Project acronym AGNES
Project ACTIVE AGEING – RESILIENCE AND EXTERNAL SUPPORT AS MODIFIERS OF THE DISABLEMENT OUTCOME
Researcher (PI) Taina Tuulikki RANTANEN
Host Institution (HI) JYVASKYLAN YLIOPISTO
Call Details Advanced Grant (AdG), SH3, ERC-2015-AdG
Summary The goals are 1. To develop a scale assessing the diversity of active ageing with four dimensions that are ability (what people can do), activity (what people do do), ambition (what are the valued activities that people want to do), and autonomy (how satisfied people are with the opportunity to do valued activities); 2. To examine health and physical and psychological functioning as the determinants and social and build environment, resilience and personal skills as modifiers of active ageing; 3. To develop a multicomponent sustainable intervention aiming to promote active ageing (methods: counselling, information technology, help from volunteers); 4. To test the feasibility and effectiveness on the intervention; and 5. To study cohort effects on the phenotypes on the pathway to active ageing.
“If You Can Measure It, You Can Change It.” Active ageing assessment needs conceptual progress, which I propose to do. A quantifiable scale will be developed that captures the diversity of active ageing stemming from the WHO definition of active ageing as the process of optimizing opportunities for health and participation in the society for all people in line with their needs, goals and capacities as they age. I will collect cross-sectional data (N=1000, ages 75, 80 and 85 years) and model the pathway to active ageing with state-of-the art statistical methods. By doing this I will create novel knowledge on preconditions for active ageing. The collected cohort data will be compared to a pre-existing cohort data that was collected 25 years ago to obtain knowledge about changes over time in functioning of older people. A randomized controlled trial (N=200) will be conducted to assess the effectiveness of the envisioned intervention promoting active ageing through participation. The project will regenerate ageing research by launching a novel scale, by training young scientists, by creating new concepts and theory development and by producing evidence for active ageing promotion
Summary
The goals are 1. To develop a scale assessing the diversity of active ageing with four dimensions that are ability (what people can do), activity (what people do do), ambition (what are the valued activities that people want to do), and autonomy (how satisfied people are with the opportunity to do valued activities); 2. To examine health and physical and psychological functioning as the determinants and social and build environment, resilience and personal skills as modifiers of active ageing; 3. To develop a multicomponent sustainable intervention aiming to promote active ageing (methods: counselling, information technology, help from volunteers); 4. To test the feasibility and effectiveness on the intervention; and 5. To study cohort effects on the phenotypes on the pathway to active ageing.
“If You Can Measure It, You Can Change It.” Active ageing assessment needs conceptual progress, which I propose to do. A quantifiable scale will be developed that captures the diversity of active ageing stemming from the WHO definition of active ageing as the process of optimizing opportunities for health and participation in the society for all people in line with their needs, goals and capacities as they age. I will collect cross-sectional data (N=1000, ages 75, 80 and 85 years) and model the pathway to active ageing with state-of-the art statistical methods. By doing this I will create novel knowledge on preconditions for active ageing. The collected cohort data will be compared to a pre-existing cohort data that was collected 25 years ago to obtain knowledge about changes over time in functioning of older people. A randomized controlled trial (N=200) will be conducted to assess the effectiveness of the envisioned intervention promoting active ageing through participation. The project will regenerate ageing research by launching a novel scale, by training young scientists, by creating new concepts and theory development and by producing evidence for active ageing promotion
Max ERC Funding
2 044 364 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym ANTILEAK
Project Development of antagonists of vascular leakage
Researcher (PI) Pipsa SAHARINEN
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Summary
Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Max ERC Funding
1 999 770 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym ANXIETY & COGNITION
Project How anxiety transforms human cognition: an Affective Neuroscience perspective
Researcher (PI) Gilles Roger Charles Pourtois
Host Institution (HI) UNIVERSITEIT GENT
Call Details Starting Grant (StG), SH3, ERC-2007-StG
Summary Anxiety, a state of apprehension or fear, may provoke cognitive or behavioural disorders and eventually lead to serious medical illnesses. The high prevalence of anxiety disorders in our society sharply contrasts with the lack of clear factual knowledge about the corresponding brain mechanisms at the origin of this profound change in the appraisal of the environment. Little is known about how the psychopathological state of anxiety ultimately turns to a medical condition. The core of this proposal is to gain insight in the neural underpinnings of anxiety and disorders related to anxiety using modern human brain-imaging such as scalp EEG and fMRI. I propose to enlighten how anxiety transforms and shapes human cognition and what the neural correlates and time-course of this modulatory effect are. The primary innovation of this project is the systematic use scalp EEG and fMRI in human participants to better understand the neural mechanisms by which anxiety profoundly influences specific cognitive functions, in particular selective attention and decision-making. The goal of this proposal is to precisely determine the exact timing (using scalp EEG), location, size and extent (using fMRI) of anxiety-related modulations on selective attention and decision-making in the human brain. Here I propose to focus on these two specific processes, because they are likely to reveal selective effects of anxiety on human cognition and can thus serve as powerful models to better figure out how anxiety operates in the human brain. Another important aspect of this project is the fact I envision to help bridge the gap in Health Psychology between fundamental research and clinical practice by proposing alternative revalidation strategies for human adult subjects affected by anxiety-related disorders, which could directly exploit the neuro-scientific discoveries generated in this scientific project.
Summary
Anxiety, a state of apprehension or fear, may provoke cognitive or behavioural disorders and eventually lead to serious medical illnesses. The high prevalence of anxiety disorders in our society sharply contrasts with the lack of clear factual knowledge about the corresponding brain mechanisms at the origin of this profound change in the appraisal of the environment. Little is known about how the psychopathological state of anxiety ultimately turns to a medical condition. The core of this proposal is to gain insight in the neural underpinnings of anxiety and disorders related to anxiety using modern human brain-imaging such as scalp EEG and fMRI. I propose to enlighten how anxiety transforms and shapes human cognition and what the neural correlates and time-course of this modulatory effect are. The primary innovation of this project is the systematic use scalp EEG and fMRI in human participants to better understand the neural mechanisms by which anxiety profoundly influences specific cognitive functions, in particular selective attention and decision-making. The goal of this proposal is to precisely determine the exact timing (using scalp EEG), location, size and extent (using fMRI) of anxiety-related modulations on selective attention and decision-making in the human brain. Here I propose to focus on these two specific processes, because they are likely to reveal selective effects of anxiety on human cognition and can thus serve as powerful models to better figure out how anxiety operates in the human brain. Another important aspect of this project is the fact I envision to help bridge the gap in Health Psychology between fundamental research and clinical practice by proposing alternative revalidation strategies for human adult subjects affected by anxiety-related disorders, which could directly exploit the neuro-scientific discoveries generated in this scientific project.
Max ERC Funding
812 986 €
Duration
Start date: 2008-11-01, End date: 2013-10-31
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 BRAVE
Project "Bicuspid Related Aortopathy, a Vibrant Exploration"
Researcher (PI) Bart Leo Loeys
Host Institution (HI) UNIVERSITEIT ANTWERPEN
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary "Bicuspid aortic valve, a heart valve with only two leaflets instead of three, is the most common congenital heart defect with an estimated prevalence of about 1-2%. The heart defect often remains asymptomatic but in at least 10% of the bicuspid aortic valve patients, an ascending aortic aneurysm develops as well. If not detected in a timely fashion, this can lead to an aortic aneurysm dissection with a high mortality. In view of the prevalent nature of this heart defect, this implies an important health care problem. Historically, it was always hypothesized that abnormal blood flow across the bicuspid aortic valve led to aneurysm formation. However in recent years, the importance of a genetic contribution has been suggested based on the high heritability and it is currently believed that the same genetic factors predispose to the developmental valve defect and the aortic aneurysm formation. The inheritance pattern is most consistent with an autosomal dominant disorder with variable penetrance and expressivity. Until now, the latter have significantly hampered the causal gene identification but the era of next generation sequencing is now offering unprecedented opportunities for a major breakthrough in this area.
Through detailed signalling pathway analysis, miRNA profiling and next generation sequencing, this project will contribute significantly to resolving the genetic causes of bicuspid related aortopathy, provide critical knowledge on the pathogenesis of aortic aneurysmal disease and deliver a mouse model for future therapeutical trials."
Summary
"Bicuspid aortic valve, a heart valve with only two leaflets instead of three, is the most common congenital heart defect with an estimated prevalence of about 1-2%. The heart defect often remains asymptomatic but in at least 10% of the bicuspid aortic valve patients, an ascending aortic aneurysm develops as well. If not detected in a timely fashion, this can lead to an aortic aneurysm dissection with a high mortality. In view of the prevalent nature of this heart defect, this implies an important health care problem. Historically, it was always hypothesized that abnormal blood flow across the bicuspid aortic valve led to aneurysm formation. However in recent years, the importance of a genetic contribution has been suggested based on the high heritability and it is currently believed that the same genetic factors predispose to the developmental valve defect and the aortic aneurysm formation. The inheritance pattern is most consistent with an autosomal dominant disorder with variable penetrance and expressivity. Until now, the latter have significantly hampered the causal gene identification but the era of next generation sequencing is now offering unprecedented opportunities for a major breakthrough in this area.
Through detailed signalling pathway analysis, miRNA profiling and next generation sequencing, this project will contribute significantly to resolving the genetic causes of bicuspid related aortopathy, provide critical knowledge on the pathogenesis of aortic aneurysmal disease and deliver a mouse model for future therapeutical trials."
Max ERC Funding
1 497 895 €
Duration
Start date: 2013-05-01, End date: 2018-04-30
Project acronym CHILDMOVE
Project The impact of flight experiences on the psychological wellbeing of unaccompanied refugee minors
Researcher (PI) Ilse DERLUYN
Host Institution (HI) UNIVERSITEIT GENT
Call Details Starting Grant (StG), SH3, ERC-2016-STG
Summary Since early 2015, the media continuously confront us with images of refugee children drowning in the Mediterranean, surviving in appalling conditions in camps or walking across Europe. Within this group of fleeing children, a considerable number is travelling without parents, the unaccompanied refugee minors.
While the media images testify to these flight experiences and their possible huge impact on unaccompanied minors’ wellbeing, there has been no systematic research to fully capture these experiences, nor their mental health impact. Equally, no evidence exists on whether the emotional impact of these flight experiences should be differentiated from the impact of the traumatic events these minors endured in their home country or from the daily stressors in the country of settlement.
This project aims to fundamentally increase our knowledge of the impact of experiences during the flight in relation to past trauma and current stressors. To achieve this aim, it is essential to set up a longitudinal follow-up of a large group of unaccompanied refugee minors, whereby our study starts from different transit countries, crosses several European countries, and uses innovative methodological and mixed-methods approaches. I will hereby not only document the psychological impact these flight experiences may have, but also the way in which care and reception structures for unaccompanied minors in both transit and settlement countries can contribute to reducing this mental health impact.
This proposal will fundamentally change the field of migration studies, by introducing a whole new area of study and novel methodological approaches to study these themes. Moreover, other fields, such as trauma studies, will be directly informed by the project, as also clinical, educational and social work interventions for victims of multiple trauma. Last, the findings on the impact of reception and care structures will be highly informative for policy makers and practitioners.
Summary
Since early 2015, the media continuously confront us with images of refugee children drowning in the Mediterranean, surviving in appalling conditions in camps or walking across Europe. Within this group of fleeing children, a considerable number is travelling without parents, the unaccompanied refugee minors.
While the media images testify to these flight experiences and their possible huge impact on unaccompanied minors’ wellbeing, there has been no systematic research to fully capture these experiences, nor their mental health impact. Equally, no evidence exists on whether the emotional impact of these flight experiences should be differentiated from the impact of the traumatic events these minors endured in their home country or from the daily stressors in the country of settlement.
This project aims to fundamentally increase our knowledge of the impact of experiences during the flight in relation to past trauma and current stressors. To achieve this aim, it is essential to set up a longitudinal follow-up of a large group of unaccompanied refugee minors, whereby our study starts from different transit countries, crosses several European countries, and uses innovative methodological and mixed-methods approaches. I will hereby not only document the psychological impact these flight experiences may have, but also the way in which care and reception structures for unaccompanied minors in both transit and settlement countries can contribute to reducing this mental health impact.
This proposal will fundamentally change the field of migration studies, by introducing a whole new area of study and novel methodological approaches to study these themes. Moreover, other fields, such as trauma studies, will be directly informed by the project, as also clinical, educational and social work interventions for victims of multiple trauma. Last, the findings on the impact of reception and care structures will be highly informative for policy makers and practitioners.
Max ERC Funding
1 432 500 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
Project acronym DelCancer
Project The role of loss-of-heterozygosity in cancer development and progression
Researcher (PI) Anna Sablina
Host Institution (HI) VIB
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary Somatically acquired loss-of-heterozygosity (LOH) is extremely common in cancer; deletions of recessive cancer genes, miRNAs, and regulatory elements, can confer selective growth advantage, whereas deletions over fragile sites are thought to reflect an increased local rate of DNA breakage. However, most LOHs in cancer genomes remain unexplained. Here we plan to combine a TALEN technology and the experimental models of cell transformation derived from primary human cells to delete specific chromosomal regions that are frequently lost in cancer samples. The development of novel strategies to introduce large chromosomal rearrangements into the genome of primary human cells will offer new perspectives for studying gene function, for elucidating chromosomal organisation, and for increasing our understanding of the molecular mechanisms and pathways underlying cancer development.Using this technology to genetically engineer cells that model cancer-associated genetic alterations, we will identify LOH regions critical for the development and progression of human cancers, and will investigate the cooperative effect of loss of genes, non-coding RNAs, and regulatory elements located within the deleted regions on cancer-associated phenotypes. We will assess how disruption of the three-dimensional chromosomal network in cells with specific chromosomal deletions contributes to cell transformation. Isogenic cell lines harbouring targeted chromosomal alterations will also serve us as a platform to identify compounds with specificity for particular genetic abnormalities. As a next step, we plan to unravel the mechanisms by which particular homozygous deletions contribute to cancer-associated phenotypes. If successful, the results of these studies will represent an important step towards understanding oncogenesis, and could yield new diagnostic and prognostic markers as well as identify potential therapeutic targets.
Summary
Somatically acquired loss-of-heterozygosity (LOH) is extremely common in cancer; deletions of recessive cancer genes, miRNAs, and regulatory elements, can confer selective growth advantage, whereas deletions over fragile sites are thought to reflect an increased local rate of DNA breakage. However, most LOHs in cancer genomes remain unexplained. Here we plan to combine a TALEN technology and the experimental models of cell transformation derived from primary human cells to delete specific chromosomal regions that are frequently lost in cancer samples. The development of novel strategies to introduce large chromosomal rearrangements into the genome of primary human cells will offer new perspectives for studying gene function, for elucidating chromosomal organisation, and for increasing our understanding of the molecular mechanisms and pathways underlying cancer development.Using this technology to genetically engineer cells that model cancer-associated genetic alterations, we will identify LOH regions critical for the development and progression of human cancers, and will investigate the cooperative effect of loss of genes, non-coding RNAs, and regulatory elements located within the deleted regions on cancer-associated phenotypes. We will assess how disruption of the three-dimensional chromosomal network in cells with specific chromosomal deletions contributes to cell transformation. Isogenic cell lines harbouring targeted chromosomal alterations will also serve us as a platform to identify compounds with specificity for particular genetic abnormalities. As a next step, we plan to unravel the mechanisms by which particular homozygous deletions contribute to cancer-associated phenotypes. If successful, the results of these studies will represent an important step towards understanding oncogenesis, and could yield new diagnostic and prognostic markers as well as identify potential therapeutic targets.
Max ERC Funding
1 498 764 €
Duration
Start date: 2012-10-01, End date: 2017-09-30
Project acronym EnDeCAD
Project Enhancers Decoding the Mechanisms Underlying CAD Risk
Researcher (PI) Minna Unelma KAIKKONEN-MÄÄTTÄ
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary In recent years, genome-wide association studies (GWAS) have discovered hundreds of single nucleotide polymorphisms (SNPs) which are significantly associated with coronary artery disease (CAD). However, the SNPs identified by GWAS explain typically only small portion of the trait heritability and vast majority of variants do not have known biological roles. This is explained by variants lying within noncoding regions such as in cell type specific enhancers and additionally ‘the lead SNP’ identified in GWAS may not be the ‘the causal SNP’ but only linked with a trait associated SNP. Therefore, a major priority for understanding disease mechanisms is to understand at the molecular level the function of each CAD loci. In this study we aim to bring the functional characterization of SNPs associated with CAD risk to date by focusing our search for causal SNPs to enhancers of disease relevant cell types, namely endothelial cells, macrophages and smooth muscle cells of the vessel wall, hepatocytes and adipocytes. By combination of massively parallel enhancer activity measurements, collection of novel eQTL data throughout cell types under disease relevant stimuli, identification of the target genes in physical interaction with the candidate enhancers and establishment of correlative relationships between enhancer activity and gene expression we hope to identify causal enhancer variants and link them with target genes to obtain a more complete picture of the gene regulatory events driving disease progression and the genetic basis of CAD. Linking these findings with our deep phenotypic data for cardiovascular risk factors, gene expression and metabolomics has the potential to improve risk prediction, biomarker identification and treatment selection in clinical practice. Ultimately, this research strives for fundamental discoveries and breakthrough that advance our knowledge of CAD and provides pioneering steps towards taking the growing array of GWAS for translatable results.
Summary
In recent years, genome-wide association studies (GWAS) have discovered hundreds of single nucleotide polymorphisms (SNPs) which are significantly associated with coronary artery disease (CAD). However, the SNPs identified by GWAS explain typically only small portion of the trait heritability and vast majority of variants do not have known biological roles. This is explained by variants lying within noncoding regions such as in cell type specific enhancers and additionally ‘the lead SNP’ identified in GWAS may not be the ‘the causal SNP’ but only linked with a trait associated SNP. Therefore, a major priority for understanding disease mechanisms is to understand at the molecular level the function of each CAD loci. In this study we aim to bring the functional characterization of SNPs associated with CAD risk to date by focusing our search for causal SNPs to enhancers of disease relevant cell types, namely endothelial cells, macrophages and smooth muscle cells of the vessel wall, hepatocytes and adipocytes. By combination of massively parallel enhancer activity measurements, collection of novel eQTL data throughout cell types under disease relevant stimuli, identification of the target genes in physical interaction with the candidate enhancers and establishment of correlative relationships between enhancer activity and gene expression we hope to identify causal enhancer variants and link them with target genes to obtain a more complete picture of the gene regulatory events driving disease progression and the genetic basis of CAD. Linking these findings with our deep phenotypic data for cardiovascular risk factors, gene expression and metabolomics has the potential to improve risk prediction, biomarker identification and treatment selection in clinical practice. Ultimately, this research strives for fundamental discoveries and breakthrough that advance our knowledge of CAD and provides pioneering steps towards taking the growing array of GWAS for translatable results.
Max ERC Funding
1 498 647 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
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 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
