Project acronym AMAIZE
Project Atlas of leaf growth regulatory networks in MAIZE
Researcher (PI) Dirk, Gustaaf Inzé
Host Institution (HI) VIB
Call Details Advanced Grant (AdG), LS9, ERC-2013-ADG
Summary "Understanding how organisms regulate size is one of the most fascinating open questions in biology. The aim of the AMAIZE project is to unravel how growth of maize leaves is controlled. Maize leaf development offers great opportunities to study the dynamics of growth regulatory networks, essentially because leaf development is a linear system with cell division at the leaf basis followed by cell expansion and maturation. Furthermore, the growth zone is relatively large allowing easy access of tissues at different positions. Four different perturbations of maize leaf size will be analyzed with cellular resolution: wild-type and plants having larger leaves (as a consequence of GA20OX1 overexpression), both grown under either well-watered or mild drought conditions. Firstly, a 3D cellular map of the growth zone of the fourth leaf will be made. RNA-SEQ of three different tissues (adaxial- and abaxial epidermis; mesophyll) obtained by laser dissection with an interval of 2.5 mm along the growth zone will allow for the analysis of the transcriptome with high resolution. Additionally, the composition of fifty selected growth regulatory protein complexes and DNA targets of transcription factors will be determined with an interval of 5 mm along the growth zone. Computational methods will be used to construct comprehensive integrative maps of the cellular and molecular processes occurring along the growth zone. Finally, selected regulatory nodes of the growth regulatory networks will be further functionally analyzed using a transactivation system in maize.
AMAIZE opens up new perspectives for the identification of optimal growth regulatory networks that can be selected for by advanced breeding or for which more robust variants (e.g. reduced susceptibility to drought) can be obtained through genetic engineering. The ability to improve the growth of maize and in analogy other cereals could have a high impact in providing food security"
Summary
"Understanding how organisms regulate size is one of the most fascinating open questions in biology. The aim of the AMAIZE project is to unravel how growth of maize leaves is controlled. Maize leaf development offers great opportunities to study the dynamics of growth regulatory networks, essentially because leaf development is a linear system with cell division at the leaf basis followed by cell expansion and maturation. Furthermore, the growth zone is relatively large allowing easy access of tissues at different positions. Four different perturbations of maize leaf size will be analyzed with cellular resolution: wild-type and plants having larger leaves (as a consequence of GA20OX1 overexpression), both grown under either well-watered or mild drought conditions. Firstly, a 3D cellular map of the growth zone of the fourth leaf will be made. RNA-SEQ of three different tissues (adaxial- and abaxial epidermis; mesophyll) obtained by laser dissection with an interval of 2.5 mm along the growth zone will allow for the analysis of the transcriptome with high resolution. Additionally, the composition of fifty selected growth regulatory protein complexes and DNA targets of transcription factors will be determined with an interval of 5 mm along the growth zone. Computational methods will be used to construct comprehensive integrative maps of the cellular and molecular processes occurring along the growth zone. Finally, selected regulatory nodes of the growth regulatory networks will be further functionally analyzed using a transactivation system in maize.
AMAIZE opens up new perspectives for the identification of optimal growth regulatory networks that can be selected for by advanced breeding or for which more robust variants (e.g. reduced susceptibility to drought) can be obtained through genetic engineering. The ability to improve the growth of maize and in analogy other cereals could have a high impact in providing food security"
Max ERC Funding
2 418 429 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym ART
Project Aberrant RNA degradation in T-cell leukemia
Researcher (PI) Jan Cools
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary "The deregulation of transcription is an important driver of leukemia development. Typically, transcription in leukemia cells is altered by the ectopic expression of transcription factors, by modulation of signaling pathways or by epigenetic changes. In addition to these factors that affect the production of RNAs, also changes in the processing of RNA (its splicing, transport and decay) may contribute to determine steady-state RNA levels in leukemia cells. Indeed, acquired mutations in various genes encoding RNA splice factors have recently been identified in myeloid leukemias and in chronic lymphocytic leukemia. In our study of T-cell acute lymphoblastic leukemia (T-ALL), we have identified mutations in RNA decay factors, including mutations in CNOT3, a protein believed to function in deadenylation of mRNA. It remains, however, unclear how mutations in RNA processing can contribute to the development of leukemia.
In this project, we aim to further characterize the mechanisms of RNA regulation in T-cell acute lymphoblastic leukemia (T-ALL) to obtain insight in the interplay between RNA generation and RNA decay and its role in leukemia development. We will study RNA decay in human T-ALL cells and mouse models of T-ALL, with the aim to identify the molecular consequences that contribute to leukemia development. We will use new technologies such as RNA-sequencing in combination with bromouridine labeling of RNA to measure RNA transcription and decay rates in a transcriptome wide manner allowing unbiased discoveries. These studies will be complemented with screens in Drosophila melanogaster using an established eye cancer model, previously also successfully used for the studies of T-ALL oncogenes.
This study will contribute to our understanding of the pathogenesis of T-ALL and may identify new targets for therapy of this leukemia. In addition, our study will provide a better understanding of how RNA processing is implicated in cancer development in general."
Summary
"The deregulation of transcription is an important driver of leukemia development. Typically, transcription in leukemia cells is altered by the ectopic expression of transcription factors, by modulation of signaling pathways or by epigenetic changes. In addition to these factors that affect the production of RNAs, also changes in the processing of RNA (its splicing, transport and decay) may contribute to determine steady-state RNA levels in leukemia cells. Indeed, acquired mutations in various genes encoding RNA splice factors have recently been identified in myeloid leukemias and in chronic lymphocytic leukemia. In our study of T-cell acute lymphoblastic leukemia (T-ALL), we have identified mutations in RNA decay factors, including mutations in CNOT3, a protein believed to function in deadenylation of mRNA. It remains, however, unclear how mutations in RNA processing can contribute to the development of leukemia.
In this project, we aim to further characterize the mechanisms of RNA regulation in T-cell acute lymphoblastic leukemia (T-ALL) to obtain insight in the interplay between RNA generation and RNA decay and its role in leukemia development. We will study RNA decay in human T-ALL cells and mouse models of T-ALL, with the aim to identify the molecular consequences that contribute to leukemia development. We will use new technologies such as RNA-sequencing in combination with bromouridine labeling of RNA to measure RNA transcription and decay rates in a transcriptome wide manner allowing unbiased discoveries. These studies will be complemented with screens in Drosophila melanogaster using an established eye cancer model, previously also successfully used for the studies of T-ALL oncogenes.
This study will contribute to our understanding of the pathogenesis of T-ALL and may identify new targets for therapy of this leukemia. In addition, our study will provide a better understanding of how RNA processing is implicated in cancer development in general."
Max ERC Funding
1 998 300 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym BIOTENSORS
Project Biomedical Data Fusion using Tensor based Blind Source Separation
Researcher (PI) Sabine Jeanne A Van Huffel
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Advanced Grant (AdG), PE6, ERC-2013-ADG
Summary "Summary: the quest for a general functional tensor framework for blind source separation
Our overall objective is the development of a general functional framework for solving tensor based blind source separation (BSS) problems in biomedical data fusion, using tensor decompositions (TDs) as basic core. We claim that TDs will allow the extraction of fairly complicated sources of biomedical activity from fairly complicated sets of uni- and multimodal data. The power of the new techniques will be demonstrated for three well-chosen representative biomedical applications for which extensive expertise and fully validated datasets are available in the PI’s team, namely:
• Metabolite quantification and brain tumour tissue typing using Magnetic Resonance Spectroscopic Imaging,
• Functional monitoring including seizure detection and polysomnography,
• Cognitive brain functioning and seizure zone localization using simultaneous Electroencephalography-functional MR Imaging integration.
Solving these challenging problems requires that algorithmic progress is made in several directions:
• Algorithms need to be based on multilinear extensions of numerical linear algebra.
• New grounds for separation, such as representability in a given function class, need to be explored.
• Prior knowledge needs to be exploited via appropriate health relevant constraints.
• Biomedical data fusion requires the combination of TDs, coupled via relevant constraints.
• Algorithms for TD updating are important for continuous long-term patient monitoring.
The algorithms are eventually integrated in an easy-to-use open source software platform that is general enough for use in other BSS applications.
Having been involved in biomedical signal processing over a period of 20 years, the PI has a good overview of the field and the opportunities. By working directly at the forefront in close collaboration with the clinical scientists who actually use our software, we can have a huge impact."
Summary
"Summary: the quest for a general functional tensor framework for blind source separation
Our overall objective is the development of a general functional framework for solving tensor based blind source separation (BSS) problems in biomedical data fusion, using tensor decompositions (TDs) as basic core. We claim that TDs will allow the extraction of fairly complicated sources of biomedical activity from fairly complicated sets of uni- and multimodal data. The power of the new techniques will be demonstrated for three well-chosen representative biomedical applications for which extensive expertise and fully validated datasets are available in the PI’s team, namely:
• Metabolite quantification and brain tumour tissue typing using Magnetic Resonance Spectroscopic Imaging,
• Functional monitoring including seizure detection and polysomnography,
• Cognitive brain functioning and seizure zone localization using simultaneous Electroencephalography-functional MR Imaging integration.
Solving these challenging problems requires that algorithmic progress is made in several directions:
• Algorithms need to be based on multilinear extensions of numerical linear algebra.
• New grounds for separation, such as representability in a given function class, need to be explored.
• Prior knowledge needs to be exploited via appropriate health relevant constraints.
• Biomedical data fusion requires the combination of TDs, coupled via relevant constraints.
• Algorithms for TD updating are important for continuous long-term patient monitoring.
The algorithms are eventually integrated in an easy-to-use open source software platform that is general enough for use in other BSS applications.
Having been involved in biomedical signal processing over a period of 20 years, the PI has a good overview of the field and the opportunities. By working directly at the forefront in close collaboration with the clinical scientists who actually use our software, we can have a huge impact."
Max ERC Funding
2 500 000 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym BlackBox
Project A collaborative platform to document performance composition: from conceptual structures in the backstage to customizable visualizations in the front-end
Researcher (PI) Carla Maria De Jesus Fernandes
Host Institution (HI) FACULDADE DE CIENCIAS SOCIAIS E HUMANAS DA UNIVERSIDADE NOVA DE LISBOA
Call Details Starting Grant (StG), SH5, ERC-2013-StG
Summary The global performing arts community is requiring innovative systems to: a) document, transmit and preserve the knowledge contained in choreographic-dramaturgic practices; b) assist artists with tools to facilitate their compositional processes, preferably on a collaborative basis. The existing digital archives of performing arts mostly function as conventional e-libraries, not allowing higher degrees of interactivity or active user intervention. They rarely contemplate accessible video annotation tools or provide relational querying functionalities based on artist-driven conceptual principles or idiosyncratic ontologies.
This proposal endeavours to fill that gap and create a new paradigm for the documentation of performance composition. It aims at the analysis of artists’ unique conceptual structures, by combining the empirical insights of contemporary creators with research theories from Multimodal Communication and Digital Media studies. The challenge is to design a model for a web-based collaborative platform enabling both a robust representation of performance composition methods and novel visualization technologies to support it. This can be done by analysing recurring body movement patterns and by fostering online contributions of users (a.o. performers and researchers) to the multimodal annotations stored in the platform. To accomplish this goal, two subjacent components must be developed: 1. the production of a video annotation-tool to allow artists in rehearsal periods to take notes over video in real-time and share them via the collaborative platform; 2. the linguistic analysis of a corpus of invited artists’ multimodal materials as source for the extraction of indicative conceptual structures, which will guide the architectural logics and interface design of the collaborative platform software.The outputs of these two components will generate critical case-studies to help understanding the human mind when engaged in cultural production processes.
Summary
The global performing arts community is requiring innovative systems to: a) document, transmit and preserve the knowledge contained in choreographic-dramaturgic practices; b) assist artists with tools to facilitate their compositional processes, preferably on a collaborative basis. The existing digital archives of performing arts mostly function as conventional e-libraries, not allowing higher degrees of interactivity or active user intervention. They rarely contemplate accessible video annotation tools or provide relational querying functionalities based on artist-driven conceptual principles or idiosyncratic ontologies.
This proposal endeavours to fill that gap and create a new paradigm for the documentation of performance composition. It aims at the analysis of artists’ unique conceptual structures, by combining the empirical insights of contemporary creators with research theories from Multimodal Communication and Digital Media studies. The challenge is to design a model for a web-based collaborative platform enabling both a robust representation of performance composition methods and novel visualization technologies to support it. This can be done by analysing recurring body movement patterns and by fostering online contributions of users (a.o. performers and researchers) to the multimodal annotations stored in the platform. To accomplish this goal, two subjacent components must be developed: 1. the production of a video annotation-tool to allow artists in rehearsal periods to take notes over video in real-time and share them via the collaborative platform; 2. the linguistic analysis of a corpus of invited artists’ multimodal materials as source for the extraction of indicative conceptual structures, which will guide the architectural logics and interface design of the collaborative platform software.The outputs of these two components will generate critical case-studies to help understanding the human mind when engaged in cultural production processes.
Max ERC Funding
1 378 200 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym C.o.C.O.
Project Circuits of con-specific observation
Researcher (PI) Marta De Aragao Pacheco Moita
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary A great deal is known about the neural basis of associative fear learning. However, many animal species are able to use social cues to recognize threats, a defence mechanism that may be less costly than learning from self-experience. We have previously shown that rats perceive the cessation of movement-evoked sound as a signal of danger and its resumption as a signal of safety. To study transmission of fear between rats we assessed the behavior of an observer while witnessing a demonstrator rat display fear responses. With this paradigm we will take advantage of the accumulated knowledge on learned fear to investigate the neural mechanisms by which the social environment regulates defense behaviors. We will unravel the neural circuits involved in detecting the transition from movement-evoked sound to silence. Moreover, since observer rats previously exposed to shock display observational freezing, but naive observer rats do not, we will determine the mechanism by which prior experience contribute to observational freezing. To this end, we will focus on the amygdala, crucial for fear learning and expression, and its auditory inputs, combining immunohistochemistry, pharmacology and optogenetics. Finally, as the detection of and responses to threat are often inherently social, we will study these behaviors in the context of large groups of individuals. To circumvent the serious limitations in using large populations of rats, we will resort to a different model system. The fruit fly is the ideal model system, as it is both amenable to the search for the neural mechanism of behavior, while at the same time allowing the study of the behavior of large groups of individuals. We will develop behavioral tasks, where conditioned demonstrator flies signal danger to other naïve ones. These experiments unravel how the brain uses defense behaviors as signals of danger and how it contributes to defense mechanisms at the population level.
Summary
A great deal is known about the neural basis of associative fear learning. However, many animal species are able to use social cues to recognize threats, a defence mechanism that may be less costly than learning from self-experience. We have previously shown that rats perceive the cessation of movement-evoked sound as a signal of danger and its resumption as a signal of safety. To study transmission of fear between rats we assessed the behavior of an observer while witnessing a demonstrator rat display fear responses. With this paradigm we will take advantage of the accumulated knowledge on learned fear to investigate the neural mechanisms by which the social environment regulates defense behaviors. We will unravel the neural circuits involved in detecting the transition from movement-evoked sound to silence. Moreover, since observer rats previously exposed to shock display observational freezing, but naive observer rats do not, we will determine the mechanism by which prior experience contribute to observational freezing. To this end, we will focus on the amygdala, crucial for fear learning and expression, and its auditory inputs, combining immunohistochemistry, pharmacology and optogenetics. Finally, as the detection of and responses to threat are often inherently social, we will study these behaviors in the context of large groups of individuals. To circumvent the serious limitations in using large populations of rats, we will resort to a different model system. The fruit fly is the ideal model system, as it is both amenable to the search for the neural mechanism of behavior, while at the same time allowing the study of the behavior of large groups of individuals. We will develop behavioral tasks, where conditioned demonstrator flies signal danger to other naïve ones. These experiments unravel how the brain uses defense behaviors as signals of danger and how it contributes to defense mechanisms at the population level.
Max ERC Funding
1 412 376 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
Project acronym CAPS
Project Capillary suspensions: a novel route for versatile, cost efficient and environmentally friendly material design
Researcher (PI) Erin Crystal Koos
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Starting Grant (StG), PE8, ERC-2013-StG
Summary A wide variety of materials including coatings and adhesives, emerging materials for nanotechnology products, as well as everyday food products are processed or delivered as suspensions. The flow properties of such suspensions must be finely adjusted according to the demands of the respective processing techniques, even for the feel of cosmetics and the perception of food products is highly influenced by their rheological properties. The recently developed capillary suspensions concept has the potential to revolutionize product formulations and material design. When a small amount (less than 1%) of a second immiscible liquid is added to the continuous phase of a suspension, the rheological properties of the mixture are dramatically altered from a fluid-like to a gel-like state or from a weak to a strong gel and the strength can be tuned in a wide range covering orders of magnitude. Capillary suspensions can be used to create smart, tunable fluids, stabilize mixtures that would otherwise phase separate, significantly reduce the amount organic or polymeric additives, and the strong particle network can be used as a precursor for the manufacturing of cost-efficient porous ceramics and foams with unprecedented properties.
This project will investigate the influence of factors determining capillary suspension formation, the strength of these admixtures as a function of these aspects, and how capillary suspensions depend on external forces. Only such a fundamental understanding of the network formation in capillary suspensions on both the micro- and macroscopic scale will allow for the design of sophisticated new materials. The main objectives of this proposal are to quantify and predict the strength of these admixtures and then use this information to design a variety of new materials in very different application areas including, e.g., porous materials, water-based coatings, ultra low fat foods, and conductive films.
Summary
A wide variety of materials including coatings and adhesives, emerging materials for nanotechnology products, as well as everyday food products are processed or delivered as suspensions. The flow properties of such suspensions must be finely adjusted according to the demands of the respective processing techniques, even for the feel of cosmetics and the perception of food products is highly influenced by their rheological properties. The recently developed capillary suspensions concept has the potential to revolutionize product formulations and material design. When a small amount (less than 1%) of a second immiscible liquid is added to the continuous phase of a suspension, the rheological properties of the mixture are dramatically altered from a fluid-like to a gel-like state or from a weak to a strong gel and the strength can be tuned in a wide range covering orders of magnitude. Capillary suspensions can be used to create smart, tunable fluids, stabilize mixtures that would otherwise phase separate, significantly reduce the amount organic or polymeric additives, and the strong particle network can be used as a precursor for the manufacturing of cost-efficient porous ceramics and foams with unprecedented properties.
This project will investigate the influence of factors determining capillary suspension formation, the strength of these admixtures as a function of these aspects, and how capillary suspensions depend on external forces. Only such a fundamental understanding of the network formation in capillary suspensions on both the micro- and macroscopic scale will allow for the design of sophisticated new materials. The main objectives of this proposal are to quantify and predict the strength of these admixtures and then use this information to design a variety of new materials in very different application areas including, e.g., porous materials, water-based coatings, ultra low fat foods, and conductive films.
Max ERC Funding
1 489 618 €
Duration
Start date: 2013-08-01, End date: 2018-07-31
Project acronym CELLFITNESS
Project Active Mechanisms of Cell Selection: From Cell Competition to Cell Fitness
Researcher (PI) Eduardo Moreno Lampaya
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS3, ERC-2013-CoG
Summary The molecular mechanisms that mediate cell competition, cell fitness and cell selection is gaining interest. With innovative approaches, molecules and ground-breaking hypothesis, this field of research can help understand several biological processes such as development, cancer and tissue degeneration. The project has 3 clear and ambitious objectives: 1. We propose to identify all the key genes mediating cell competition and their molecular mechanisms. In order to reach this objective we will use data from two whole genome screens in Drosophila where we have identified 7 key genes. By the end of this CoG grant, we should have no big gaps in our knowledge of how slow dividing cells are recognised and eliminated in Drosophila. 2. In addition, we will explore how general the cell competition pathways are and how they can impact biomedical research, with a focus in cancer and tissue degeneration. The interest in cancer is based on experiments in Drosophila and mice where we and others have found that an active process of cell selection determines tumour growth. Preliminary results suggest that the pathways identified do not only play important roles in the elimination of slow dividing cells, but also during cancer initiation and progression. 3. We will further explore the role of cell competition in neuronal selection, specially during neurodegeneration, development of the retina and adult brain regeneration in Drosophila. This proposal is of an interdisciplinary nature because it takes a basic cellular mechanism (the genetic pathways that select cells within tissues) and crosses boundaries between different fields of research: development, cancer, regeneration and tissue degeneration. In this ERC CoG proposal, we are committed to continue our efforts from basic science to biomedical approaches. The phenomena of cell competition and its participating genes have the potential to discover novel biomarkers and therapeutic strategies against cancer and tissue degeneration.
Summary
The molecular mechanisms that mediate cell competition, cell fitness and cell selection is gaining interest. With innovative approaches, molecules and ground-breaking hypothesis, this field of research can help understand several biological processes such as development, cancer and tissue degeneration. The project has 3 clear and ambitious objectives: 1. We propose to identify all the key genes mediating cell competition and their molecular mechanisms. In order to reach this objective we will use data from two whole genome screens in Drosophila where we have identified 7 key genes. By the end of this CoG grant, we should have no big gaps in our knowledge of how slow dividing cells are recognised and eliminated in Drosophila. 2. In addition, we will explore how general the cell competition pathways are and how they can impact biomedical research, with a focus in cancer and tissue degeneration. The interest in cancer is based on experiments in Drosophila and mice where we and others have found that an active process of cell selection determines tumour growth. Preliminary results suggest that the pathways identified do not only play important roles in the elimination of slow dividing cells, but also during cancer initiation and progression. 3. We will further explore the role of cell competition in neuronal selection, specially during neurodegeneration, development of the retina and adult brain regeneration in Drosophila. This proposal is of an interdisciplinary nature because it takes a basic cellular mechanism (the genetic pathways that select cells within tissues) and crosses boundaries between different fields of research: development, cancer, regeneration and tissue degeneration. In this ERC CoG proposal, we are committed to continue our efforts from basic science to biomedical approaches. The phenomena of cell competition and its participating genes have the potential to discover novel biomarkers and therapeutic strategies against cancer and tissue degeneration.
Max ERC Funding
1 968 062 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym CHAMELEON
Project Cellular Hypoxia Alters DNA MEthylation through Loss of Epigenome OxidatioN
Researcher (PI) Diether Lambrechts
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS2, ERC-2013-CoG
Summary "DNA methylation was originally described in the 1970s as an epigenetic mark involved in transcriptional silencing, but the existence of DNA demethylation and the enzymes involved in this process were only recently discovered. In particular, it was established that TET hydroxylases catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) through a reaction requiring oxygen (O2) and 2-oxoglutarate (2OG). DNA demethylation as mediated by TET hydroxylases has so far predominantly been studied in the context of stem cells, but its precise contribution to carcinogenesis remains largely enigmatic. Nevertheless, somatic mutations in TETs have been identified in numerous cancers.
Tumor hypoxia is linked to increased malignancy, poor prognosis and resistance to cancer therapies. In this proposal, we aim to assess how hypoxia directly impacts on the cancer epigenome through the dependence of TET-mediated DNA demethylation on O2. First of all, we will study the effect of O2 and 2OG concentration on TET hydroxylase activity, as well as the overall and locus-specific changes of their product (5hmC). Secondly, because much of the hypoxic response is executed through HIFs, we will investigate how HIF binding is influenced by DNA methylation and if so, whether TET hydroxylases are targeted to HIF (or other) binding sites to maintain them transcriptionally active. Thirdly, we will assess to what extent 5hmC profiles differ between tumor types and construct a comprehensive panel of (tumor-specific) 5hmC sites to assess the global and locus-specific relevance of 5hmC in various cancers. Finally, since hypoxia is a key regulator of the cancer stem cell (CSC) niche and within the tumor microenvironment also promotes metastasis, we will establish the in vivo relevance of DNA demethylation, as imposed by tumor hypoxia, in the CSC niche and during metastasis. Overall, we thus aim to establish the interplay between tumor hypoxia and the DNA methylome."
Summary
"DNA methylation was originally described in the 1970s as an epigenetic mark involved in transcriptional silencing, but the existence of DNA demethylation and the enzymes involved in this process were only recently discovered. In particular, it was established that TET hydroxylases catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) through a reaction requiring oxygen (O2) and 2-oxoglutarate (2OG). DNA demethylation as mediated by TET hydroxylases has so far predominantly been studied in the context of stem cells, but its precise contribution to carcinogenesis remains largely enigmatic. Nevertheless, somatic mutations in TETs have been identified in numerous cancers.
Tumor hypoxia is linked to increased malignancy, poor prognosis and resistance to cancer therapies. In this proposal, we aim to assess how hypoxia directly impacts on the cancer epigenome through the dependence of TET-mediated DNA demethylation on O2. First of all, we will study the effect of O2 and 2OG concentration on TET hydroxylase activity, as well as the overall and locus-specific changes of their product (5hmC). Secondly, because much of the hypoxic response is executed through HIFs, we will investigate how HIF binding is influenced by DNA methylation and if so, whether TET hydroxylases are targeted to HIF (or other) binding sites to maintain them transcriptionally active. Thirdly, we will assess to what extent 5hmC profiles differ between tumor types and construct a comprehensive panel of (tumor-specific) 5hmC sites to assess the global and locus-specific relevance of 5hmC in various cancers. Finally, since hypoxia is a key regulator of the cancer stem cell (CSC) niche and within the tumor microenvironment also promotes metastasis, we will establish the in vivo relevance of DNA demethylation, as imposed by tumor hypoxia, in the CSC niche and during metastasis. Overall, we thus aim to establish the interplay between tumor hypoxia and the DNA methylome."
Max ERC Funding
1 920 000 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
Project acronym Cholstim
Project Cholinergic modulation of immune homeostasis: new opportunities for treatment
Researcher (PI) Guy Eduard Elisabeth Boeckxstaens
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Advanced Grant (AdG), LS7, ERC-2013-ADG
Summary In the gastrointestinal tract, the balance between activation of the mucosal immune system and tolerance should be tightly regulated to maintain immune homeostasis to prevent chronic inflammation and tissue damage. Recently, the new concept was introduced that the vagus nerve plays an important role in modulating immune homeostasis as part of a so-called inflammatory reflex. We provided evidence for this concept in the gastrointestinal tract and showed that vagus nerve stimulation (VNS) reduced inflammation of the intestinal muscle layer. Moreover, we showed that this effect was mediated by activation of enteric cholinergic neurons (cholinergic tone) interacting with intestinal macrophages in the muscle layer. Of interest, we have collected exciting data that the vagus nerve (and thus the cholinergic tone) also significantly contributes to mucosal immune homeostasis. Mice that underwent vagotomy lost their ability to develop tolerance to oral feeding of an antigen, whereas VNS reduced mucosal inflammation in a model of food allergy. Based on these data, we hypothesize that the cholinergic tone is a major determinant of the tolerogenic microenvironment of the mucosal immune system, and want to further explore the immune-modulatory effect of the vagal innervation and enteric neurons on the macrophages residing in the lamina propria. In addition, we will further explore the therapeutic potential and the mechanisms involved of chronic VNS in colitis and food allergy. Finally, we will translate our preclinical findings to the human situation. The anti-inflammatory effect of VNS (applied during surgery) will be studied in human intestinal tissue whereas the therapeutic potential of chronic VNS in Crohn’s disease will be studied in a pilot trial.
The outcome of this project will be ground-breaking and will have an immense impact on clinical management as it will provide new therapeutic opportunities for the treatment of immune-mediated gastrointestinal disorders.
Summary
In the gastrointestinal tract, the balance between activation of the mucosal immune system and tolerance should be tightly regulated to maintain immune homeostasis to prevent chronic inflammation and tissue damage. Recently, the new concept was introduced that the vagus nerve plays an important role in modulating immune homeostasis as part of a so-called inflammatory reflex. We provided evidence for this concept in the gastrointestinal tract and showed that vagus nerve stimulation (VNS) reduced inflammation of the intestinal muscle layer. Moreover, we showed that this effect was mediated by activation of enteric cholinergic neurons (cholinergic tone) interacting with intestinal macrophages in the muscle layer. Of interest, we have collected exciting data that the vagus nerve (and thus the cholinergic tone) also significantly contributes to mucosal immune homeostasis. Mice that underwent vagotomy lost their ability to develop tolerance to oral feeding of an antigen, whereas VNS reduced mucosal inflammation in a model of food allergy. Based on these data, we hypothesize that the cholinergic tone is a major determinant of the tolerogenic microenvironment of the mucosal immune system, and want to further explore the immune-modulatory effect of the vagal innervation and enteric neurons on the macrophages residing in the lamina propria. In addition, we will further explore the therapeutic potential and the mechanisms involved of chronic VNS in colitis and food allergy. Finally, we will translate our preclinical findings to the human situation. The anti-inflammatory effect of VNS (applied during surgery) will be studied in human intestinal tissue whereas the therapeutic potential of chronic VNS in Crohn’s disease will be studied in a pilot trial.
The outcome of this project will be ground-breaking and will have an immense impact on clinical management as it will provide new therapeutic opportunities for the treatment of immune-mediated gastrointestinal disorders.
Max ERC Funding
2 495 200 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym COLOURATOM
Project Colouring Atoms in 3 Dimensions
Researcher (PI) Sara Bals
Host Institution (HI) UNIVERSITEIT ANTWERPEN
Call Details Starting Grant (StG), PE4, ERC-2013-StG
Summary "Matter is a three dimensional (3D) agglomeration of atoms. The properties of materials are determined by the positions of the atoms, their chemical nature and the bonding between them. If we are able to determine these parameters in 3D, we will be able to provide the necessary input for predicting the properties and we can guide the synthesis and development of new nanomaterials.
The aim of this project is therefore to provide a complete 3D characterisation of complex hetero-nanosystems down to the atomic scale. The combination of advanced aberration corrected electron microscopy and novel 3D reconstruction algorithms is envisioned as a groundbreaking new approach to quantify the position AND the colour (chemical nature and bonding) of each individual atom in 3D for any given nanomaterial.
So far, only 3D imaging at the atomic scale was carried out for model-like systems. Measuring the position and the colour of the atoms in a complex nanomaterial can therefore be considered as an extremely challenging goal that will lead to a wealth of new information. Our objectives will enable 3D strain measurements at the atomic scale, localisation of atomic vacancies and interface characterisation in hetero-nanocrystals or hybrid soft-hard matter nanocompounds. Quantification of the oxidation states of surface atoms and of 3D surface relaxation will yield new insights concerning preferential functionalities.
Although these goals already go beyond the state-of-the-art, we plan to break fundamental limits and completely eliminate the need to tilt the sample for electron tomography. Especially for beam sensitive materials, this technique, so-called ""multi-detector stereoscopy"", can be considered as a groundbreaking approach to obtain 3D information at the atomic scale. As an ultimate ambition, we will investigate the dynamic behaviour of ultra-small binary clusters."
Summary
"Matter is a three dimensional (3D) agglomeration of atoms. The properties of materials are determined by the positions of the atoms, their chemical nature and the bonding between them. If we are able to determine these parameters in 3D, we will be able to provide the necessary input for predicting the properties and we can guide the synthesis and development of new nanomaterials.
The aim of this project is therefore to provide a complete 3D characterisation of complex hetero-nanosystems down to the atomic scale. The combination of advanced aberration corrected electron microscopy and novel 3D reconstruction algorithms is envisioned as a groundbreaking new approach to quantify the position AND the colour (chemical nature and bonding) of each individual atom in 3D for any given nanomaterial.
So far, only 3D imaging at the atomic scale was carried out for model-like systems. Measuring the position and the colour of the atoms in a complex nanomaterial can therefore be considered as an extremely challenging goal that will lead to a wealth of new information. Our objectives will enable 3D strain measurements at the atomic scale, localisation of atomic vacancies and interface characterisation in hetero-nanocrystals or hybrid soft-hard matter nanocompounds. Quantification of the oxidation states of surface atoms and of 3D surface relaxation will yield new insights concerning preferential functionalities.
Although these goals already go beyond the state-of-the-art, we plan to break fundamental limits and completely eliminate the need to tilt the sample for electron tomography. Especially for beam sensitive materials, this technique, so-called ""multi-detector stereoscopy"", can be considered as a groundbreaking approach to obtain 3D information at the atomic scale. As an ultimate ambition, we will investigate the dynamic behaviour of ultra-small binary clusters."
Max ERC Funding
1 461 466 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
