Project acronym CentrioleBirthDeath
Project Mechanism of centriole inheritance and maintenance
Researcher (PI) Monica BETTENCOURT CARVALHO DIAS
Host Institution (HI) FUNDACAO CALOUSTE GULBENKIAN
Call Details Consolidator Grant (CoG), LS3, ERC-2015-CoG
Summary Centrioles assemble centrosomes and cilia/flagella, critical structures for cell division, polarity, motility and signalling, which are often deregulated in human disease. Centriole inheritance, in particular the preservation of their copy number and position in the cell is critical in many eukaryotes. I propose to investigate, in an integrative and quantitative way, how centrioles are formed in the right numbers at the right time and place, and how they are maintained to ensure their function and inheritance. We first ask how centrioles guide their own assembly position and centriole copy number. Our recent work highlighted several properties of the system, including positive and negative feedbacks and spatial cues. We explore critical hypotheses through a combination of biochemistry, quantitative live cell microscopy and computational modelling. We then ask how the centrosome and the cell cycle are both coordinated. We recently identified the triggering event in centriole biogenesis and how its regulation is akin to cell cycle control of DNA replication and centromere assembly. We will explore new hypotheses to understand how assembly time is coupled to the cell cycle. Lastly, we ask how centriole maintenance is regulated. By studying centriole disappearance in the female germline we uncovered that centrioles need to be actively maintained by their surrounding matrix. We propose to investigate how that matrix provides stability to the centrioles, whether this is differently regulated in different cell types and the possible consequences of its misregulation for the organism (infertility and ciliopathy-like symptoms). We will take advantage of several experimental systems (in silico, ex-vivo, flies and human cells), tailoring the assay to the question and allowing for comparisons across experimental systems to provide a deeper understanding of the process and its regulation.
Summary
Centrioles assemble centrosomes and cilia/flagella, critical structures for cell division, polarity, motility and signalling, which are often deregulated in human disease. Centriole inheritance, in particular the preservation of their copy number and position in the cell is critical in many eukaryotes. I propose to investigate, in an integrative and quantitative way, how centrioles are formed in the right numbers at the right time and place, and how they are maintained to ensure their function and inheritance. We first ask how centrioles guide their own assembly position and centriole copy number. Our recent work highlighted several properties of the system, including positive and negative feedbacks and spatial cues. We explore critical hypotheses through a combination of biochemistry, quantitative live cell microscopy and computational modelling. We then ask how the centrosome and the cell cycle are both coordinated. We recently identified the triggering event in centriole biogenesis and how its regulation is akin to cell cycle control of DNA replication and centromere assembly. We will explore new hypotheses to understand how assembly time is coupled to the cell cycle. Lastly, we ask how centriole maintenance is regulated. By studying centriole disappearance in the female germline we uncovered that centrioles need to be actively maintained by their surrounding matrix. We propose to investigate how that matrix provides stability to the centrioles, whether this is differently regulated in different cell types and the possible consequences of its misregulation for the organism (infertility and ciliopathy-like symptoms). We will take advantage of several experimental systems (in silico, ex-vivo, flies and human cells), tailoring the assay to the question and allowing for comparisons across experimental systems to provide a deeper understanding of the process and its regulation.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym CODECHECK
Project CRACKING THE CODE BEHIND MITOTIC FIDELITY: the roles of tubulin post-translational modifications and a chromosome separation checkpoint
Researcher (PI) Helder Jose Martins Maiato
Host Institution (HI) INSTITUTO DE BIOLOGIA MOLECULAR E CELULAR-IBMC
Call Details Consolidator Grant (CoG), LS3, ERC-2015-CoG
Summary During the human lifetime 10000 trillion cell divisions take place to ensure tissue homeostasis and several vital functions in the organism. Mitosis is the process that ensures that dividing cells preserve the chromosome number of their progenitors, while deviation from this, a condition known as aneuploidy, represents the most common feature in human cancers. Here we will test two original concepts with strong implications for chromosome segregation fidelity. The first concept is based on the “tubulin code” hypothesis, which predicts that molecular motors “read” tubulin post-translational modifications on spindle microtubules. Our proof-of-concept experiments demonstrate that tubulin detyrosination works as a navigation system that guides chromosomes towards the cell equator. Thus, in addition to regulating the motors required for chromosome motion, the cell might regulate the tracks in which they move on. We will combine proteomic, super-resolution and live-cell microscopy, with in vitro reconstitutions, to perform a comprehensive survey of the tubulin code and the respective implications for motors involved in chromosome motion, mitotic spindle assembly and correction of kinetochore-microtubule attachments. The second concept is centered on the recently uncovered chromosome separation checkpoint mediated by a midzone-associated Aurora B gradient, which delays nuclear envelope reformation in response to incompletely separated chromosomes. We aim to identify Aurora B targets involved in the spatiotemporal regulation of the anaphase-telophase transition. We will establish powerful live-cell microscopy assays and a novel mammalian model system to dissect how this checkpoint allows the detection and correction of lagging/long chromosomes and DNA bridges that would otherwise contribute to genomic instability. Overall, this work will establish a paradigm shift in our understanding of how spatial information is conveyed to faithfully segregate chromosomes during mitosis.
Summary
During the human lifetime 10000 trillion cell divisions take place to ensure tissue homeostasis and several vital functions in the organism. Mitosis is the process that ensures that dividing cells preserve the chromosome number of their progenitors, while deviation from this, a condition known as aneuploidy, represents the most common feature in human cancers. Here we will test two original concepts with strong implications for chromosome segregation fidelity. The first concept is based on the “tubulin code” hypothesis, which predicts that molecular motors “read” tubulin post-translational modifications on spindle microtubules. Our proof-of-concept experiments demonstrate that tubulin detyrosination works as a navigation system that guides chromosomes towards the cell equator. Thus, in addition to regulating the motors required for chromosome motion, the cell might regulate the tracks in which they move on. We will combine proteomic, super-resolution and live-cell microscopy, with in vitro reconstitutions, to perform a comprehensive survey of the tubulin code and the respective implications for motors involved in chromosome motion, mitotic spindle assembly and correction of kinetochore-microtubule attachments. The second concept is centered on the recently uncovered chromosome separation checkpoint mediated by a midzone-associated Aurora B gradient, which delays nuclear envelope reformation in response to incompletely separated chromosomes. We aim to identify Aurora B targets involved in the spatiotemporal regulation of the anaphase-telophase transition. We will establish powerful live-cell microscopy assays and a novel mammalian model system to dissect how this checkpoint allows the detection and correction of lagging/long chromosomes and DNA bridges that would otherwise contribute to genomic instability. Overall, this work will establish a paradigm shift in our understanding of how spatial information is conveyed to faithfully segregate chromosomes during mitosis.
Max ERC Funding
2 323 468 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym COREMA
Project Cell division and the origin of embryonic aneuploidy in preimplantation mouse development
Researcher (PI) Jan ELLENBERG
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Call Details Advanced Grant (AdG), LS3, ERC-2015-AdG
Summary Cell division is fundamental for development. In the early mammalian embryo it drives the rapid proliferation of totipotent cells, the basis for forming the fetus. Given its crucial importance, it is surprising that cell division is particularly error-prone at the beginning of mammalian life, resulting in spontaneous abortion or severe developmental retardation, the incidence of which is increasing with age of the mother. Why aneuploidy is so prevalent and how early embryonic development nevertheless achieves robustness is largely unknown. The goal of this project is a comprehensive analysis of cell divisions in the mouse preimplantation embryo to determine the molecular mechanisms underlying aneuploidy and its effects on normal development. Recent technological breakthroughs, including light sheet microscopy and rapid loss-of-function approaches in the mouse embryo will allow us for the first time to tackle the molecular mechanisms of aneuploidy generation and establish the preimplantation mouse embryo as a standard cell biological model system. For that purpose we will develop next generation light sheet microscopy to enable automated chromosome tracking in the whole embryo. Mapping of cell division errors will reveal when, where, and how aneuploidy occurs, what the fate of aneuploid cells is in the embryo, and how this changes with maternal age. We will then perform high resolution functional imaging assays to identify the mitotic pathways responsible for aneuploidy and understand why they do not fully function in early development. Key proteins will be functionally characterised in detail integrating light sheet imaging with single molecule biophysics in embryos from young and aged females to achieve a mechanistic understanding of the unique aspects of cell division underlying embryonic aneuploidy. The achieved knowledge gain will have an important impact for our understanding of mammalian, including human infertility.
Summary
Cell division is fundamental for development. In the early mammalian embryo it drives the rapid proliferation of totipotent cells, the basis for forming the fetus. Given its crucial importance, it is surprising that cell division is particularly error-prone at the beginning of mammalian life, resulting in spontaneous abortion or severe developmental retardation, the incidence of which is increasing with age of the mother. Why aneuploidy is so prevalent and how early embryonic development nevertheless achieves robustness is largely unknown. The goal of this project is a comprehensive analysis of cell divisions in the mouse preimplantation embryo to determine the molecular mechanisms underlying aneuploidy and its effects on normal development. Recent technological breakthroughs, including light sheet microscopy and rapid loss-of-function approaches in the mouse embryo will allow us for the first time to tackle the molecular mechanisms of aneuploidy generation and establish the preimplantation mouse embryo as a standard cell biological model system. For that purpose we will develop next generation light sheet microscopy to enable automated chromosome tracking in the whole embryo. Mapping of cell division errors will reveal when, where, and how aneuploidy occurs, what the fate of aneuploid cells is in the embryo, and how this changes with maternal age. We will then perform high resolution functional imaging assays to identify the mitotic pathways responsible for aneuploidy and understand why they do not fully function in early development. Key proteins will be functionally characterised in detail integrating light sheet imaging with single molecule biophysics in embryos from young and aged females to achieve a mechanistic understanding of the unique aspects of cell division underlying embryonic aneuploidy. The achieved knowledge gain will have an important impact for our understanding of mammalian, including human infertility.
Max ERC Funding
2 497 156 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym DanioPattern
Project Development and Evolution of Colour Patterns in Danio species
Researcher (PI) Christiane NÜSSLEIN-VOLHARD
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Advanced Grant (AdG), LS3, ERC-2015-AdG
Summary Colour patterns are prominent features of many animals and have important functions in communication such as camouflage, kin recognition and mate selection. Colour patterns are highly variable and evolve rapidly leading to large diversities even within a single genus. As targets for natural as well as sexual selection, they are of high evolutionary significance. The zebrafish (Danio rerio), a vertebrate model organism for the study of development and disease, displays a conspicuous pattern of alternating blue and golden stripes on the body and on the anal- and tailfins. Mutants with spectacularly altered patterns have been analysed, and novel approaches in lineage tracing have provided first insights into the cellular and molecular basis of colour patterning. These studies revealed that the mechanisms at play are novel and of fundamental interest to the biology of pattern formation. Closely related Danio species have very divergent colour patterns in body and fins offering the unique opportunity to study development and evolution of colour patterns in vertebrates building on the thorough analysis of one model species. Our research in zebrafish will explore the basis of direct interactions between chromatophores mediated by channels and junctions. We will investigate the divergent mode of stripe formation in the fins and the molecular influence of the cellular environment on chromatophore interactions. In closely related Danio species, we will investigate the cellular interactions during pattern formation. We will analyse transcriptomes and genome sequences to identify candidate genes providing the molecular basis for pigment pattern diversity. These candidate genes will be tested by creating mutants and exchanging allelic variants using the CRISPR/Cas9 system. The work will lay the foundation to understand not only the genetic basis of variation in colour pattern formation between Danio species, but also the evolution of biodiversity in other vertebrates.
Summary
Colour patterns are prominent features of many animals and have important functions in communication such as camouflage, kin recognition and mate selection. Colour patterns are highly variable and evolve rapidly leading to large diversities even within a single genus. As targets for natural as well as sexual selection, they are of high evolutionary significance. The zebrafish (Danio rerio), a vertebrate model organism for the study of development and disease, displays a conspicuous pattern of alternating blue and golden stripes on the body and on the anal- and tailfins. Mutants with spectacularly altered patterns have been analysed, and novel approaches in lineage tracing have provided first insights into the cellular and molecular basis of colour patterning. These studies revealed that the mechanisms at play are novel and of fundamental interest to the biology of pattern formation. Closely related Danio species have very divergent colour patterns in body and fins offering the unique opportunity to study development and evolution of colour patterns in vertebrates building on the thorough analysis of one model species. Our research in zebrafish will explore the basis of direct interactions between chromatophores mediated by channels and junctions. We will investigate the divergent mode of stripe formation in the fins and the molecular influence of the cellular environment on chromatophore interactions. In closely related Danio species, we will investigate the cellular interactions during pattern formation. We will analyse transcriptomes and genome sequences to identify candidate genes providing the molecular basis for pigment pattern diversity. These candidate genes will be tested by creating mutants and exchanging allelic variants using the CRISPR/Cas9 system. The work will lay the foundation to understand not only the genetic basis of variation in colour pattern formation between Danio species, but also the evolution of biodiversity in other vertebrates.
Max ERC Funding
2 250 000 €
Duration
Start date: 2016-11-01, End date: 2021-04-30
Project acronym Neurogenesis
Project Exploration and promotion of neurogenesis in the adult brain
Researcher (PI) Jonas FRISÉN
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS3, ERC-2015-AdG
Summary It is now well established that new neurons are added to certain regions of the adult brain. There is today considerable interest in the development of regenerative therapies based on modulating endogenous neurogenesis, but it is necessary to better understand these events to assess whether this is rational and realistic.
This application takes its initiation in two recent discoveries that we have made: that astrocytes in the mouse striatum give rise to new neurons after stroke or inhibition of Notch signaling (Magnusson et al., Science, 2014) and that neurogenesis is a continuous process in the human striatum throughout adulthood (Ernst et al., Cell, 2014). We propose to characterize the molecular regulation of neurogenesis from striatal astrocytes in detail, and compare these astrocytes with those in other regions to understand why striatal astrocytes are uniquely neurogenic and whether astrocytes in other parts of the brain can be induced to give rise to new neurons. We will, moreover, assess the role of integration of new neurons in the striatal circuitry by inducing neurogenesis in the striatum in adult mice by blocking Notch signaling or by inducing stroke and modulate the activity of the new neurons by optogenetics and chemogenetics. We will, furthermore, study whether striatal neurogenesis is altered in human neurological diseases by retrospective birth dating by measuring the integration of 14C from nuclear bomb tests. We will assess whether inducing striatal neurogenesis in corresponding mouse models of neurological diseases has therapeutic potential.
This project will elucidate the molecular regulation of neurogenesis from astrocytes and the neurogenic potential of astrocytes in different parts of the brain, reveal the role of new neurons in the striatum, answer whether striatal neurogenesis is altered in common neurological conditions in humans and reveal whether inducing striatal neurogenesis may have therapeutic potential.
Summary
It is now well established that new neurons are added to certain regions of the adult brain. There is today considerable interest in the development of regenerative therapies based on modulating endogenous neurogenesis, but it is necessary to better understand these events to assess whether this is rational and realistic.
This application takes its initiation in two recent discoveries that we have made: that astrocytes in the mouse striatum give rise to new neurons after stroke or inhibition of Notch signaling (Magnusson et al., Science, 2014) and that neurogenesis is a continuous process in the human striatum throughout adulthood (Ernst et al., Cell, 2014). We propose to characterize the molecular regulation of neurogenesis from striatal astrocytes in detail, and compare these astrocytes with those in other regions to understand why striatal astrocytes are uniquely neurogenic and whether astrocytes in other parts of the brain can be induced to give rise to new neurons. We will, moreover, assess the role of integration of new neurons in the striatal circuitry by inducing neurogenesis in the striatum in adult mice by blocking Notch signaling or by inducing stroke and modulate the activity of the new neurons by optogenetics and chemogenetics. We will, furthermore, study whether striatal neurogenesis is altered in human neurological diseases by retrospective birth dating by measuring the integration of 14C from nuclear bomb tests. We will assess whether inducing striatal neurogenesis in corresponding mouse models of neurological diseases has therapeutic potential.
This project will elucidate the molecular regulation of neurogenesis from astrocytes and the neurogenic potential of astrocytes in different parts of the brain, reveal the role of new neurons in the striatum, answer whether striatal neurogenesis is altered in common neurological conditions in humans and reveal whether inducing striatal neurogenesis may have therapeutic potential.
Max ERC Funding
2 500 000 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym REDOXCYCLE
Project The molecular interface between cell cycle and redox regulation
Researcher (PI) Jörg Mansfeld
Host Institution (HI) TECHNISCHE UNIVERSITAET DRESDEN
Call Details Starting Grant (StG), LS3, ERC-2015-STG
Summary Aberrant cell cycle and redox regulation are hallmarks of cancer. While cell cycle and redox signaling are extensively studied, it remains poorly understood how both communicate in physiological conditions. One reason is the emphasis on oxidative stress as a signature of cancer cells. Only recently, emerging evidence indicates that reactive oxygen species (ROS) also function as signaling molecules in physiological conditions, and that some of their key targets are cysteine residues on cell cycle proteins. This indicates that more subtle changes in redox signaling can affect proliferation and have the potential to promote cancer.
I propose to investigate how the cell cycle and redox homeostasis are coupled in a spatial-temporal manner and reveal the differences that distinguish physiological from pathological redox signaling. I will use genetic engineering to label endogenous cell cycle and redox proteins with fluorescent markers. I will measure relative and absolute molecule numbers of cell cycle and redox proteins, relate this to cell cycle and redox states, and determine the cysteines modified on cell cycle proteins. To functionally investigate the pathological potential of identified modifications I will use mammary 3D cell culture – a model that recapitulates many aspects of mammary architecture in vivo and is used to study early steps of breast tumorigenesis.
I expect our work to provide us with a quantitative description of the interface between cell cycle and redox regulation. Although intracellular cell behavior is never completely deterministic, a reasonable quantitative model should be predictive to some degree and reveal how different levels of ROS can affect cell cycle decisions. Shedding light on the cell cycle targets of ROS will indicate the nodes that can be hijacked by cancer cells. Together, this work will provide a significantly improved basis for our understanding of redox signaling in tumorigenesis and indicate new strategies for treatment.
Summary
Aberrant cell cycle and redox regulation are hallmarks of cancer. While cell cycle and redox signaling are extensively studied, it remains poorly understood how both communicate in physiological conditions. One reason is the emphasis on oxidative stress as a signature of cancer cells. Only recently, emerging evidence indicates that reactive oxygen species (ROS) also function as signaling molecules in physiological conditions, and that some of their key targets are cysteine residues on cell cycle proteins. This indicates that more subtle changes in redox signaling can affect proliferation and have the potential to promote cancer.
I propose to investigate how the cell cycle and redox homeostasis are coupled in a spatial-temporal manner and reveal the differences that distinguish physiological from pathological redox signaling. I will use genetic engineering to label endogenous cell cycle and redox proteins with fluorescent markers. I will measure relative and absolute molecule numbers of cell cycle and redox proteins, relate this to cell cycle and redox states, and determine the cysteines modified on cell cycle proteins. To functionally investigate the pathological potential of identified modifications I will use mammary 3D cell culture – a model that recapitulates many aspects of mammary architecture in vivo and is used to study early steps of breast tumorigenesis.
I expect our work to provide us with a quantitative description of the interface between cell cycle and redox regulation. Although intracellular cell behavior is never completely deterministic, a reasonable quantitative model should be predictive to some degree and reveal how different levels of ROS can affect cell cycle decisions. Shedding light on the cell cycle targets of ROS will indicate the nodes that can be hijacked by cancer cells. Together, this work will provide a significantly improved basis for our understanding of redox signaling in tumorigenesis and indicate new strategies for treatment.
Max ERC Funding
1 499 688 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym RULLIVER
Project Rules of self-organization and reengineering of liver tissue
Researcher (PI) Marino ZERIAL
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Advanced Grant (AdG), LS3, ERC-2015-AdG
Summary We want to understand the rules of self-organization underlying tissue structure and function. To address this problem, we have chosen the mouse liver with its complex apico-basal polarity of hepatocytes and its unique 3D tissue organization. We aim at identifying the rules of self-organization of liver tissue and their implementation at the molecular level. Our ultimate goal is to demonstrate that it is possible to reengineer liver tissue structure. The first aim will be to develop a digital geometrical model of liver tissue, i.e. an accurate 3D digital representation of the cells, forming the tissue and their sub-cellular components, in the developing, adult and regenerating liver, and unravel the principles for how the cells are organized to generate liver cell architecture. In aims 2 and 3, we will identify the molecular mechanisms underlying such geometrical rules. In particular, the second aim will be to characterize the molecular mechanisms responsible for hepatocyte cell polarity and predictably modify cell organization in vitro. The third aim will consist of introducing genetic perturbations to alter hepatocyte cell organization (cell polarity) and cell-cell interactions to predictably modify the structure and function of liver tissue. The fourth aim will be to develop a physical model of liver tissue self-assembly and organization. The project is ambitious as it aims to understand the rules of tissue organization in 3D in a mammalian organ to such an extent that it is possible to make predictions of tissue response to genetic perturbations and reengineer it to modify its structural and functional properties.
Summary
We want to understand the rules of self-organization underlying tissue structure and function. To address this problem, we have chosen the mouse liver with its complex apico-basal polarity of hepatocytes and its unique 3D tissue organization. We aim at identifying the rules of self-organization of liver tissue and their implementation at the molecular level. Our ultimate goal is to demonstrate that it is possible to reengineer liver tissue structure. The first aim will be to develop a digital geometrical model of liver tissue, i.e. an accurate 3D digital representation of the cells, forming the tissue and their sub-cellular components, in the developing, adult and regenerating liver, and unravel the principles for how the cells are organized to generate liver cell architecture. In aims 2 and 3, we will identify the molecular mechanisms underlying such geometrical rules. In particular, the second aim will be to characterize the molecular mechanisms responsible for hepatocyte cell polarity and predictably modify cell organization in vitro. The third aim will consist of introducing genetic perturbations to alter hepatocyte cell organization (cell polarity) and cell-cell interactions to predictably modify the structure and function of liver tissue. The fourth aim will be to develop a physical model of liver tissue self-assembly and organization. The project is ambitious as it aims to understand the rules of tissue organization in 3D in a mammalian organ to such an extent that it is possible to make predictions of tissue response to genetic perturbations and reengineer it to modify its structural and functional properties.
Max ERC Funding
2 498 013 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym ZMOD
Project Blood Vessel Development and Homeostasis: Identification and Functional Analysis of Genetic Modifiers
Researcher (PI) Didier STAINIER
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Advanced Grant (AdG), LS3, ERC-2015-AdG
Summary The vascular system is a complex network of blood vessels that transports gases, nutrients and hormones throughout the organism. Most blood vessels that form during development and growth arise by the sprouting of new capillaries from pre-existing vessels, a process termed angiogenesis. An imbalance in angiogenesis contributes to the pathogenesis of numerous disease states: insufficient angiogenesis limits tissue recovery in ischemic disease, whereas stimulation of angiogenesis by cancer cells promotes tumor vascularization and growth. Angiogenesis inhibitors are already in clinical use for anti-tumor therapy; however, multiple reports of resistance are calling for the identification of additional targets. Furthermore, vascular malformations are a significant cause of morbidity and mortality. While the genetic basis for some vascular malformations is known, many genetic factors, including modifiers that affect the age-of-onset and severity of phenotypes, remain to be identified. Identifying modifier genes is important not only to fully assess genetic risk, but also to provide novel targets for therapy; however, identifying modifier genes has proven challenging. We recently uncovered a novel and simple way to identify modifier genes. By investigating gene and protein expression differences between knockout (mutant) and knockdown (antisense treated) zebrafish embryos, we found that mutations in specific genes, including some encoding angiogenic factors, lead to the upregulation of compensating (i.e., modifier) genes while knocking down these same genes does not. We hypothesize that the modifier genes identified through this approach in zebrafish also play important roles in humans. Thus, we will use this simple strategy to identify new genes that regulate vascular formation and homeostasis, and subsequently analyze their function in zebrafish as well as in mammalian models, as they are likely to play key roles in vascular development and disease.
Summary
The vascular system is a complex network of blood vessels that transports gases, nutrients and hormones throughout the organism. Most blood vessels that form during development and growth arise by the sprouting of new capillaries from pre-existing vessels, a process termed angiogenesis. An imbalance in angiogenesis contributes to the pathogenesis of numerous disease states: insufficient angiogenesis limits tissue recovery in ischemic disease, whereas stimulation of angiogenesis by cancer cells promotes tumor vascularization and growth. Angiogenesis inhibitors are already in clinical use for anti-tumor therapy; however, multiple reports of resistance are calling for the identification of additional targets. Furthermore, vascular malformations are a significant cause of morbidity and mortality. While the genetic basis for some vascular malformations is known, many genetic factors, including modifiers that affect the age-of-onset and severity of phenotypes, remain to be identified. Identifying modifier genes is important not only to fully assess genetic risk, but also to provide novel targets for therapy; however, identifying modifier genes has proven challenging. We recently uncovered a novel and simple way to identify modifier genes. By investigating gene and protein expression differences between knockout (mutant) and knockdown (antisense treated) zebrafish embryos, we found that mutations in specific genes, including some encoding angiogenic factors, lead to the upregulation of compensating (i.e., modifier) genes while knocking down these same genes does not. We hypothesize that the modifier genes identified through this approach in zebrafish also play important roles in humans. Thus, we will use this simple strategy to identify new genes that regulate vascular formation and homeostasis, and subsequently analyze their function in zebrafish as well as in mammalian models, as they are likely to play key roles in vascular development and disease.
Max ERC Funding
2 500 000 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
