Project acronym ECOSTRESS
Project Physiological Reaction to Predation- A General Way to Link Individuals to Ecosystems
Researcher (PI) Dror Hawlena
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS8, ERC-2013-StG
Summary This proposal aims to advance a new general theory that links plasticity in prey responses to predation and biogeochemical processes to explain context-dependent variations in ecosystem functioning. The physiological reaction of prey to predation involves allocating resources from production to support emergency functions. An example of such a reaction is an increase in maintenance respiration concomitant with higher carbohydrate and lower N demand. Such changes in prey energy and elemental budget should alter the role prey play in regulating the quality of detrital inputs to soils. Nutrient content of detritus is an important determinant of the way soil communities regulate ecosystem processes. Thus, the physiological reaction of prey to predation can potentially explicate changes in ecosystem functioning. My first empirical examination of a few selected mechanisms of this theory has yielded very promising insights.
The main objectives of this proposal are: (1) To systematically test whether prey reactions to predation are consistent with the proposed theory’s predictions across species and ecosystems; (2) to examine the interface between stress physiology and anti-predatory behaviors in explaining predator induced diet shift, and (3) to evaluate how predator induced responses at the individual level regulate ecosystem processes. To address these objectives, I propose combining manipulative field experiments, highly controlled laboratory and garden experiments, and stable-isotopes pulse chase approaches. I will examine individual prey responses and the emerging patterns across five food-chains that represent phylogenetically distant taxa and disparate ecosystems. The proposed study is expected to revolutionize our understanding of the mechanisms by which aboveground predators regulate ecosystem processes. Promoting such a mechanistic understanding is crucial to predict how human-induced changes in biodiversity will affect life-supporting ecosystem services.
Summary
This proposal aims to advance a new general theory that links plasticity in prey responses to predation and biogeochemical processes to explain context-dependent variations in ecosystem functioning. The physiological reaction of prey to predation involves allocating resources from production to support emergency functions. An example of such a reaction is an increase in maintenance respiration concomitant with higher carbohydrate and lower N demand. Such changes in prey energy and elemental budget should alter the role prey play in regulating the quality of detrital inputs to soils. Nutrient content of detritus is an important determinant of the way soil communities regulate ecosystem processes. Thus, the physiological reaction of prey to predation can potentially explicate changes in ecosystem functioning. My first empirical examination of a few selected mechanisms of this theory has yielded very promising insights.
The main objectives of this proposal are: (1) To systematically test whether prey reactions to predation are consistent with the proposed theory’s predictions across species and ecosystems; (2) to examine the interface between stress physiology and anti-predatory behaviors in explaining predator induced diet shift, and (3) to evaluate how predator induced responses at the individual level regulate ecosystem processes. To address these objectives, I propose combining manipulative field experiments, highly controlled laboratory and garden experiments, and stable-isotopes pulse chase approaches. I will examine individual prey responses and the emerging patterns across five food-chains that represent phylogenetically distant taxa and disparate ecosystems. The proposed study is expected to revolutionize our understanding of the mechanisms by which aboveground predators regulate ecosystem processes. Promoting such a mechanistic understanding is crucial to predict how human-induced changes in biodiversity will affect life-supporting ecosystem services.
Max ERC Funding
1 379 600 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym ELECTROTALK
Project Starting an electrical conversation between microorganisms and electrodes to achieve bioproduction
Researcher (PI) Korneel Pieter Herman Leo Ann Rabaey
Host Institution (HI) UNIVERSITEIT GENT
Call Details Starting Grant (StG), LS9, ERC-2012-StG_20111109
Summary "Electrochemically active bacteria enable a host of novel processes in bioproduction, bioenergy and bioremediation. Key to the success of these processes is effective adherence of the bacterial cells to an electrode surface and subsequent equally effective electron exchange with the electrode. While the cellular mechanisms for electron transfer are increasingly known, what drives bacterial adsorption and desorption to positively or negatively polarized electrodes is largely unknown. Particularly processes driven by cathodes tend to be slow, and suffer from limited microbial adherence and lack of growth of the microorganisms. ELECTROTALK aims at developing a mechanistic understanding of mobility towards and microbial adherence at surfaces, from single cell level to complete biofilm formation. Based on this knowledge, effectively catalyzed bio-electrodes will be developed for novel bioproduction processes. Such bioproduction processes, termed microbial electrosynthesis, are independent of arable land availability, promise high production densities and enable the capture of CO2 or more efficient resource-usage for a range of products. Understanding the nature of the microorganism-electrode interaction will create a window of opportunity to improve this process and achieve effective bioproduction. Moreover, as the electrical interaction directly relates to microbial activity electrodes may serve as a means to start up a conversation with the cells. To achieve our aims we will: (i) select and characterize biocatalysts both as pure cultures and microbial communities; (ii) investigate cell adherence and electron transfer in function of electrode topography and chemistry as well as under different operational conditions; (iii) develop an electrode-microorganism combination achieving effective electron transfer; and (iv) electrochemically construct biofilms with defined structure or stratification."
Summary
"Electrochemically active bacteria enable a host of novel processes in bioproduction, bioenergy and bioremediation. Key to the success of these processes is effective adherence of the bacterial cells to an electrode surface and subsequent equally effective electron exchange with the electrode. While the cellular mechanisms for electron transfer are increasingly known, what drives bacterial adsorption and desorption to positively or negatively polarized electrodes is largely unknown. Particularly processes driven by cathodes tend to be slow, and suffer from limited microbial adherence and lack of growth of the microorganisms. ELECTROTALK aims at developing a mechanistic understanding of mobility towards and microbial adherence at surfaces, from single cell level to complete biofilm formation. Based on this knowledge, effectively catalyzed bio-electrodes will be developed for novel bioproduction processes. Such bioproduction processes, termed microbial electrosynthesis, are independent of arable land availability, promise high production densities and enable the capture of CO2 or more efficient resource-usage for a range of products. Understanding the nature of the microorganism-electrode interaction will create a window of opportunity to improve this process and achieve effective bioproduction. Moreover, as the electrical interaction directly relates to microbial activity electrodes may serve as a means to start up a conversation with the cells. To achieve our aims we will: (i) select and characterize biocatalysts both as pure cultures and microbial communities; (ii) investigate cell adherence and electron transfer in function of electrode topography and chemistry as well as under different operational conditions; (iii) develop an electrode-microorganism combination achieving effective electron transfer; and (iv) electrochemically construct biofilms with defined structure or stratification."
Max ERC Funding
1 494 126 €
Duration
Start date: 2012-10-01, End date: 2017-09-30
Project acronym ELIMINATESENESCENT
Project The Role of Elimination of Senescent Cells in Cancer Development
Researcher (PI) Valery Krizhanovsky
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary Cellular senescence, which is a terminal cell cycle arrest, is a potent tumor suppressor mechanism that limits cancer initiation and progression; it also limits tissue damage response. While senescence is protective in the cell autonomous manner, senescent cells secrete a variety of factors that lead to inflammation, tissue destruction and promote tumorigenesis and metastasis in the sites of their presence. Here we propose a unique approach – to eliminate senescent cells from tissues in order to prevent the deleterious cell non-autonomous effects of these cells. We will use our understanding in immune surveillance of senescent cells, and in cell-intrinsic molecular pathways regulating cell viability, to identify the molecular “Achilles’ heal” of senescent cells. We will identify the mechanisms of interaction of senescent cells with NK cells and other immune cells, and harness these mechanisms for elimination of senescent cells. The impact of components of the main pathways regulating cell viability, apoptosis and autophagy, will then be evaluated for their specific contribution to the viability of senescent cells.
The molecular players identified by all these approaches will be readily implemented for the elimination of senescent cells in vivo. We will consequently be able to evaluate the impact of the elimination of senescent cells on tumor progression, in mouse models, where these cells are present during initial stages of tumorigenesis. Additionally, we will develop a novel mouse model that will allow identification of senescent cells in vivo in real time. This model is particularly challenging and valuable due to absence of single molecular marker for senescent cells.
The ability to eliminate senescent cells will lead to the understanding of the role of presence of senescent cells in tissues and the mechanisms regulating their viability. This might suggest novel ways of cancer prevention and treatment.
Summary
Cellular senescence, which is a terminal cell cycle arrest, is a potent tumor suppressor mechanism that limits cancer initiation and progression; it also limits tissue damage response. While senescence is protective in the cell autonomous manner, senescent cells secrete a variety of factors that lead to inflammation, tissue destruction and promote tumorigenesis and metastasis in the sites of their presence. Here we propose a unique approach – to eliminate senescent cells from tissues in order to prevent the deleterious cell non-autonomous effects of these cells. We will use our understanding in immune surveillance of senescent cells, and in cell-intrinsic molecular pathways regulating cell viability, to identify the molecular “Achilles’ heal” of senescent cells. We will identify the mechanisms of interaction of senescent cells with NK cells and other immune cells, and harness these mechanisms for elimination of senescent cells. The impact of components of the main pathways regulating cell viability, apoptosis and autophagy, will then be evaluated for their specific contribution to the viability of senescent cells.
The molecular players identified by all these approaches will be readily implemented for the elimination of senescent cells in vivo. We will consequently be able to evaluate the impact of the elimination of senescent cells on tumor progression, in mouse models, where these cells are present during initial stages of tumorigenesis. Additionally, we will develop a novel mouse model that will allow identification of senescent cells in vivo in real time. This model is particularly challenging and valuable due to absence of single molecular marker for senescent cells.
The ability to eliminate senescent cells will lead to the understanding of the role of presence of senescent cells in tissues and the mechanisms regulating their viability. This might suggest novel ways of cancer prevention and treatment.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-11-01, End date: 2017-10-31
Project acronym ENCODE
Project Design Principles in Encoding Complex Noisy Environments
Researcher (PI) Alon Zaslaver
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS2, ERC-2013-StG
Summary Animals constantly face complex environments consisted of multiple fluctuating cues. Accurate detection and efficient integration of such perplexing information are essential as animals’ fitness and consequently survival depend on making the right behavioral decisions. However, little is known about how multifaceted stimuli are integrated by neural systems, and how this information flows in the neural network in a single-neuron resolution.
Here we aim to address these fundamental questions using C. elegans worms as a model system. With a compact and fully-mapped neural network, C. elegans offers a unique opportunity of generating novel breakthroughs and significantly advance the field.
To study functional dynamics on a network-wide scale with an unprecedented single-neuron resolution, we will construct a comprehensive library of transgenic animals expressing state-of-the-art optogenetic tools and Calcium indicators in individual neurons. Moreover, we will study the entire encoding process, beginning with the sensory layer, through integration in the neural network, to behavioral outputs. At the sensory level, we aim to reveal how small sensory systems efficiently encode the complex external world. Next, we will decipher the design principles by which neural circuits integrate and process information. The optogenetic transgenic animals will allow us interrogating computational roles of various circuits by manipulating individual neurons in the network. At the end, we will integrate the gathered knowledge to study how encoding eventually translates to decision making behavioral outputs.
Throughout this project, we will use a combination of cutting-edge experimental techniques coupled with extensive computational analyses, modelling and theory. The aims of this interdisciplinary project together with the system-level approaches put it in the front line of research in the Systems Biology field.
Summary
Animals constantly face complex environments consisted of multiple fluctuating cues. Accurate detection and efficient integration of such perplexing information are essential as animals’ fitness and consequently survival depend on making the right behavioral decisions. However, little is known about how multifaceted stimuli are integrated by neural systems, and how this information flows in the neural network in a single-neuron resolution.
Here we aim to address these fundamental questions using C. elegans worms as a model system. With a compact and fully-mapped neural network, C. elegans offers a unique opportunity of generating novel breakthroughs and significantly advance the field.
To study functional dynamics on a network-wide scale with an unprecedented single-neuron resolution, we will construct a comprehensive library of transgenic animals expressing state-of-the-art optogenetic tools and Calcium indicators in individual neurons. Moreover, we will study the entire encoding process, beginning with the sensory layer, through integration in the neural network, to behavioral outputs. At the sensory level, we aim to reveal how small sensory systems efficiently encode the complex external world. Next, we will decipher the design principles by which neural circuits integrate and process information. The optogenetic transgenic animals will allow us interrogating computational roles of various circuits by manipulating individual neurons in the network. At the end, we will integrate the gathered knowledge to study how encoding eventually translates to decision making behavioral outputs.
Throughout this project, we will use a combination of cutting-edge experimental techniques coupled with extensive computational analyses, modelling and theory. The aims of this interdisciplinary project together with the system-level approaches put it in the front line of research in the Systems Biology field.
Max ERC Funding
1 498 400 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym ENGVASC
Project Engineering Vascularized Tissues
Researcher (PI) Shulamit Levenberg
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), LS7, ERC-2011-StG_20101109
Summary Vascularization, the process in which new blood vessels assemble, is fundamental to tissue vitality. Vessel network assembly within 3D tissues can be induced in-vitro by means of multicellular culturing of endothelial cells (EC), fibroblasts and cells specific to the tissue of interest. This approach supports formation of endothelial vessels and promotes EC and tissue-specific cell interactions. Such EC-dependent tube-like openings may also form the basis for improved media penetration to the inner regions of thick 3D constructs, allowing for enhanced construct survival and for effective engineering of large complex tissues in the lab. Moreover, our own breakthrough results describe the beneficial impact of in vitro prevascularization of engineered muscle tissue on its survival and vascularization upon implantation. These studies have also demonstrated that implanted vascular networks of in vitro engineered constructs, can anastomose with host vasculature and form functional blood vessels in vivo. However, the mechanisms underlying enhanced vascularization of endothelialized engineered constructs and implant-host vessel integration remain unclear. In this proposal, our research objectives are (1) to uncover the mechanisms governing in vitro vessel network formation in engineered 3D tissues and (2) to elucidate the process of graft-host vessel network integration and implant vessel-stimulated promotion of neovascularization in vivo. In addition, the impact of construct prevascularization on implant survival and function will be explored in animal disease models. While there are still many challenges ahead, should we succeed, our research could lay the foundation for significantly enhanced tissue construct vascularization procedures and for their application in regenerative medicine. In addition, it may provide alternative models for studying the vascularization processes in embryogenesis and disease.
Summary
Vascularization, the process in which new blood vessels assemble, is fundamental to tissue vitality. Vessel network assembly within 3D tissues can be induced in-vitro by means of multicellular culturing of endothelial cells (EC), fibroblasts and cells specific to the tissue of interest. This approach supports formation of endothelial vessels and promotes EC and tissue-specific cell interactions. Such EC-dependent tube-like openings may also form the basis for improved media penetration to the inner regions of thick 3D constructs, allowing for enhanced construct survival and for effective engineering of large complex tissues in the lab. Moreover, our own breakthrough results describe the beneficial impact of in vitro prevascularization of engineered muscle tissue on its survival and vascularization upon implantation. These studies have also demonstrated that implanted vascular networks of in vitro engineered constructs, can anastomose with host vasculature and form functional blood vessels in vivo. However, the mechanisms underlying enhanced vascularization of endothelialized engineered constructs and implant-host vessel integration remain unclear. In this proposal, our research objectives are (1) to uncover the mechanisms governing in vitro vessel network formation in engineered 3D tissues and (2) to elucidate the process of graft-host vessel network integration and implant vessel-stimulated promotion of neovascularization in vivo. In addition, the impact of construct prevascularization on implant survival and function will be explored in animal disease models. While there are still many challenges ahead, should we succeed, our research could lay the foundation for significantly enhanced tissue construct vascularization procedures and for their application in regenerative medicine. In addition, it may provide alternative models for studying the vascularization processes in embryogenesis and disease.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-10-01, End date: 2017-09-30
Project acronym ENIGMO
Project "Gut microbiota, innate immunity and endocannabinoid system interactions link metabolic inflammation with the hallmarks of obesity and type 2 diabetes"
Researcher (PI) Patrice Daniel Cani
Host Institution (HI) UNIVERSITE CATHOLIQUE DE LOUVAIN
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary "Obesity and type 2 diabetes are characterized by metabolic inflammation and an altered endocannabinoid system (eCB) tone. We have provided evidence that gut microbiota modulate both intestinal and adipose tissue eCB system tone. Insulin resistance and inflammation have been linked to microbiota-host interaction via different Toll-Like Receptors (TLR’s). Our preliminary data show that tamoxifen-induced epithelial intestinal cells deletion of the key signalling adaptor MyD88 (myeloid differentiation primary-response gene 88), that encompass most of the TLR’s, protect mice against diet-induced obesity and inflammation. A phenomenon closely linked with changes in the intestinal eCB system tone and antimicrobial peptides production. Moreover, we discovered that the recently identified bacteria living in the mucus layer, namely Akkermansia muciniphila, plays a central role in the regulation of host energy metabolism by putative mechanisms linking both the intestinal eCB system and the innate immune system. Thus these preliminary data support the existence of unidentified mechanisms linking the innate immune system, the gut microbiota and host metabolism. In this high-risk/high-gain research program, we propose to elucidate what could be one of the most fundamental processes shared by different key hallmarks of obesity and related diseases. A careful and thorough analysis of the molecular and cellular events linking gut microbiota, the innate immune system and eCB system in specific organs has the potential to unravel new therapeutic targets. We anticipate the key role of MyD88 and the enzyme NAPE-PLD (N-acylphosphatidylethanolamine phospholipase-D) involved in the synthesis of N-acylethanolamines family to be key determinant in such pathophysiological aspects. Thus, these approaches could provide different perspectives about disease pathogenesis and knowledge-based evidence of new therapeutic options for obesity and associated metabolic disorders in the future."
Summary
"Obesity and type 2 diabetes are characterized by metabolic inflammation and an altered endocannabinoid system (eCB) tone. We have provided evidence that gut microbiota modulate both intestinal and adipose tissue eCB system tone. Insulin resistance and inflammation have been linked to microbiota-host interaction via different Toll-Like Receptors (TLR’s). Our preliminary data show that tamoxifen-induced epithelial intestinal cells deletion of the key signalling adaptor MyD88 (myeloid differentiation primary-response gene 88), that encompass most of the TLR’s, protect mice against diet-induced obesity and inflammation. A phenomenon closely linked with changes in the intestinal eCB system tone and antimicrobial peptides production. Moreover, we discovered that the recently identified bacteria living in the mucus layer, namely Akkermansia muciniphila, plays a central role in the regulation of host energy metabolism by putative mechanisms linking both the intestinal eCB system and the innate immune system. Thus these preliminary data support the existence of unidentified mechanisms linking the innate immune system, the gut microbiota and host metabolism. In this high-risk/high-gain research program, we propose to elucidate what could be one of the most fundamental processes shared by different key hallmarks of obesity and related diseases. A careful and thorough analysis of the molecular and cellular events linking gut microbiota, the innate immune system and eCB system in specific organs has the potential to unravel new therapeutic targets. We anticipate the key role of MyD88 and the enzyme NAPE-PLD (N-acylphosphatidylethanolamine phospholipase-D) involved in the synthesis of N-acylethanolamines family to be key determinant in such pathophysiological aspects. Thus, these approaches could provide different perspectives about disease pathogenesis and knowledge-based evidence of new therapeutic options for obesity and associated metabolic disorders in the future."
Max ERC Funding
1 494 640 €
Duration
Start date: 2013-10-01, End date: 2018-09-30
Project acronym ENVIROIMMUNE
Project Environmental modulators of the immune cell balance in health and disease
Researcher (PI) Markus Kleinewietfeld
Host Institution (HI) VIB
Call Details Starting Grant (StG), LS6, ERC-2014-STG
Summary The incidence of autoimmune diseases in developed societies is increasing at high rates, but the underlying cause for this phenomenon has not been elucidated yet. Since the genetic architect remains considerably stable, this increase is likely associated with changes in the environment. Autoimmunity is linked to an imbalance of pro-inflammatory Th17 cells and anti-inflammatory Foxp3+ regulatory T cells (Treg). However, little is known regarding environmental factors that influence the Th17/Treg balance. We recently discovered that a sodium-rich diet severely exacerbates experimental autoimmune encephalomyelitis (EAE) through an increased induction of pathogenic Th17 cells. Surprisingly, our preliminary data indicate that high-salt conditions also significantly impair Treg function, resembling a phenotype observed in several human autoimmune diseases. In addition, we have evidence that a high-salt diet affects the gut microbiota, implicating possible indirect effects on immune cells in vivo. Based on these findings we hypothesize that excess dietary salt represents an environmental risk factor for autoimmune diseases by modulating the Th17/Treg balance by several direct and indirect mechanisms. To address this hypothesis we will 1) examine the underlying mechanisms of high-salt induced Treg dysfunction and effects on the Treg/Th17 balance by molecular and functional analysis in vitro and compare it to known risk variants of human autoimmune diseases, and 2) define direct and indirect effects of excess dietary salt on the Th17/Treg balance and autoimmunity in vivo and explore potential novel pathways for targeted interventions. Thus, the proposed study will uncover the impact of a newly discovered environmental modulator of the immune cell balance and will ultimately pave the way for new approaches in therapy and prevention of autoimmune diseases.
Summary
The incidence of autoimmune diseases in developed societies is increasing at high rates, but the underlying cause for this phenomenon has not been elucidated yet. Since the genetic architect remains considerably stable, this increase is likely associated with changes in the environment. Autoimmunity is linked to an imbalance of pro-inflammatory Th17 cells and anti-inflammatory Foxp3+ regulatory T cells (Treg). However, little is known regarding environmental factors that influence the Th17/Treg balance. We recently discovered that a sodium-rich diet severely exacerbates experimental autoimmune encephalomyelitis (EAE) through an increased induction of pathogenic Th17 cells. Surprisingly, our preliminary data indicate that high-salt conditions also significantly impair Treg function, resembling a phenotype observed in several human autoimmune diseases. In addition, we have evidence that a high-salt diet affects the gut microbiota, implicating possible indirect effects on immune cells in vivo. Based on these findings we hypothesize that excess dietary salt represents an environmental risk factor for autoimmune diseases by modulating the Th17/Treg balance by several direct and indirect mechanisms. To address this hypothesis we will 1) examine the underlying mechanisms of high-salt induced Treg dysfunction and effects on the Treg/Th17 balance by molecular and functional analysis in vitro and compare it to known risk variants of human autoimmune diseases, and 2) define direct and indirect effects of excess dietary salt on the Th17/Treg balance and autoimmunity in vivo and explore potential novel pathways for targeted interventions. Thus, the proposed study will uncover the impact of a newly discovered environmental modulator of the immune cell balance and will ultimately pave the way for new approaches in therapy and prevention of autoimmune diseases.
Max ERC Funding
1 499 041 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
Project acronym ENVIRONAGE
Project Unravelling environmental exposures
in the core axis of ageing
Researcher (PI) Tim Nawrot
Host Institution (HI) UNIVERSITEIT HASSELT
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary "AGEing is a complex phenotype responsive to a plethora of ENVIRONmental inputs (ENVIRONAGE). Age related conditions in adults often find their origin in risk factors operative in early life. The molecular mechanisms behind these phenomena remain largely unknown. Mitochondria are involved in a variety of critical cell functions, including oxidative energy production and programmed cell death. Recently, I established in a study of 175 newborns, a strong association between mitochondrial DNA content and in utero exposure to particulate air pollution. Telomere length is highly heritable and erosion leads to an increasingly vulnerable structural integrity of the chromosomes. It is considered a marker of overall biological age compared with chronological age. In this regard, I demonstrated the heritability of telomere length and the influence of smoking on telomere erosion. These results support the ENVIRONAGE hypothesis, i.e. that environmental inputs influence biomolecular markers of ageing including mitochondrial function, telomere length along with DNA repair and epigenetics as the ‘core axis of ageing’. The aim is to establish prospective epidemiological evidence for molecular mechanisms or early biomarkers, which may underlie the origins or reflect the risk of age-related diseases and to understand its association with other processes and the influence of environmental factors. To this end, I will establish a birth cohort and a cohort in middle-aged and elderly. I measure environmental pollutants, in interaction with parameters that I consider to have an important role in the ageing process (mitochondrial function, telomere length, epigenetics and DNA repair capacity). ENVIRONAGE integrates environmental influences and molecular mechanisms on ageing. The common molecular epidemiological strategies in newborns, middle-aged and elderly to unravel the environmental influence on ageing are groundbreaking."
Summary
"AGEing is a complex phenotype responsive to a plethora of ENVIRONmental inputs (ENVIRONAGE). Age related conditions in adults often find their origin in risk factors operative in early life. The molecular mechanisms behind these phenomena remain largely unknown. Mitochondria are involved in a variety of critical cell functions, including oxidative energy production and programmed cell death. Recently, I established in a study of 175 newborns, a strong association between mitochondrial DNA content and in utero exposure to particulate air pollution. Telomere length is highly heritable and erosion leads to an increasingly vulnerable structural integrity of the chromosomes. It is considered a marker of overall biological age compared with chronological age. In this regard, I demonstrated the heritability of telomere length and the influence of smoking on telomere erosion. These results support the ENVIRONAGE hypothesis, i.e. that environmental inputs influence biomolecular markers of ageing including mitochondrial function, telomere length along with DNA repair and epigenetics as the ‘core axis of ageing’. The aim is to establish prospective epidemiological evidence for molecular mechanisms or early biomarkers, which may underlie the origins or reflect the risk of age-related diseases and to understand its association with other processes and the influence of environmental factors. To this end, I will establish a birth cohort and a cohort in middle-aged and elderly. I measure environmental pollutants, in interaction with parameters that I consider to have an important role in the ageing process (mitochondrial function, telomere length, epigenetics and DNA repair capacity). ENVIRONAGE integrates environmental influences and molecular mechanisms on ageing. The common molecular epidemiological strategies in newborns, middle-aged and elderly to unravel the environmental influence on ageing are groundbreaking."
Max ERC Funding
1 473 910 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym EpiTALL
Project Dynamic interplay between DNA methylation, histone modifications and super enhancer activity in normal T cells and during malignant T cell transformation
Researcher (PI) Pieter Van vlierberghe
Host Institution (HI) UNIVERSITEIT GENT
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary Dynamic interplay between histone modifications and DNA methylation defines the chromatin structure of the humane genome and serves as a conceptual framework to understand transcriptional regulation in normal development and human disease. The ultimate goal of this research proposal is to study the chromatin architecture during normal and malignant T cell differentiation in order to define how DNA methylation drives oncogenic gene expression as a novel concept in cancer research.
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of pediatric and 25% of adult ALL cases and was originally identified as a highly aggressive tumor entity. T-ALL therapy has been intensified leading to gradual improvements in survival. However, 20% of pediatric and 50% of adult T-ALL cases still relapse and ultimately die because of refractory disease. Research efforts have unravelled the complex genetic basis of T-ALL but failed to identify new promising targets for precision therapy.
Recent studies have identified a subset of T-ALLs whose transcriptional programs resemble those of early T-cell progenitors (ETPs), myeloid precursors and hematopoietic stem cells. Importantly, these so-called ETP-ALLs are characterized by early treatment failure and an extremely poor prognosis. The unique ETP-ALL gene expression signature suggests that the epigenomic landscape in ETP-ALL is markedly different as compared to other genetic subtypes of human T-ALL.
My project aims to identify genome-wide patterns of DNA methylation and histone modifications in genetic subtypes of human T-ALL as a basis for elucidating how DNA methylation drives the expression of critical oncogenes in the context of poor prognostic ETP-ALL. Given that these ETP-ALL patients completely fail current chemotherapy treatment, tackling this completely novel aspect of ETP-ALL genetics will yield new targets for therapeutic intervention in this aggressive haematological malignancy.
Summary
Dynamic interplay between histone modifications and DNA methylation defines the chromatin structure of the humane genome and serves as a conceptual framework to understand transcriptional regulation in normal development and human disease. The ultimate goal of this research proposal is to study the chromatin architecture during normal and malignant T cell differentiation in order to define how DNA methylation drives oncogenic gene expression as a novel concept in cancer research.
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of pediatric and 25% of adult ALL cases and was originally identified as a highly aggressive tumor entity. T-ALL therapy has been intensified leading to gradual improvements in survival. However, 20% of pediatric and 50% of adult T-ALL cases still relapse and ultimately die because of refractory disease. Research efforts have unravelled the complex genetic basis of T-ALL but failed to identify new promising targets for precision therapy.
Recent studies have identified a subset of T-ALLs whose transcriptional programs resemble those of early T-cell progenitors (ETPs), myeloid precursors and hematopoietic stem cells. Importantly, these so-called ETP-ALLs are characterized by early treatment failure and an extremely poor prognosis. The unique ETP-ALL gene expression signature suggests that the epigenomic landscape in ETP-ALL is markedly different as compared to other genetic subtypes of human T-ALL.
My project aims to identify genome-wide patterns of DNA methylation and histone modifications in genetic subtypes of human T-ALL as a basis for elucidating how DNA methylation drives the expression of critical oncogenes in the context of poor prognostic ETP-ALL. Given that these ETP-ALL patients completely fail current chemotherapy treatment, tackling this completely novel aspect of ETP-ALL genetics will yield new targets for therapeutic intervention in this aggressive haematological malignancy.
Max ERC Funding
958 750 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym EQUOP
Project Equal opportunities for migrant youth in educational systems with high levels of social and ethnic segregation: assessing the impact of school team resources
Researcher (PI) Dirk Jean Alexander Jacobs
Host Institution (HI) UNIVERSITE LIBRE DE BRUXELLES
Call Details Starting Grant (StG), SH2, ERC-2011-StG_20101124
Summary Although a gap in educational performance of migrant children compared to children without a migration background is to be observed in most industrialized countries, it is particularly big in countries as Belgium, Germany, Austria and the Netherlands, as has been attested by the PISA-data. Social and ethnic segregation, which is particularly high in these educational systems, seems to be one of the important explanatory factors. This project wants to disentangle what are the crucial factors by which this high level of segregation impacts on unequal opportunities for immigrant children. Going beyond the classic composition effect model (looking at peer group effects, i.e. positive or negative influences of pupils on each other), this project wants to also examine the potential impact of differentiated teacher profiles on group performance. The project wishes to test the hypothesis that the link between school composition and educational performance is a (partly) spurious effect, caused by mediating effect of teacher characteristics. We hypothesize that better skilled and more positively oriented teachers are overrepresented in schools with an 'easier' school population, while so-called 'difficult' schools (populated by working-class immigrant children) have difficulty in attracting and - especially - keeping competent and motivated staff. In order to examine this hypothesis a mixed methods approach will be used, combining quantitative statistical analysis (on new and existing data, for instance multi-level analysis of the PISA-data set and other eligible datasets), qualitative case studies and focus groups. Secondary analysis of existing data-sets (PISA, TIMMS, PIRLS) will be undertaken and new data will be collected (taking the Flemish and Francophone educational systems in Belgium as case-studies).
Summary
Although a gap in educational performance of migrant children compared to children without a migration background is to be observed in most industrialized countries, it is particularly big in countries as Belgium, Germany, Austria and the Netherlands, as has been attested by the PISA-data. Social and ethnic segregation, which is particularly high in these educational systems, seems to be one of the important explanatory factors. This project wants to disentangle what are the crucial factors by which this high level of segregation impacts on unequal opportunities for immigrant children. Going beyond the classic composition effect model (looking at peer group effects, i.e. positive or negative influences of pupils on each other), this project wants to also examine the potential impact of differentiated teacher profiles on group performance. The project wishes to test the hypothesis that the link between school composition and educational performance is a (partly) spurious effect, caused by mediating effect of teacher characteristics. We hypothesize that better skilled and more positively oriented teachers are overrepresented in schools with an 'easier' school population, while so-called 'difficult' schools (populated by working-class immigrant children) have difficulty in attracting and - especially - keeping competent and motivated staff. In order to examine this hypothesis a mixed methods approach will be used, combining quantitative statistical analysis (on new and existing data, for instance multi-level analysis of the PISA-data set and other eligible datasets), qualitative case studies and focus groups. Secondary analysis of existing data-sets (PISA, TIMMS, PIRLS) will be undertaken and new data will be collected (taking the Flemish and Francophone educational systems in Belgium as case-studies).
Max ERC Funding
1 276 071 €
Duration
Start date: 2012-01-01, End date: 2017-06-30
