiometry and positioning - for the MR and study differences in uptake, routing and antigen presentation.
A 2nd aim is to uncover what happens to the antigen after uptake by the MR. I.e. whether changes in antigen routing and proteolysis are responsible for enhanced cross presentation of different glycoforms. A 3rd aim is to develop a new method to study the kinetics of surface appearance of epitopes without T-cell reagents to quantify differences between glycoforms.
With this approach I aim to gain new insight into methods for enhancing cross-presentation resulting in improved immune therapies against cancer. My background in carbohydrate and protein modification chemistry will provide the toolkit to synthesise the relevant reagents and my background in immunology will ensure the successful immunological validation of the synthetic single glycoforms.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym inCITe
Project Seeing Citrulline: A Molecular Toolbox for Peptidyl Arginine Deiminases
Researcher (PI) Kimberly BONGER
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Starting Grant (StG), PE5, ERC-2018-STG
Summary Roughly 1% of the world’s population is affected by rheumatoid arthritis (RA); a devastating autoimmune disease causing cartilage destruction and bone erosion. Recent evidences suggest that dysregulation of Peptidyl Arginine Deiminase (PAD) levels are associated with the onset of the disease, leading to the production of antibodies targeting the citrullinated neoepitopes. The exact role of each of the PAD isotypes in these pathological processes is unknown and fundamental questions on the intracellular activation mechanism and substrate specificity remain unanswered. Moreover, isoform specific and high affinity enzyme inhibitors are lacking thereby not only hampering fundamental research towards each PAD isotype, but also excluding PAD as a potential therapeutic target for these diseases.
This proposal is aimed at developing innovative chemical biology- and molecular tools to study PAD functioning and protein citrullination in health and disease. The work reflects my interdisciplinary experiences as well as my interest I have obtained over the last years in chemical immunology as well as my ambition to improve patients wellbeing. More detailed, I aim to 1) find unknown PAD modulators, 2) find PAD substrates, 3) find selective and high affinity PAD inhibitors using enzyme-templated inhibitor evolution as novel lead discovery strategy, 4) explore multifunctional targeted PAD ‘nanosponges’ as advanced avidity-based nanomedicine approach and 5) explore unprecedented citrulline ‘eraser’ enzymes by innovative chemical biology strategies.
The workpackages described in this ambitious and highly interdisciplinary proposal deliver high-end molecules and methods that can be used to answer fundamental (conflicting) questions on citrullination and PAD biology. Moreover, possible molecular leads and advanced therapeutic insights are provided thereby centring PAD as therapeutic target for citrulline-mediated autoimmune diseases such as RA.
Summary
Roughly 1% of the world’s population is affected by rheumatoid arthritis (RA); a devastating autoimmune disease causing cartilage destruction and bone erosion. Recent evidences suggest that dysregulation of Peptidyl Arginine Deiminase (PAD) levels are associated with the onset of the disease, leading to the production of antibodies targeting the citrullinated neoepitopes. The exact role of each of the PAD isotypes in these pathological processes is unknown and fundamental questions on the intracellular activation mechanism and substrate specificity remain unanswered. Moreover, isoform specific and high affinity enzyme inhibitors are lacking thereby not only hampering fundamental research towards each PAD isotype, but also excluding PAD as a potential therapeutic target for these diseases.
This proposal is aimed at developing innovative chemical biology- and molecular tools to study PAD functioning and protein citrullination in health and disease. The work reflects my interdisciplinary experiences as well as my interest I have obtained over the last years in chemical immunology as well as my ambition to improve patients wellbeing. More detailed, I aim to 1) find unknown PAD modulators, 2) find PAD substrates, 3) find selective and high affinity PAD inhibitors using enzyme-templated inhibitor evolution as novel lead discovery strategy, 4) explore multifunctional targeted PAD ‘nanosponges’ as advanced avidity-based nanomedicine approach and 5) explore unprecedented citrulline ‘eraser’ enzymes by innovative chemical biology strategies.
The workpackages described in this ambitious and highly interdisciplinary proposal deliver high-end molecules and methods that can be used to answer fundamental (conflicting) questions on citrullination and PAD biology. Moreover, possible molecular leads and advanced therapeutic insights are provided thereby centring PAD as therapeutic target for citrulline-mediated autoimmune diseases such as RA.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym IntratumoralNiche
Project Defining heterocellular signalling within the intratumoral stem cell niche of colorectal cancer
Researcher (PI) Hugo SNIPPERT
Host Institution (HI) UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary Purpose: Cells in a tumor are highly heterogeneous. The role and consequence of having multiple cell types within a cancer is mostly centered towards the function of cancer stem cells (CSCs) since they are the driving forces of tumor growth. However, the exact signaling cues that support CSC function remain to be understood. For instance, what are the roles of immediate descendant tumor cells in relation to CSC support? Do colorectal tumors make their own niche?
Preliminary data: To study communication between different cell types (heterocellular signaling) in human colorectal cancers (CRCs), my lab developed movieSTAR technology to mark CSCs in patient-derived CRC organoids (PDOs) for high-resolution live imaging of their dynamics and behavior. Although niche factor dependency decreases along the adenoma-carcinoma transition, we identified a strong interdependency between CSCs and other tumor cells in colorectal PDOs of malignant nature.
Hypothesis: We hypothesize a continuous existence of an intratumoral stem cell niche that remains essential for tumor growth and metastasis formation. Which types of heterocellular signaling support CSC function, especially at malignant stages, is unknown.
Approach: This project aims to define heterocellular signaling between CSCs and intratumoral niche cells. Therefore, I) we will combine our expertise in human organoid technology for in-depth characterization of the nature of heterocellular communication within the intratumoral niche, II) high-resolution live imaging of PDOs to interrogate heterogeneity of signaling activities at cellular resolution and in real-time, as well as III) in vivo mouse models for validation and further studies of essential intratumoral signaling pathways.
Innovation: Our integrative use of novel approaches will provide comprehensive insight into intratumoral niche function during tumorigenesis, establishing novel technologies for future cancer research and new concepts to improve cancer therapy.
Summary
Purpose: Cells in a tumor are highly heterogeneous. The role and consequence of having multiple cell types within a cancer is mostly centered towards the function of cancer stem cells (CSCs) since they are the driving forces of tumor growth. However, the exact signaling cues that support CSC function remain to be understood. For instance, what are the roles of immediate descendant tumor cells in relation to CSC support? Do colorectal tumors make their own niche?
Preliminary data: To study communication between different cell types (heterocellular signaling) in human colorectal cancers (CRCs), my lab developed movieSTAR technology to mark CSCs in patient-derived CRC organoids (PDOs) for high-resolution live imaging of their dynamics and behavior. Although niche factor dependency decreases along the adenoma-carcinoma transition, we identified a strong interdependency between CSCs and other tumor cells in colorectal PDOs of malignant nature.
Hypothesis: We hypothesize a continuous existence of an intratumoral stem cell niche that remains essential for tumor growth and metastasis formation. Which types of heterocellular signaling support CSC function, especially at malignant stages, is unknown.
Approach: This project aims to define heterocellular signaling between CSCs and intratumoral niche cells. Therefore, I) we will combine our expertise in human organoid technology for in-depth characterization of the nature of heterocellular communication within the intratumoral niche, II) high-resolution live imaging of PDOs to interrogate heterogeneity of signaling activities at cellular resolution and in real-time, as well as III) in vivo mouse models for validation and further studies of essential intratumoral signaling pathways.
Innovation: Our integrative use of novel approaches will provide comprehensive insight into intratumoral niche function during tumorigenesis, establishing novel technologies for future cancer research and new concepts to improve cancer therapy.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym LIGHTPORT
Project From light-stimulated anion receptors to transmembrane carriers and pumps
Researcher (PI) Sander WEZENBERG
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Call Details Starting Grant (StG), PE5, ERC-2018-STG
Summary The transport of anions across the cell membrane, which is mediated by transport proteins, is essential to many important biological processes. Dysregulation of this transport has been associated to various diseases and therefore, chemists endeavour to develop artificial receptors that mimic the function of natural transporters. Despite much progress over the last decade, the current artificial systems are mostly static, while proteins are able to change their activity dynamically in response to stimuli in the environment. To integrate such stimuli-controlled behavior in synthetic systems is a key contemporary challenge. In view of this, the goal of the proposed research program is to develop anion receptors in which the binding properties can be effectively modulated by light and to apply these receptors as transmembrane carriers and pumps, in order to regulate passive transport (i.e. down a concentration gradient) and to induce active transport (i.e. against a concentration gradient). This interdisciplinary program is divided into three work packages: WP1 aims at the development of structurally rigid and visible-light-actuated photoswitches and their use as platforms for constructing anion receptors; WP2 deals with the development of mechanically interlocked structures as photoswitchable anionic hosts; WP3 is directed at utilizing these receptors for light-gated transport and light-driven pumping of anions across phospholipid bilayers, whereas also an alternative dual-responsive anion channel will be prepared. Eventually, it is expected that this work will open a new route toward light-based localized pharmacological treatment, e.g. via light-triggered cancer or bacterial cell death. Furthermore, active transport systems, that are able to build up and maintain concentration gradients across membranes, could provide a completely new view on how to convert and store light (solar) energy.
Summary
The transport of anions across the cell membrane, which is mediated by transport proteins, is essential to many important biological processes. Dysregulation of this transport has been associated to various diseases and therefore, chemists endeavour to develop artificial receptors that mimic the function of natural transporters. Despite much progress over the last decade, the current artificial systems are mostly static, while proteins are able to change their activity dynamically in response to stimuli in the environment. To integrate such stimuli-controlled behavior in synthetic systems is a key contemporary challenge. In view of this, the goal of the proposed research program is to develop anion receptors in which the binding properties can be effectively modulated by light and to apply these receptors as transmembrane carriers and pumps, in order to regulate passive transport (i.e. down a concentration gradient) and to induce active transport (i.e. against a concentration gradient). This interdisciplinary program is divided into three work packages: WP1 aims at the development of structurally rigid and visible-light-actuated photoswitches and their use as platforms for constructing anion receptors; WP2 deals with the development of mechanically interlocked structures as photoswitchable anionic hosts; WP3 is directed at utilizing these receptors for light-gated transport and light-driven pumping of anions across phospholipid bilayers, whereas also an alternative dual-responsive anion channel will be prepared. Eventually, it is expected that this work will open a new route toward light-based localized pharmacological treatment, e.g. via light-triggered cancer or bacterial cell death. Furthermore, active transport systems, that are able to build up and maintain concentration gradients across membranes, could provide a completely new view on how to convert and store light (solar) energy.
Max ERC Funding
1 499 461 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym MetaFlex
Project Metabolic flexibility: breaking down food effectively to prolong life
Researcher (PI) Richardus Hendricus Leonardus Houtkooper
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary Aging has long been considered a passive process. More recently studies have defined an important, active role for metabolic pathways in aging and age-related diseases. I have previously demonstrated a marked dysregulation of fat metabolism in aged mice that contributes to their overweight and glucose intolerance. Here, I propose a model that links healthy aging to efficient processing of nutrients, a state termed metabolic flexibility: reducing protein or carbohydrate metabolism will strongly stimulate fat breakdown. I suggest that improved metabolic flexibility will thus prevent the accumulation of lipids and protect against its detrimental effects.
In this project, I aim to elucidate how nutrient breakdown is regulated and can be adapted to improve metabolic flexibility and promote healthy aging. I will use C. elegans, as well as mammalian models and human population studies. Specifically, I aim to (1) dissect the molecular actors of metabolic aging pathways; (2) identify genes that translate nutritional cues to lifespan variation; (3) find novel genetic regulators that prevent toxicity and accelerated aging caused by fat-rich diets; (4) identify associations between variants in genes involved in metabolic flexibility and aging phenotypes in humans.
This set of experiments should clarify the role of nutrient breakdown and metabolic flexibility in aging. Better understanding of these processes can lead to a prolonged healthy state of aged individuals.
Summary
Aging has long been considered a passive process. More recently studies have defined an important, active role for metabolic pathways in aging and age-related diseases. I have previously demonstrated a marked dysregulation of fat metabolism in aged mice that contributes to their overweight and glucose intolerance. Here, I propose a model that links healthy aging to efficient processing of nutrients, a state termed metabolic flexibility: reducing protein or carbohydrate metabolism will strongly stimulate fat breakdown. I suggest that improved metabolic flexibility will thus prevent the accumulation of lipids and protect against its detrimental effects.
In this project, I aim to elucidate how nutrient breakdown is regulated and can be adapted to improve metabolic flexibility and promote healthy aging. I will use C. elegans, as well as mammalian models and human population studies. Specifically, I aim to (1) dissect the molecular actors of metabolic aging pathways; (2) identify genes that translate nutritional cues to lifespan variation; (3) find novel genetic regulators that prevent toxicity and accelerated aging caused by fat-rich diets; (4) identify associations between variants in genes involved in metabolic flexibility and aging phenotypes in humans.
This set of experiments should clarify the role of nutrient breakdown and metabolic flexibility in aging. Better understanding of these processes can lead to a prolonged healthy state of aged individuals.
Max ERC Funding
1 499 446 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym PRISM
Project Ice-binding proteins: from antifreeze mechanism to resistant soft materials
Researcher (PI) Ilja Karina Voets
Host Institution (HI) TECHNISCHE UNIVERSITEIT EINDHOVEN
Call Details Starting Grant (StG), PE5, ERC-2014-STG
Summary Crystallization of water into ice is lethal to most organisms and detrimental to many soft materials. Freeze-tolerant fish living in polar seas evolved to tackle this problem with an unusual coping strategy. They produce ‘antifreeze’ proteins that block the growth of nascent ice crystals within a narrow temperature range known as the ‘thermal hysteresis gap’ enabling survival under extreme conditions. Encoding this functionality into synthetic polymers would open up new avenues in biomedicine, agrifood and materials science for e.g. cryopreservation, crop hardiness, ice-templating, dispersion stability, and advanced coatings. Progress requires a profound understanding of the mechanism of non-colligative freezing point depression at the molecular level and allows for efficient strategies for the design and preparation of powerful macromolecular antifreezes.
I propose to unravel how antifreeze proteins work and to build upon these insights to explore effective routes towards ice-binding polymers aiming to make sensitive soft materials freeze-resistant. Within this challenge we first focus on single-molecule experiments to visualize bound proteins and study the strength of the non-covalent interaction with ice. We will study if and when adsorption on ‘foreign’ interfaces and solution assembly impact activity. These fundamental insights will guide our research towards synthetic antifreeze agents with superior functionality to achieve record supercooling in complex environments. This knowledge-based design of polymers with high affinity for crystalline interfaces holds great promise for many areas of science and technology in which crystallization plays a decisive role.
Summary
Crystallization of water into ice is lethal to most organisms and detrimental to many soft materials. Freeze-tolerant fish living in polar seas evolved to tackle this problem with an unusual coping strategy. They produce ‘antifreeze’ proteins that block the growth of nascent ice crystals within a narrow temperature range known as the ‘thermal hysteresis gap’ enabling survival under extreme conditions. Encoding this functionality into synthetic polymers would open up new avenues in biomedicine, agrifood and materials science for e.g. cryopreservation, crop hardiness, ice-templating, dispersion stability, and advanced coatings. Progress requires a profound understanding of the mechanism of non-colligative freezing point depression at the molecular level and allows for efficient strategies for the design and preparation of powerful macromolecular antifreezes.
I propose to unravel how antifreeze proteins work and to build upon these insights to explore effective routes towards ice-binding polymers aiming to make sensitive soft materials freeze-resistant. Within this challenge we first focus on single-molecule experiments to visualize bound proteins and study the strength of the non-covalent interaction with ice. We will study if and when adsorption on ‘foreign’ interfaces and solution assembly impact activity. These fundamental insights will guide our research towards synthetic antifreeze agents with superior functionality to achieve record supercooling in complex environments. This knowledge-based design of polymers with high affinity for crystalline interfaces holds great promise for many areas of science and technology in which crystallization plays a decisive role.
Max ERC Funding
1 661 605 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym TESLA
Project Living on the Edge: Tunable Electronics from Edge Structures in 1D Layered Materials
Researcher (PI) Sonia Conesa Boj
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Starting Grant (StG), PE5, ERC-2018-STG
Summary One of the driving forces of the ongoing nanotechnology revolution is the ever-improving ability to understand and control the properties of quantum matter even down to the atomic scale. Key drivers of this revolution are layered materials like transition metal dichalcogenides (TMD). The realisation of novel TMD-based electronic devices relies heavily on understanding the relation between structural and electrical properties at the nanoscale. Crucially, one-dimensional (1D) TMDs have been predicted to exhibit striking functionalities including metallic edge states, ferromagnetic behaviour, and mobilities that are not suppressed as compared to their 2D counterparts. Indeed, in the 1D nanoscale limit, the lateral edges of TMDs become dominant, opening novel opportunities to tune edge-induced electrical properties leading to i.e. enhanced charge carrier mobility.
However, these predictions for novel phenomena in 1D TMDs lack experimental verification, due to the challenge in accessing the relevant information at the nanoscale. I propose to unravel the interplay between structural and electrical edge-induced properties by exploiting recent breakthroughs in electron microscopy (EM) allowing simultaneous unprecedented spatial and spectral resolution. I will focus on MoS2 nanoribbons, and use electron-energy loss spectroscopy to map the electronic properties at the nanometer-scale. Beyond the optimization of EM for 1D TMD characterization, I will investigate semiconducting-to-metal and ferromagnetic transitions by realising controllable edge structures. I have an extensive track record in pushing the frontier of EM characterization and growing nanostructures. I recently demonstrated the feasibility of pinning down the interplay between structure and electronic properties at the edges of 2D MoS2. This proposal will provide input towards novel quantum technologies for developing low-energy-consumption tunable electronics, efficient signal processing and quantum computation.
Summary
One of the driving forces of the ongoing nanotechnology revolution is the ever-improving ability to understand and control the properties of quantum matter even down to the atomic scale. Key drivers of this revolution are layered materials like transition metal dichalcogenides (TMD). The realisation of novel TMD-based electronic devices relies heavily on understanding the relation between structural and electrical properties at the nanoscale. Crucially, one-dimensional (1D) TMDs have been predicted to exhibit striking functionalities including metallic edge states, ferromagnetic behaviour, and mobilities that are not suppressed as compared to their 2D counterparts. Indeed, in the 1D nanoscale limit, the lateral edges of TMDs become dominant, opening novel opportunities to tune edge-induced electrical properties leading to i.e. enhanced charge carrier mobility.
However, these predictions for novel phenomena in 1D TMDs lack experimental verification, due to the challenge in accessing the relevant information at the nanoscale. I propose to unravel the interplay between structural and electrical edge-induced properties by exploiting recent breakthroughs in electron microscopy (EM) allowing simultaneous unprecedented spatial and spectral resolution. I will focus on MoS2 nanoribbons, and use electron-energy loss spectroscopy to map the electronic properties at the nanometer-scale. Beyond the optimization of EM for 1D TMD characterization, I will investigate semiconducting-to-metal and ferromagnetic transitions by realising controllable edge structures. I have an extensive track record in pushing the frontier of EM characterization and growing nanostructures. I recently demonstrated the feasibility of pinning down the interplay between structure and electronic properties at the edges of 2D MoS2. This proposal will provide input towards novel quantum technologies for developing low-energy-consumption tunable electronics, efficient signal processing and quantum computation.
Max ERC Funding
1 499 475 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
