Project acronym BabyVir
Project The role of the virome in shaping the gut ecosystem during the first year of life
Researcher (PI) Alexandra Petrovna ZHERNAKOVA
Host Institution (HI) ACADEMISCH ZIEKENHUIS GRONINGEN
Call Details Starting Grant (StG), LS8, ERC-2016-STG
Summary The role of intestinal bacteria in human health and disease has been intensively studied; however the viral composition of the microbiome, the virome, remains largely unknown. As many of the viruses are bacteriophages, they are expected to be a major factor shaping the human microbiome. The dynamics of the virome during early life, its interaction with host and environmental factors, is likely to have profound effects on human physiology. Therefore it is extremely timely to study the virome in depth and on a wide scale.
This ERC project aims at understanding how the gut virome develops during the first year of life and how that relates to the composition of the bacterial microbiome. In particular, we will determine which intrinsic and environmental factors, including genetics and the mother’s microbiome and diet, interact with the virome in shaping the early gut microbiome ecosystem. In a longitudinal study of 1,000 newborns followed at 7 time points from birth till age 12 months, I will investigate: (1) the composition and evolution of the virome and bacterial microbiome in the first year of life; (2) the role of factors coming from the mother and from the host genome on virome and bacterial microbiome development and their co-evolution; and (3) the role of environmental factors, like infectious diseases, vaccinations and diet habits, on establishing the virome and overall microbiome composition during the first year of life.
This project will provide crucial knowledge about composition and maturation of the virome during the first year of life, and its symbiotic relation with the bacterial microbiome. This longitudinal dataset will be instrumental for identification of microbiome markers of diseases and for the follow up analysis of the long-term effect of microbiota maturation later in life. Knowledge of the role of viruses in shaping the microbiota may promote future directions for manipulating the human gut microbiota in health and disease.
Summary
The role of intestinal bacteria in human health and disease has been intensively studied; however the viral composition of the microbiome, the virome, remains largely unknown. As many of the viruses are bacteriophages, they are expected to be a major factor shaping the human microbiome. The dynamics of the virome during early life, its interaction with host and environmental factors, is likely to have profound effects on human physiology. Therefore it is extremely timely to study the virome in depth and on a wide scale.
This ERC project aims at understanding how the gut virome develops during the first year of life and how that relates to the composition of the bacterial microbiome. In particular, we will determine which intrinsic and environmental factors, including genetics and the mother’s microbiome and diet, interact with the virome in shaping the early gut microbiome ecosystem. In a longitudinal study of 1,000 newborns followed at 7 time points from birth till age 12 months, I will investigate: (1) the composition and evolution of the virome and bacterial microbiome in the first year of life; (2) the role of factors coming from the mother and from the host genome on virome and bacterial microbiome development and their co-evolution; and (3) the role of environmental factors, like infectious diseases, vaccinations and diet habits, on establishing the virome and overall microbiome composition during the first year of life.
This project will provide crucial knowledge about composition and maturation of the virome during the first year of life, and its symbiotic relation with the bacterial microbiome. This longitudinal dataset will be instrumental for identification of microbiome markers of diseases and for the follow up analysis of the long-term effect of microbiota maturation later in life. Knowledge of the role of viruses in shaping the microbiota may promote future directions for manipulating the human gut microbiota in health and disease.
Max ERC Funding
1 499 881 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym BALANCED LETHALS
Project Untangling the Evolution of a Balanced Lethal System
Researcher (PI) Biense WIELSTRA
Host Institution (HI) UNIVERSITEIT LEIDEN
Call Details Starting Grant (StG), LS8, ERC-2018-STG
Summary Natural selection is supposed to keep lethal alleles (dysfunctional or deleted copies of crucial genes) in check. Yet, in a balanced lethal system the frequency of lethal alleles is inflated. Because two forms of a chromosome carry distinct lethal alleles that are reciprocally compensated for by functional genes on the alternate chromosome form, both chromosome forms – and in effect their linked lethal alleles – are required for survival. The inability of natural selection to purge balanced lethal systems appears to defy evolutionary theory. How do balanced lethal systems originate and persist in nature? I suspect the answer to this pressing but neglected research question can be found in the context of supergenes in a balanced polymorphism – a current, hot topic in evolutionary biology. Chromosome rearrangements can lock distinct beneficial sets of alleles (i.e. supergenes) on two chromosome forms by suppressing recombination. Now, balancing selection would favour possession of both supergenes. However, as a consequence of suppressed recombination, unique lethal alleles could become fixed on each supergene, with natural selection powerless to prevent collapse of the arrangement into a balanced lethal system. I aim to explain the evolution of balanced lethal systems in nature. As empirical example I will use chromosome 1 syndrome, a balanced lethal system observed in newts of the genus Triturus. My research team will: Reconstruct the genomic architecture of this balanced lethal system at its point of origin [PI project]; Conduct comparative genomics with related, unaffected species [PhD project]; Determine gene order of the two supergenes involved [Postdoc project I]; and Model the conditions under which this balanced lethal system could theoretically have evolved [Postdoc project II]. Solving the paradox of chromosome 1 syndrome will allow us to understand balanced lethal systems in general and address the challenges they pose to evolutionary theory.
Summary
Natural selection is supposed to keep lethal alleles (dysfunctional or deleted copies of crucial genes) in check. Yet, in a balanced lethal system the frequency of lethal alleles is inflated. Because two forms of a chromosome carry distinct lethal alleles that are reciprocally compensated for by functional genes on the alternate chromosome form, both chromosome forms – and in effect their linked lethal alleles – are required for survival. The inability of natural selection to purge balanced lethal systems appears to defy evolutionary theory. How do balanced lethal systems originate and persist in nature? I suspect the answer to this pressing but neglected research question can be found in the context of supergenes in a balanced polymorphism – a current, hot topic in evolutionary biology. Chromosome rearrangements can lock distinct beneficial sets of alleles (i.e. supergenes) on two chromosome forms by suppressing recombination. Now, balancing selection would favour possession of both supergenes. However, as a consequence of suppressed recombination, unique lethal alleles could become fixed on each supergene, with natural selection powerless to prevent collapse of the arrangement into a balanced lethal system. I aim to explain the evolution of balanced lethal systems in nature. As empirical example I will use chromosome 1 syndrome, a balanced lethal system observed in newts of the genus Triturus. My research team will: Reconstruct the genomic architecture of this balanced lethal system at its point of origin [PI project]; Conduct comparative genomics with related, unaffected species [PhD project]; Determine gene order of the two supergenes involved [Postdoc project I]; and Model the conditions under which this balanced lethal system could theoretically have evolved [Postdoc project II]. Solving the paradox of chromosome 1 syndrome will allow us to understand balanced lethal systems in general and address the challenges they pose to evolutionary theory.
Max ERC Funding
1 499 869 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym BRITE
Project Elucidating the molecular mechanisms underlying brite adipocyte specification and activation
Researcher (PI) Ferdinand VON MEYENN
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary Brown adipocytes can dissipate energy in a process called adaptive thermogenesis. Whilst the classical brown adipose tissue (BAT) depots disappear during early life in humans, cold exposure can promote the appearance of brown-like adipocytes within the white adipose tissue (WAT), termed brite (brown-in-white). Increased BAT activity results in increased energy expenditure and has been correlated with leanness in humans. Hence, recruitment of brite adipocytes may constitute a promising therapeutic strategy to treat obesity and its associated metabolic diseases. Despite the beneficial metabolic properties of brown and brite adipocytes, little is known about the molecular mechanisms underlying their specification and activation in vivo. This proposal focuses on understanding the complex biology of thermogenic adipocyte biology by studying the epigenetic and transcriptional aspects of WAT britening and BAT recruitment in vivo to identify pathways of therapeutic relevance and to better define the brite precursor cells. Specific aims are to 1) investigate epigenetic and transcriptional states and heterogeneity in human and mouse adipose tissue; 2) develop a novel time-resolved method to correlate preceding chromatin states and cell fate decisions during adipose tissue remodelling; 3) identify and validate key (drugable) epigenetic and transcriptional regulators involved in brite adipocyte specification. Experimentally, I will use adipose tissue samples from human donors and mouse models, to asses at the single-cell level cellular heterogeneity, transcriptional and epigenetic states, to identify subpopulations, and to define the adaptive responses to cold or β-adrenergic stimulation. Using computational methods and in vitro and in vivo validation experiments, I will define epigenetic and transcriptional networks that control WAT britening, and develop a model of the molecular events underlying adipocyte tissue plasticity.
Summary
Brown adipocytes can dissipate energy in a process called adaptive thermogenesis. Whilst the classical brown adipose tissue (BAT) depots disappear during early life in humans, cold exposure can promote the appearance of brown-like adipocytes within the white adipose tissue (WAT), termed brite (brown-in-white). Increased BAT activity results in increased energy expenditure and has been correlated with leanness in humans. Hence, recruitment of brite adipocytes may constitute a promising therapeutic strategy to treat obesity and its associated metabolic diseases. Despite the beneficial metabolic properties of brown and brite adipocytes, little is known about the molecular mechanisms underlying their specification and activation in vivo. This proposal focuses on understanding the complex biology of thermogenic adipocyte biology by studying the epigenetic and transcriptional aspects of WAT britening and BAT recruitment in vivo to identify pathways of therapeutic relevance and to better define the brite precursor cells. Specific aims are to 1) investigate epigenetic and transcriptional states and heterogeneity in human and mouse adipose tissue; 2) develop a novel time-resolved method to correlate preceding chromatin states and cell fate decisions during adipose tissue remodelling; 3) identify and validate key (drugable) epigenetic and transcriptional regulators involved in brite adipocyte specification. Experimentally, I will use adipose tissue samples from human donors and mouse models, to asses at the single-cell level cellular heterogeneity, transcriptional and epigenetic states, to identify subpopulations, and to define the adaptive responses to cold or β-adrenergic stimulation. Using computational methods and in vitro and in vivo validation experiments, I will define epigenetic and transcriptional networks that control WAT britening, and develop a model of the molecular events underlying adipocyte tissue plasticity.
Max ERC Funding
1 552 620 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym CALMIRS
Project RNA-based regulation of signal transduction –
Regulation of calcineurin/NFAT signaling by microRNA-based mechanisms
Researcher (PI) Leon Johannes De Windt
Host Institution (HI) UNIVERSITEIT MAASTRICHT
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary "Heart failure is a serious clinical disorder that represents the primary cause of hospitalization and death in Europe and the United States. There is a dire need for new paradigms and therapeutic approaches for treatment of this devastating disease. The heart responds to mechanical load and various extracellular stimuli by hypertrophic growth and sustained pathological hypertrophy is a major clinical predictor of heart failure. A variety of stress-responsive signaling pathways promote cardiac hypertrophy, but the precise mechanisms that link these pathways to cardiac disease are only beginning to be unveiled. Signal transduction is traditionally concentrated on the protein coding part of the genome, but it is now appreciated that the protein coding part of the genome only constitutes 1.5% of the genome. RNA based mechanisms may provide a more complete understanding of the fundamentals of cellular signaling. As a proof-of-principle, we focus on a principal hypertrophic signaling cascade, cardiac calcineurin/NFAT signaling. Here we will establish that microRNAs are intimately interwoven with this signaling cascade, influence signaling strength by unexpected upstream mechanisms. Secondly, we will firmly establish that microRNA target genes critically contribute to genesis of heart failure. Third, the surprising stability of circulating microRNAs has opened the possibility to develop the next generation of biomarkers and provide unexpected mechanisms how genetic information is transported between cells in multicellular organs and fascilitate inter-cellular communication. Finally, microRNA-based therapeutic silencing is remarkably powerful and offers opportunities to specifically intervene in pathological signaling as the next generation heart failure therapeutics. CALMIRS aims to mine the wealth of these RNA mechanisms to enable the development of next generation RNA based signal transduction biology, with surprising new diagnostic and therapeutic opportunities."
Summary
"Heart failure is a serious clinical disorder that represents the primary cause of hospitalization and death in Europe and the United States. There is a dire need for new paradigms and therapeutic approaches for treatment of this devastating disease. The heart responds to mechanical load and various extracellular stimuli by hypertrophic growth and sustained pathological hypertrophy is a major clinical predictor of heart failure. A variety of stress-responsive signaling pathways promote cardiac hypertrophy, but the precise mechanisms that link these pathways to cardiac disease are only beginning to be unveiled. Signal transduction is traditionally concentrated on the protein coding part of the genome, but it is now appreciated that the protein coding part of the genome only constitutes 1.5% of the genome. RNA based mechanisms may provide a more complete understanding of the fundamentals of cellular signaling. As a proof-of-principle, we focus on a principal hypertrophic signaling cascade, cardiac calcineurin/NFAT signaling. Here we will establish that microRNAs are intimately interwoven with this signaling cascade, influence signaling strength by unexpected upstream mechanisms. Secondly, we will firmly establish that microRNA target genes critically contribute to genesis of heart failure. Third, the surprising stability of circulating microRNAs has opened the possibility to develop the next generation of biomarkers and provide unexpected mechanisms how genetic information is transported between cells in multicellular organs and fascilitate inter-cellular communication. Finally, microRNA-based therapeutic silencing is remarkably powerful and offers opportunities to specifically intervene in pathological signaling as the next generation heart failure therapeutics. CALMIRS aims to mine the wealth of these RNA mechanisms to enable the development of next generation RNA based signal transduction biology, with surprising new diagnostic and therapeutic opportunities."
Max ERC Funding
1 499 528 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym CAMERA
Project Characterizing Adaptation and Migration Events with Modern and Ancient Genomes
Researcher (PI) Anna-Sapfo Malaspinas
Host Institution (HI) UNIVERSITAET BERN
Call Details Starting Grant (StG), LS8, ERC-2015-STG
Summary BACKGROUND Ancient DNA research has recently entered the genomics era. Performing “ancient population genomics” is now technically possible. Utilizing the temporal aspect of this new data, we can address fundamental evolutionary questions such as the amount of selection acting on the genome or the mode and tempo of the colonization of the world. AIMS The overall goal of the proposed research is to (i) generate and analyse data to answer two long standing questions in human evolution: understanding the molecular basis of human adaptation to high altitude and investigating the timing of the Polynesian-South American contact, (ii) develop statistical approaches that combine ancient and modern genetic data to estimate the timing and the intensity of a selective sweep and an admixture event. METHODOLOGY Application: We will collect, date and DNA sequence human remains. Combining the ancient genetic data, 14C dates with existing modern genomic data will allow us to increase the resolution as to the timing of the adaptive and the admixture event, respectively, while generating unique datasets. Theory: We will build on existing methods based on one-locus classical population genetic models to develop tools to analyse whole genome time serial data. RELEVANCE Ecological: The results will address the fundamental question of how much of the human genome is undergoing selection, better characterize one of the textbook examples of adaptation in humans and contribute to our understanding of the peopling of the Americas. Medical: We will gain insights into the fundamental stress physiology experienced at high altitude and therefore into altitude-related illnesses. Methodological: The methods developed in this project will not only benefit the growing field of ancient genomics but also other fields where data is collected in a temporal manner, such as experimental evolution and epidemiology
Summary
BACKGROUND Ancient DNA research has recently entered the genomics era. Performing “ancient population genomics” is now technically possible. Utilizing the temporal aspect of this new data, we can address fundamental evolutionary questions such as the amount of selection acting on the genome or the mode and tempo of the colonization of the world. AIMS The overall goal of the proposed research is to (i) generate and analyse data to answer two long standing questions in human evolution: understanding the molecular basis of human adaptation to high altitude and investigating the timing of the Polynesian-South American contact, (ii) develop statistical approaches that combine ancient and modern genetic data to estimate the timing and the intensity of a selective sweep and an admixture event. METHODOLOGY Application: We will collect, date and DNA sequence human remains. Combining the ancient genetic data, 14C dates with existing modern genomic data will allow us to increase the resolution as to the timing of the adaptive and the admixture event, respectively, while generating unique datasets. Theory: We will build on existing methods based on one-locus classical population genetic models to develop tools to analyse whole genome time serial data. RELEVANCE Ecological: The results will address the fundamental question of how much of the human genome is undergoing selection, better characterize one of the textbook examples of adaptation in humans and contribute to our understanding of the peopling of the Americas. Medical: We will gain insights into the fundamental stress physiology experienced at high altitude and therefore into altitude-related illnesses. Methodological: The methods developed in this project will not only benefit the growing field of ancient genomics but also other fields where data is collected in a temporal manner, such as experimental evolution and epidemiology
Max ERC Funding
1 498 478 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym CANCER INVASION
Project Deciphering and targeting the invasive nature of Diffuse Intrinsic Pontine Glioma
Researcher (PI) Anne RIOS
Host Institution (HI) PRINSES MAXIMA CENTRUM VOOR KINDERONCOLOGIE BV
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary Introduction: The ability of a cancer cell to invade into the surrounding tissue is the main feature of malignant cancer progression. Diffuse Intrinsic Pontine Glioma (DIPG) is a paediatric high-grade brain tumour with no chance of survival due to its highly invasive nature.
Goal: By combining state-of-the-art imaging and transcriptomics, we aim to identify and target the key mechanisms driving the highly invasive growth of DIPG.
Technology advances: Two unique single cell resolution imaging techniques that we have recently developed will be implemented: Large-scale Single-cell Resolution 3D imaging (LSR-3D) that allows visualization of complete tumour specimens and intravital microscopy using a cranial imaging window that allows imaging of tumour cell behaviour in living mice. In addition, we will apply a technique of live imaging Patch-seq to perform behaviour studies together with single cell RNA profiling.
Expected results: Using a glioma murine model in which the disease is induced in neonates and a new embryonic model based on in utero electroporation, we expect to gain knowledge on the progression of DIPG in maturing brain. LSR-3D imaging on human and murine specimens will provide insight into the cellular tumour composition and its integration in the neuroglial network. With intravital imaging, we will characterize invasive cancer cell behaviour and functional connections with healthy brain cells. In combination with Patch-seq, we will identify transcriptional program(s) specific to invasive behaviour. Altogether, we expect to identify novel key players in cancer invasion and assess their potential to prevent DIPG progression.
Future perspective: With the studies proposed, we will gain fundamental insights into the cancer cell invasion mechanisms that govern DIPG which may provide new potential therapeutic target(s) for this dismal disease. Overall, the knowledge and advanced technologies obtained here will be of great value for the tumour biology field.
Summary
Introduction: The ability of a cancer cell to invade into the surrounding tissue is the main feature of malignant cancer progression. Diffuse Intrinsic Pontine Glioma (DIPG) is a paediatric high-grade brain tumour with no chance of survival due to its highly invasive nature.
Goal: By combining state-of-the-art imaging and transcriptomics, we aim to identify and target the key mechanisms driving the highly invasive growth of DIPG.
Technology advances: Two unique single cell resolution imaging techniques that we have recently developed will be implemented: Large-scale Single-cell Resolution 3D imaging (LSR-3D) that allows visualization of complete tumour specimens and intravital microscopy using a cranial imaging window that allows imaging of tumour cell behaviour in living mice. In addition, we will apply a technique of live imaging Patch-seq to perform behaviour studies together with single cell RNA profiling.
Expected results: Using a glioma murine model in which the disease is induced in neonates and a new embryonic model based on in utero electroporation, we expect to gain knowledge on the progression of DIPG in maturing brain. LSR-3D imaging on human and murine specimens will provide insight into the cellular tumour composition and its integration in the neuroglial network. With intravital imaging, we will characterize invasive cancer cell behaviour and functional connections with healthy brain cells. In combination with Patch-seq, we will identify transcriptional program(s) specific to invasive behaviour. Altogether, we expect to identify novel key players in cancer invasion and assess their potential to prevent DIPG progression.
Future perspective: With the studies proposed, we will gain fundamental insights into the cancer cell invasion mechanisms that govern DIPG which may provide new potential therapeutic target(s) for this dismal disease. Overall, the knowledge and advanced technologies obtained here will be of great value for the tumour biology field.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym CITISENSE
Project Evolving communication systems in response to altered sensory environments
Researcher (PI) Wouter Halfwerk
Host Institution (HI) STICHTING VU
Call Details Starting Grant (StG), LS8, ERC-2018-STG
Summary How animal communication systems evolve is a fundamental question in ecology and evolution and crucial for our understanding of adaptation and speciation. I will make use of the process of urbanization to address how communication signals adapt to changes in the sensory environment. I will focus on the impact of noise and light pollution on acoustic communication of Neotropical frogs and address the following questions:
1) How do senders, such as a male frog, adjust their signals to altered sensory environments? I will assess plasticity and heritability of signal divergence found between urban and forest populations of the tungara frog. 2) How do signals evolve in response to direct (via sender) and indirect (via receivers) selection pressures? I will expose forest sites to noise and light pollution, parse out importance of multiple selection pressures and carry out experimental evolution using artificial phenotypes.
3) What are the evolutionary consequences of signal divergence? I will assess inter-and-intra sexual responses to signal divergence between urban and forest populations. 4) Can we predict how species adapt their signals to the sensory environment? I will use a trait-based comparative approach to study signal divergence among closely related species with known urban populations.
Our state-of-the-art automated sender-receiver system allows for experimental evolution using long-lived species and opens new ways to study selection pressures operating on animal behaviour under real field conditions. Our expected results will provide crucial insight into the early stages of signal divergence that may ultimately lead to reproductive isolation and speciation.
Summary
How animal communication systems evolve is a fundamental question in ecology and evolution and crucial for our understanding of adaptation and speciation. I will make use of the process of urbanization to address how communication signals adapt to changes in the sensory environment. I will focus on the impact of noise and light pollution on acoustic communication of Neotropical frogs and address the following questions:
1) How do senders, such as a male frog, adjust their signals to altered sensory environments? I will assess plasticity and heritability of signal divergence found between urban and forest populations of the tungara frog. 2) How do signals evolve in response to direct (via sender) and indirect (via receivers) selection pressures? I will expose forest sites to noise and light pollution, parse out importance of multiple selection pressures and carry out experimental evolution using artificial phenotypes.
3) What are the evolutionary consequences of signal divergence? I will assess inter-and-intra sexual responses to signal divergence between urban and forest populations. 4) Can we predict how species adapt their signals to the sensory environment? I will use a trait-based comparative approach to study signal divergence among closely related species with known urban populations.
Our state-of-the-art automated sender-receiver system allows for experimental evolution using long-lived species and opens new ways to study selection pressures operating on animal behaviour under real field conditions. Our expected results will provide crucial insight into the early stages of signal divergence that may ultimately lead to reproductive isolation and speciation.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym CRCStemCellDynamics
Project Molecular Subtype Specific Stem Cell Dynamics in Developing and Established Colorectal Cancers
Researcher (PI) Louis Vermeulen
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary Annually 1.2 million new cases of colorectal cancer (CRC) are seen worldwide and over 50% of patients die of the disease making it a leading cause of cancer-related mortality. A crucial contributing factor to these disappointing figures is that CRC is a heterogeneous disease and tumours differ extensively in the clinical presentation and response to therapy. Recent unsupervised classification studies highlight that only a proportion of this heterogeneity can be explained by the variation in commonly found (epi-)genetic aberrations. Hence the origins of CRC heterogeneity remain poorly understood.
The central hypothesis of this research project is that the cell of origin contributes to the phenotype and functional properties of the pre-malignant clone and the resulting malignancy. To study this concept I will generate cell of origin- and mutation-specific molecular profiles of oncogenic clones and relate those to human CRC samples. Furthermore, I will quantitatively investigate how mutations and the cell of origin act in concert to determine the functional characteristics of the pre-malignant clone that ultimately develops into an invasive intestinal tumour. These studies are paralleled by the investigation of stem cell dynamics within established human CRCs by means of a novel marker independent lineage tracing strategy in combination with mathematical analysis techniques. This will provide critical and quantitative information on the relevance of the cancer stem cell concept in CRC and on the degree of inter-tumour variation with respect to the frequency and functional features of stem-like cells within individual CRCs and molecular subtypes of the disease.
I am convinced that a better and quantitative understanding of the dynamical properties of stem cells during tumour development and within established CRCs will be pivotal for an improved classification, prevention and treatment of CRC.
Summary
Annually 1.2 million new cases of colorectal cancer (CRC) are seen worldwide and over 50% of patients die of the disease making it a leading cause of cancer-related mortality. A crucial contributing factor to these disappointing figures is that CRC is a heterogeneous disease and tumours differ extensively in the clinical presentation and response to therapy. Recent unsupervised classification studies highlight that only a proportion of this heterogeneity can be explained by the variation in commonly found (epi-)genetic aberrations. Hence the origins of CRC heterogeneity remain poorly understood.
The central hypothesis of this research project is that the cell of origin contributes to the phenotype and functional properties of the pre-malignant clone and the resulting malignancy. To study this concept I will generate cell of origin- and mutation-specific molecular profiles of oncogenic clones and relate those to human CRC samples. Furthermore, I will quantitatively investigate how mutations and the cell of origin act in concert to determine the functional characteristics of the pre-malignant clone that ultimately develops into an invasive intestinal tumour. These studies are paralleled by the investigation of stem cell dynamics within established human CRCs by means of a novel marker independent lineage tracing strategy in combination with mathematical analysis techniques. This will provide critical and quantitative information on the relevance of the cancer stem cell concept in CRC and on the degree of inter-tumour variation with respect to the frequency and functional features of stem-like cells within individual CRCs and molecular subtypes of the disease.
I am convinced that a better and quantitative understanding of the dynamical properties of stem cells during tumour development and within established CRCs will be pivotal for an improved classification, prevention and treatment of CRC.
Max ERC Funding
1 499 875 €
Duration
Start date: 2015-04-01, End date: 2021-03-31
Project acronym deFIBER
Project Dissecting the cellular and molecular dynamics of bone marrow fibrosis for improved diagnostics and treatment
Researcher (PI) Rebekka SCHNEIDER-KRAMANN
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Starting Grant (StG), LS4, ERC-2017-STG
Summary Bone marrow (BM) fibrosis is the continuous replacement of blood forming cells in the bone marrow by scar tissue, ultimately leading to failure of the body to produce blood cells. Primary myelofibrosis (PMF), an incurable blood cancer, is the prototypic example of the step-wise development of BM fibrosis. The specific mechanisms that cause BM fibrosis are not understood, in particular as the cells driving fibrosis have remained obscure.
My recent findings demonstrate that Gli1+ cells are fibrosis-driving cells in PMF, that their frequency correlates with fibrosis severity in patients, and that their ablation ameliorates BM fibrosis. These results indicate that Gli1+ cells are the primary effector cells in BM fibrosis and that they represent a highly attractive therapeutic target. This puts me in a unique position to vastly expand our knowledge of the BM fibrosis pathogenesis, improve diagnostics, and discover new therapeutic strategies for this fatal disease. I will do this by: 1) dissecting the molecular and cellular mechanisms of the fibrotic transformation, 2) defining the stepwise disease evolution by genetic fate tracing and analysis of the previously unknown critical effector cells of BM fibrosis , 3) understanding early forms of BM fibrosis for improved diagnostics in patients, all with the ultimate aim to identify novel therapeutic targets to directly block the cellular and molecular changes occuring in BM fibrosis.
I will apply state-of-the-art techniques, including genetic fate tracing experiments, conditional genetic knockout mouse models, tissue engineering of the bone marrow niche and in vivo and in vitro CRISPR/Cas9 gene editing, to unravel the complex molecular and cellular interaction between fibrosis-causing cells and the malignant hematopoietic cells. I will translate these findings into patient samples with the aim to improve the early diagnosis of the disease and to ultimately develop novel targeted therapies with curative intentions.
Summary
Bone marrow (BM) fibrosis is the continuous replacement of blood forming cells in the bone marrow by scar tissue, ultimately leading to failure of the body to produce blood cells. Primary myelofibrosis (PMF), an incurable blood cancer, is the prototypic example of the step-wise development of BM fibrosis. The specific mechanisms that cause BM fibrosis are not understood, in particular as the cells driving fibrosis have remained obscure.
My recent findings demonstrate that Gli1+ cells are fibrosis-driving cells in PMF, that their frequency correlates with fibrosis severity in patients, and that their ablation ameliorates BM fibrosis. These results indicate that Gli1+ cells are the primary effector cells in BM fibrosis and that they represent a highly attractive therapeutic target. This puts me in a unique position to vastly expand our knowledge of the BM fibrosis pathogenesis, improve diagnostics, and discover new therapeutic strategies for this fatal disease. I will do this by: 1) dissecting the molecular and cellular mechanisms of the fibrotic transformation, 2) defining the stepwise disease evolution by genetic fate tracing and analysis of the previously unknown critical effector cells of BM fibrosis , 3) understanding early forms of BM fibrosis for improved diagnostics in patients, all with the ultimate aim to identify novel therapeutic targets to directly block the cellular and molecular changes occuring in BM fibrosis.
I will apply state-of-the-art techniques, including genetic fate tracing experiments, conditional genetic knockout mouse models, tissue engineering of the bone marrow niche and in vivo and in vitro CRISPR/Cas9 gene editing, to unravel the complex molecular and cellular interaction between fibrosis-causing cells and the malignant hematopoietic cells. I will translate these findings into patient samples with the aim to improve the early diagnosis of the disease and to ultimately develop novel targeted therapies with curative intentions.
Max ERC Funding
1 498 544 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym DETECT
Project Describing Evolution with Theoretical, Empirical, and Computational Tools
Researcher (PI) Jeffrey Jensen
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Starting Grant (StG), LS8, ERC-2012-StG_20111109
Summary As evolutionary biologists we are of course motivated by the desire to gain further insight in to the evolution of natural populations. The main goals of this proposal are to (i) develop theory and methodology that will enable the identification of adaptively evolving genomic regions using polymorphism data, (ii) develop theory and methodology for the estimation of whole-genome rates of adaptive evolution, and (iii) apply the developed theory in two strategic collaborative applications. Capitalizing on recently available and soon-to-be available whole genome polymorphism data across multiple taxa, these approaches are expected to significantly improve the identification and localization of recent selective events, as well as provide long sought after information regarding the genomic distributions of selective effects. Additionally, through these on-going collaborations with empirical and experimental labs, this methodology will allow for specific hypothesis testing that will further illuminate classical examples of adaptation. Together, this proposal seeks to Describe Evolution with Theoretical, Empirical and Computational Tools (DETECT), seeking to accurately describe the very mode and tempo of Darwinian adaptation.
Summary
As evolutionary biologists we are of course motivated by the desire to gain further insight in to the evolution of natural populations. The main goals of this proposal are to (i) develop theory and methodology that will enable the identification of adaptively evolving genomic regions using polymorphism data, (ii) develop theory and methodology for the estimation of whole-genome rates of adaptive evolution, and (iii) apply the developed theory in two strategic collaborative applications. Capitalizing on recently available and soon-to-be available whole genome polymorphism data across multiple taxa, these approaches are expected to significantly improve the identification and localization of recent selective events, as well as provide long sought after information regarding the genomic distributions of selective effects. Additionally, through these on-going collaborations with empirical and experimental labs, this methodology will allow for specific hypothesis testing that will further illuminate classical examples of adaptation. Together, this proposal seeks to Describe Evolution with Theoretical, Empirical and Computational Tools (DETECT), seeking to accurately describe the very mode and tempo of Darwinian adaptation.
Max ERC Funding
1 071 729 €
Duration
Start date: 2013-01-01, End date: 2017-08-31
