Project acronym AutoRecon
Project Molecular mechanisms of autophagosome formation during selective autophagy
Researcher (PI) Sascha Martens
Host Institution (HI) UNIVERSITAT WIEN
Call Details Consolidator Grant (CoG), LS3, ERC-2014-CoG
Summary I propose to study how eukaryotic cells generate autophagosomes, organelles bounded by a double membrane. These are formed during autophagy and mediate the degradation of cytoplasmic substances within the lysosomal compartment. Autophagy thereby protects the organism from pathological conditions such as neurodegeneration, cancer and infections. Many core factors required for autophagosome formation have been identified but the order in which they act and their mode of action is still unclear. We will use a combination of biochemical and cell biological approaches to elucidate the choreography and mechanism of these core factors. In particular, we will focus on selective autophagy and determine how the autophagic machinery generates an autophagosome that selectively contains the cargo.
To this end we will focus on the cytoplasm-to-vacuole-targeting pathway in S. cerevisiae that mediates the constitutive delivery of the prApe1 enzyme into the vacuole. We will use cargo mimetics or prApe1 complexes in combination with purified autophagy proteins and vesicles to reconstitute the process and so determine which factors are both necessary and sufficient for autophagosome formation, as well as elucidating their mechanism of action.
In parallel we will study selective autophagosome formation in human cells. This will reveal common principles and special adaptations. In particular, we will use cell lysates from genome-edited cells in combination with purified autophagy proteins to reconstitute selective autophagosome formation around ubiquitin-positive cargo material. The insights and hypotheses obtained from these reconstituted systems will be validated using cell biological approaches.
Taken together, our experiments will allow us to delineate the major steps of autophagosome formation during selective autophagy. Our results will yield detailed insights into how cells form and shape organelles in a de novo manner, which is major question in cell- and developmental biology.
Summary
I propose to study how eukaryotic cells generate autophagosomes, organelles bounded by a double membrane. These are formed during autophagy and mediate the degradation of cytoplasmic substances within the lysosomal compartment. Autophagy thereby protects the organism from pathological conditions such as neurodegeneration, cancer and infections. Many core factors required for autophagosome formation have been identified but the order in which they act and their mode of action is still unclear. We will use a combination of biochemical and cell biological approaches to elucidate the choreography and mechanism of these core factors. In particular, we will focus on selective autophagy and determine how the autophagic machinery generates an autophagosome that selectively contains the cargo.
To this end we will focus on the cytoplasm-to-vacuole-targeting pathway in S. cerevisiae that mediates the constitutive delivery of the prApe1 enzyme into the vacuole. We will use cargo mimetics or prApe1 complexes in combination with purified autophagy proteins and vesicles to reconstitute the process and so determine which factors are both necessary and sufficient for autophagosome formation, as well as elucidating their mechanism of action.
In parallel we will study selective autophagosome formation in human cells. This will reveal common principles and special adaptations. In particular, we will use cell lysates from genome-edited cells in combination with purified autophagy proteins to reconstitute selective autophagosome formation around ubiquitin-positive cargo material. The insights and hypotheses obtained from these reconstituted systems will be validated using cell biological approaches.
Taken together, our experiments will allow us to delineate the major steps of autophagosome formation during selective autophagy. Our results will yield detailed insights into how cells form and shape organelles in a de novo manner, which is major question in cell- and developmental biology.
Max ERC Funding
1 999 640 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym DeFiNER
Project Nucleotide Excision Repair: Decoding its Functional Role in Mammals
Researcher (PI) Georgios Garinis
Host Institution (HI) IDRYMA TECHNOLOGIAS KAI EREVNAS
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Genome maintenance, chromatin remodelling and transcription are tightly linked biological processes that are currently poorly understood and vastly unexplored. Nucleotide excision repair (NER) is a major DNA repair pathway that mammalian cells employ to maintain their genome intact and faithfully transmit it into their progeny. Besides cancer and aging, however, defects in NER give rise to developmental disorders whose clinical heterogeneity and varying severity can only insufficiently be explained by the DNA repair defect. Recent work reveals that NER factors play a role, in addition to DNA repair, in transcription and the three-dimensional organization of our genome. Indeed, NER factors are now known to function in the regulation of gene expression, the transcriptional reprogramming of pluripotent stem cells and the fine-tuning of growth hormones during mammalian development. In this regard, the non-random organization of our genome, chromatin and the process of transcription itself are expected to play paramount roles in how NER factors coordinate, prioritize and execute their distinct tasks during development and disease progression. At present, however, no solid evidence exists as to how NER is functionally involved in such complex processes, what are the NER-associated protein complexes and underlying gene networks or how NER factors operate within the complex chromatin architecture. This is primarily due to our difficulties in dissecting the diverse functional contributions of NER proteins in an intact organism. Here, we propose to use a unique series of knock-in, transgenic and NER progeroid mice to decode the functional role of NER in mammals, thus paving the way for understanding how genome maintenance pathways are connected to developmental defects and disease mechanisms in vivo.
Summary
Genome maintenance, chromatin remodelling and transcription are tightly linked biological processes that are currently poorly understood and vastly unexplored. Nucleotide excision repair (NER) is a major DNA repair pathway that mammalian cells employ to maintain their genome intact and faithfully transmit it into their progeny. Besides cancer and aging, however, defects in NER give rise to developmental disorders whose clinical heterogeneity and varying severity can only insufficiently be explained by the DNA repair defect. Recent work reveals that NER factors play a role, in addition to DNA repair, in transcription and the three-dimensional organization of our genome. Indeed, NER factors are now known to function in the regulation of gene expression, the transcriptional reprogramming of pluripotent stem cells and the fine-tuning of growth hormones during mammalian development. In this regard, the non-random organization of our genome, chromatin and the process of transcription itself are expected to play paramount roles in how NER factors coordinate, prioritize and execute their distinct tasks during development and disease progression. At present, however, no solid evidence exists as to how NER is functionally involved in such complex processes, what are the NER-associated protein complexes and underlying gene networks or how NER factors operate within the complex chromatin architecture. This is primarily due to our difficulties in dissecting the diverse functional contributions of NER proteins in an intact organism. Here, we propose to use a unique series of knock-in, transgenic and NER progeroid mice to decode the functional role of NER in mammals, thus paving the way for understanding how genome maintenance pathways are connected to developmental defects and disease mechanisms in vivo.
Max ERC Funding
1 995 000 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym Enhancer ID
Project Identification and functional characterization of mammalian enhancers and transcriptional co-factors during cellular signaling and cell fate transitions
Researcher (PI) Alexander Stark
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Consolidator Grant (CoG), LS2, ERC-2014-CoG
Summary A major goal in biology is to understand how gene regulatory information is encoded by the human genome and how it defines different gene expression programs and cell types. Enhancers are genomic elements that control transcription, yet despite their importance, only a minority of enhancers are known and functionally characterized. In particular, their activity changes during cellular signalling or cell type transitions are largely elusive. Furthermore, fundamental questions about transcriptional co-factors have remained unanswered even though they regulate enhancer activities and have become attractive therapeutic targets, e.g. for cancer treatment.
Here, I propose a functional genomics approach in mammalian cells with three specific objectives: First, we will identify and functionally characterize transcriptional enhancers in selected human and mouse cells using the recently developed quantitative enhancer activity assay STARR-seq. Second, we will determine enhancer activity changes quantitatively during steroid hormone signalling, cell differentiation, and malignant transformation to reveal enhancers that are important for these processes. Third, we will systematically dissect the functional relationship of enhancers and transcriptional co-factors.
This proposal uses emerging in-house technology to address fundamental questions in enhancer biology and complement the genome-wide profiling of gene expression and chromatin states (e.g. by ENCODE). We will gain insights into the genomic organization of active enhancers and reveal chromatin or sequence features associated with dynamic activity changes. I also expect that we will be able to define co-factor requirements for enhancer function and reveal if different types of enhancers exist. Given our expertise in experimental and computational approaches and STARR-seq, I anticipate that we reach our aims and make major contributions to the understanding of gene regulation in mammals.
Summary
A major goal in biology is to understand how gene regulatory information is encoded by the human genome and how it defines different gene expression programs and cell types. Enhancers are genomic elements that control transcription, yet despite their importance, only a minority of enhancers are known and functionally characterized. In particular, their activity changes during cellular signalling or cell type transitions are largely elusive. Furthermore, fundamental questions about transcriptional co-factors have remained unanswered even though they regulate enhancer activities and have become attractive therapeutic targets, e.g. for cancer treatment.
Here, I propose a functional genomics approach in mammalian cells with three specific objectives: First, we will identify and functionally characterize transcriptional enhancers in selected human and mouse cells using the recently developed quantitative enhancer activity assay STARR-seq. Second, we will determine enhancer activity changes quantitatively during steroid hormone signalling, cell differentiation, and malignant transformation to reveal enhancers that are important for these processes. Third, we will systematically dissect the functional relationship of enhancers and transcriptional co-factors.
This proposal uses emerging in-house technology to address fundamental questions in enhancer biology and complement the genome-wide profiling of gene expression and chromatin states (e.g. by ENCODE). We will gain insights into the genomic organization of active enhancers and reveal chromatin or sequence features associated with dynamic activity changes. I also expect that we will be able to define co-factor requirements for enhancer function and reveal if different types of enhancers exist. Given our expertise in experimental and computational approaches and STARR-seq, I anticipate that we reach our aims and make major contributions to the understanding of gene regulation in mammals.
Max ERC Funding
1 999 906 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym iDysChart
Project Charting key molecules and mechanisms of human immune Dysregulation
Researcher (PI) Ahmet Kaan BOZTUG
Host Institution (HI) LUDWIG BOLTZMANN GESELLSCHAFT GMBH
Call Details Consolidator Grant (CoG), LS6, ERC-2018-COG
Summary The central challenge for the immune system is to efficiently recognize and neutralize foreign antigen while protecting self. If the latter fails, autoimmunity and/or autoinflammation may occur, as observed in many human diseases. Though several human genes involved in the process have been identified we still lack: i) a comprehensive appreciation of all contributing molecular pathways, ii) an understanding of the interplay and epistatic relationships among the various elements and iii) a satisfactory strategy to counteract dysregulation based on an understanding of the regulatory logic.
I hypothesize that there is only a finite number of pathways involved and that it should be possible to mount a synergistic strategy to create a first chart of the entire “territory”. Key to this endeavor is the identification of sufficient elements by mapping immune dysregulation genes to “anchor” the chart onto signposts of which the human pathophysiological relevance is certain. From these signposts, contextualization and integration is achieved by interaction proteomics and network informatics mining the existing data universe, validated through biochemical and imaging tools to power an established set of immune assays. While it may be preposterous to claim feasibility with one ERC grant, I propose that once such a chart exists, even at initial low resolution, it can help reconcile disconnected observations and coalesce future work while being immensely improved in accuracy and mechanistic understanding by the entire community. iDysChart will work towards these goals by 1) identifying novel monogenic causes of autoimmune/autoinflammatory diseases, enabling elucidation of fundamental mechanisms, 2) creating a network-level understanding of molecular pathways of immune dysregulation and 3) employing chemical and genetic screens to complement human disease gene discovery in predicting the core human immune dysregulome and investigating potential avenues for therapeutic modulation.
Summary
The central challenge for the immune system is to efficiently recognize and neutralize foreign antigen while protecting self. If the latter fails, autoimmunity and/or autoinflammation may occur, as observed in many human diseases. Though several human genes involved in the process have been identified we still lack: i) a comprehensive appreciation of all contributing molecular pathways, ii) an understanding of the interplay and epistatic relationships among the various elements and iii) a satisfactory strategy to counteract dysregulation based on an understanding of the regulatory logic.
I hypothesize that there is only a finite number of pathways involved and that it should be possible to mount a synergistic strategy to create a first chart of the entire “territory”. Key to this endeavor is the identification of sufficient elements by mapping immune dysregulation genes to “anchor” the chart onto signposts of which the human pathophysiological relevance is certain. From these signposts, contextualization and integration is achieved by interaction proteomics and network informatics mining the existing data universe, validated through biochemical and imaging tools to power an established set of immune assays. While it may be preposterous to claim feasibility with one ERC grant, I propose that once such a chart exists, even at initial low resolution, it can help reconcile disconnected observations and coalesce future work while being immensely improved in accuracy and mechanistic understanding by the entire community. iDysChart will work towards these goals by 1) identifying novel monogenic causes of autoimmune/autoinflammatory diseases, enabling elucidation of fundamental mechanisms, 2) creating a network-level understanding of molecular pathways of immune dysregulation and 3) employing chemical and genetic screens to complement human disease gene discovery in predicting the core human immune dysregulome and investigating potential avenues for therapeutic modulation.
Max ERC Funding
1 999 263 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym Mari.Time
Project Dissecting the mechanistic basis of moon-controlled monthly timing mechanisms in marine environments
Researcher (PI) Karla Gisela Kristin TESSMAR-RAIBLE
Host Institution (HI) UNIVERSITAT WIEN
Call Details Consolidator Grant (CoG), LS8, ERC-2018-COG
Summary The correct timing of biological processes is crucial for organisms. The moon is an important timing cue for numerous marine species, ranging from brown and green algae to corals, worms and fishes. It acts either directly or via the synchronization of monthly (circalunar) inner clocks. Such lunar timing mechanisms typically control the gonadal maturation and behavioral changes associated with reproductive rhythms, including spectacular mass-spawning events. Despite their biological importance, the mechanisms underlying circalunar clocks, as well as their responses to naturalistic stimuli are unknown.
My lab has spearheaded research into the mechanisms underlying circalunar timing systems, establishing tools and resources for two well-suited, complementary animal models: Platynereis dumerilii and Clunio marinus. We unraveled first principles of the circalunar clock, e.g. its continuous function in the absence of oscillation of the daily (circadian) clock. Recent unpublished work revealed the first gene that functionally impacts on circalunar rhythms.
By capitalizing on these powerful tools and key findings, my lab is in a leading position to dissect the mechanisms of circalunar clocks and their interaction with other rhythms and the environment via three objectives:
(1) A reverse genetic approach to unravel how nocturnal light sets the phase of the monthly clock.
(2) A forward genetic screen to identify molecules involved in the circalunar clock, an experimental strategy that was the key to unravel the principles of animal circadian clocks.
(3) By growing animals in outside tanks and subjecting them to established analyses, we will test our lab-based results in more naturalistic conditions.
This project will substantially deepen our mechanistic insight into marine rhythms – ecologically important phenomena – and provide a first basis to predict how environmental changes might impact on timing systems of crucial importance to many marine species and likely beyond.
Summary
The correct timing of biological processes is crucial for organisms. The moon is an important timing cue for numerous marine species, ranging from brown and green algae to corals, worms and fishes. It acts either directly or via the synchronization of monthly (circalunar) inner clocks. Such lunar timing mechanisms typically control the gonadal maturation and behavioral changes associated with reproductive rhythms, including spectacular mass-spawning events. Despite their biological importance, the mechanisms underlying circalunar clocks, as well as their responses to naturalistic stimuli are unknown.
My lab has spearheaded research into the mechanisms underlying circalunar timing systems, establishing tools and resources for two well-suited, complementary animal models: Platynereis dumerilii and Clunio marinus. We unraveled first principles of the circalunar clock, e.g. its continuous function in the absence of oscillation of the daily (circadian) clock. Recent unpublished work revealed the first gene that functionally impacts on circalunar rhythms.
By capitalizing on these powerful tools and key findings, my lab is in a leading position to dissect the mechanisms of circalunar clocks and their interaction with other rhythms and the environment via three objectives:
(1) A reverse genetic approach to unravel how nocturnal light sets the phase of the monthly clock.
(2) A forward genetic screen to identify molecules involved in the circalunar clock, an experimental strategy that was the key to unravel the principles of animal circadian clocks.
(3) By growing animals in outside tanks and subjecting them to established analyses, we will test our lab-based results in more naturalistic conditions.
This project will substantially deepen our mechanistic insight into marine rhythms – ecologically important phenomena – and provide a first basis to predict how environmental changes might impact on timing systems of crucial importance to many marine species and likely beyond.
Max ERC Funding
2 000 000 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym NeuroMag
Project The Neurological Basis of the Magnetic Sense
Researcher (PI) David KEAYS
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary Each year millions of animals undertake remarkable migratory journeys, across oceans and through hemispheres, guided by the Earth’s magnetic field. While there is unequivocal behavioural evidence demonstrating the existence of the magnetic sense, it is the least understood of all sensory faculties. The biophysical, molecular, cellular, and neurological underpinnings of the sense remain opaque. In this application we aim to remedy this situation, exploiting an established assay, our unique infrastructure, and state-of-the-art methodology, using pigeons as a model system. The proposal will address three questions:
1) Where are the primary magnetosensors?
2) Where is magnetic information processed in the brain?
3) How is magnetic information encoded in the brain?
In Aim 1 we will explore whether inner ear hair cells are the primary sensors, and if the detection of magnetic stimuli depends on the presence of magnetic crystals or electromagnetic induction. We will employ a range of physical methods to locate magnetite, and a molecular approach to identify putative electroreceptors. In Aim 2 we will use light sheet microscopy coupled with clearing methods to undertake whole brain mapping of magnetically-induced neuronal activation in the pigeon. We will complement these studies with transcriptomic methods to molecularly and anatomically define magnetosensitive circuits within the pigeon brain. We will build on this work in Aim 3 utilising in vivo 2-photon microscopy to investigate how cells within the pigeon brain encode magnetic information. We will determine whether neurons encode for specific components of the magnetic field (i.e. inclination, intensity, and polarity) and explore whether there are spatially restricted ensembles, providing a dynamic picture of magnetically induced neuronal activity. We anticipate that these experiments will reveal a secret that nature has kept hidden for millennia; How do animals detect magnetic fields?
Summary
Each year millions of animals undertake remarkable migratory journeys, across oceans and through hemispheres, guided by the Earth’s magnetic field. While there is unequivocal behavioural evidence demonstrating the existence of the magnetic sense, it is the least understood of all sensory faculties. The biophysical, molecular, cellular, and neurological underpinnings of the sense remain opaque. In this application we aim to remedy this situation, exploiting an established assay, our unique infrastructure, and state-of-the-art methodology, using pigeons as a model system. The proposal will address three questions:
1) Where are the primary magnetosensors?
2) Where is magnetic information processed in the brain?
3) How is magnetic information encoded in the brain?
In Aim 1 we will explore whether inner ear hair cells are the primary sensors, and if the detection of magnetic stimuli depends on the presence of magnetic crystals or electromagnetic induction. We will employ a range of physical methods to locate magnetite, and a molecular approach to identify putative electroreceptors. In Aim 2 we will use light sheet microscopy coupled with clearing methods to undertake whole brain mapping of magnetically-induced neuronal activation in the pigeon. We will complement these studies with transcriptomic methods to molecularly and anatomically define magnetosensitive circuits within the pigeon brain. We will build on this work in Aim 3 utilising in vivo 2-photon microscopy to investigate how cells within the pigeon brain encode magnetic information. We will determine whether neurons encode for specific components of the magnetic field (i.e. inclination, intensity, and polarity) and explore whether there are spatially restricted ensembles, providing a dynamic picture of magnetically induced neuronal activity. We anticipate that these experiments will reveal a secret that nature has kept hidden for millennia; How do animals detect magnetic fields?
Max ERC Funding
1 990 376 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym ProMiDis
Project A unified drug discovery platform for protein misfolding diseases
Researcher (PI) Georgios SKRETAS
Host Institution (HI) ETHNIKO IDRYMA EREVNON
Call Details Consolidator Grant (CoG), LS9, ERC-2018-COG
Summary It is now widely recognized that a variety of major diseases, such as Alzheimer’s disease, Huntington’s disease, systemic amyloidosis, cystic fibrosis, type 2 diabetes etc., are characterized by a common molecular origin: the misfolding of specific proteins. These disorders have been termed protein misfolding diseases (PMDs) and the vast majority of them remain incurable. Here, I propose the development of a unified approach for the discovery of potential therapeutics against PMDs. I will generate engineered bacterial cells that function as a broadly applicable discovery platform for compounds that rescue the misfolding of PMD-associated proteins (MisPs). These compounds will be selected from libraries of drug-like molecules biosynthesized in engineered bacteria using a technology that allows the facile production of billions of different test molecules. These libraries will then be screened in the same bacterial cells that produce them and the rare molecules that rescue MisP misfolding effectively will be selected using an ultrahigh-throughput genetic screen. The effect of the selected compounds on MisP folding will then be evaluated by biochemical and biophysical methods, while their ability to inhibit MisP-induced pathogenicity will be tested in appropriate mammalian cell assays and in established animal models of the associated PMD. The molecules that rescue the misfolding of the target MisPs and antagonize their associated pathogenicity both in vitro and in vivo, will become drug candidates against the corresponding diseases. This procedure will be applied for different MisPs to identify potential therapeutics for four major PMDs: Huntington’s disease, cardiotoxic light chain amyloidosis, dialysis-related amyloidosis and retinitis pigmentosa. Successful realization of ProMiDis will provide invaluable therapeutic leads against major diseases and a unified framework for anti-PMD drug discovery.
Summary
It is now widely recognized that a variety of major diseases, such as Alzheimer’s disease, Huntington’s disease, systemic amyloidosis, cystic fibrosis, type 2 diabetes etc., are characterized by a common molecular origin: the misfolding of specific proteins. These disorders have been termed protein misfolding diseases (PMDs) and the vast majority of them remain incurable. Here, I propose the development of a unified approach for the discovery of potential therapeutics against PMDs. I will generate engineered bacterial cells that function as a broadly applicable discovery platform for compounds that rescue the misfolding of PMD-associated proteins (MisPs). These compounds will be selected from libraries of drug-like molecules biosynthesized in engineered bacteria using a technology that allows the facile production of billions of different test molecules. These libraries will then be screened in the same bacterial cells that produce them and the rare molecules that rescue MisP misfolding effectively will be selected using an ultrahigh-throughput genetic screen. The effect of the selected compounds on MisP folding will then be evaluated by biochemical and biophysical methods, while their ability to inhibit MisP-induced pathogenicity will be tested in appropriate mammalian cell assays and in established animal models of the associated PMD. The molecules that rescue the misfolding of the target MisPs and antagonize their associated pathogenicity both in vitro and in vivo, will become drug candidates against the corresponding diseases. This procedure will be applied for different MisPs to identify potential therapeutics for four major PMDs: Huntington’s disease, cardiotoxic light chain amyloidosis, dialysis-related amyloidosis and retinitis pigmentosa. Successful realization of ProMiDis will provide invaluable therapeutic leads against major diseases and a unified framework for anti-PMD drug discovery.
Max ERC Funding
1 972 000 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym SomSOM
Project Self-organisation of microbial soil organic matter turnover
Researcher (PI) Christina KAISER
Host Institution (HI) UNIVERSITAT WIEN
Call Details Consolidator Grant (CoG), LS8, ERC-2018-COG
Summary Microbial turnover of soil organic matter (SOM) is key for the terrestrial carbon (C) cycle. Its underlying mechanisms, however, are not fully understood. The role of soil microbes for organic matter turnover has so far been studied mainly from the point of view of microbial physiology, stoichiometry or community composition. I propose to shed new light on it from the perspective of complex systems science.
Microbial decomposition of organic matter requires the concerted action of functionally different microbes interacting with each other in a spatially structured environment. From complex systems theory, it is known that interactions among individuals at the microscale can lead to an ‘emergent’ system behavior, or ‘self-organisation’, at the macroscale, which adds a new quality to the system that cannot be derived from the traits of the interacting agents. Importantly, if microbial decomposer systems are self-organised, they may behave in a different way as currently assumed, especially under changing environmental conditions.
The aim of this project is thus to investigate i) if microbial decomposition of organic matter is driven by emergent behaviour, and ii) what consequences this has for soil C and nitrogen cycling. Combining state-of-the-art methods from soil biogeochemistry, microbial ecology, and complex systems science I will
• Investigate mechanisms of spatial self-organization of microbial decomposer communities by linking microscale observations from experimental microcosms to mathematical, individual-based modelling,
• Elucidate microbial interaction networks across the soil’s microarchitecture by linking microbial community composition, process rates and chemical composition of spatially explicit soil micro-units at an unprecedented small and pertinent scale.
• Explore fundamental patterns of self-organisation by applying the framework of complex systems science to high-resolution spatial and temporal data of soil microstructure and process rates.
Summary
Microbial turnover of soil organic matter (SOM) is key for the terrestrial carbon (C) cycle. Its underlying mechanisms, however, are not fully understood. The role of soil microbes for organic matter turnover has so far been studied mainly from the point of view of microbial physiology, stoichiometry or community composition. I propose to shed new light on it from the perspective of complex systems science.
Microbial decomposition of organic matter requires the concerted action of functionally different microbes interacting with each other in a spatially structured environment. From complex systems theory, it is known that interactions among individuals at the microscale can lead to an ‘emergent’ system behavior, or ‘self-organisation’, at the macroscale, which adds a new quality to the system that cannot be derived from the traits of the interacting agents. Importantly, if microbial decomposer systems are self-organised, they may behave in a different way as currently assumed, especially under changing environmental conditions.
The aim of this project is thus to investigate i) if microbial decomposition of organic matter is driven by emergent behaviour, and ii) what consequences this has for soil C and nitrogen cycling. Combining state-of-the-art methods from soil biogeochemistry, microbial ecology, and complex systems science I will
• Investigate mechanisms of spatial self-organization of microbial decomposer communities by linking microscale observations from experimental microcosms to mathematical, individual-based modelling,
• Elucidate microbial interaction networks across the soil’s microarchitecture by linking microbial community composition, process rates and chemical composition of spatially explicit soil micro-units at an unprecedented small and pertinent scale.
• Explore fundamental patterns of self-organisation by applying the framework of complex systems science to high-resolution spatial and temporal data of soil microstructure and process rates.
Max ERC Funding
1 896 129 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym STEMMING-FROM-NERVE
Project Targeted Cell Recruitment During Organogenesis And Regeneration: Glia Makes The Tooth
Researcher (PI) Igor Adameyko
Host Institution (HI) MEDIZINISCHE UNIVERSITAET WIEN
Call Details Consolidator Grant (CoG), LS3, ERC-2014-CoG
Summary Recently we discovered an entirely new phenomenon in developmental biology – targeted recruitment of stem cells from the pervasive peripheral nerves. For example, we demonstrated that majority of melanocytes – our pigment cells, are born from peripheral glial cells. To further extend this far-reaching principle we will use tooth development as a model. Current opinion holds that sensory innervation of the tooth has a minor or no role in making a structure of the tooth during development and adulthood. On the contrary, our preliminary data strongly suggest that sensory nerve contributes pulp cells and matrix-producing cells of odontoblast lineage to the growing tooth. Our hypothesis implies that nerve-associated glial cells can be recruited from the nerve by unknown molecules presented inside of the tooth environment, and that these recruited cells are capable of producing pulp cells and odontoblasts.
WE PROPOSE TO ADDRESS THE ROLE OF A SENSORY NERVE AS A PROVIDER OF DENTAL STEM CELLS DURING THE DEVELOPMENT, ADULTHOOD AND REGENERATION.
To experimentally address our hypothesis we developed innovative and powerful approaches: we will use advanced genetics tracing with multicolor reporters, completely novel unconventional individual cell transcriptome analysis, transgenic mice with cell type-specific modifications in signaling, microsurgery and grafting, and, finally, 3D-imaging of developing tooth structures.
This project is interesting to a wide community of scientists because it addresses a novel function of peripheral nervous system which is contributing stem cells as building blocks to local tissues in development and regeneration.
The MEDICAL IMPLICATION of this project will include better understanding of tooth regeneration providing new approaches to dentin recovery and tooth restoration following trauma.
Summary
Recently we discovered an entirely new phenomenon in developmental biology – targeted recruitment of stem cells from the pervasive peripheral nerves. For example, we demonstrated that majority of melanocytes – our pigment cells, are born from peripheral glial cells. To further extend this far-reaching principle we will use tooth development as a model. Current opinion holds that sensory innervation of the tooth has a minor or no role in making a structure of the tooth during development and adulthood. On the contrary, our preliminary data strongly suggest that sensory nerve contributes pulp cells and matrix-producing cells of odontoblast lineage to the growing tooth. Our hypothesis implies that nerve-associated glial cells can be recruited from the nerve by unknown molecules presented inside of the tooth environment, and that these recruited cells are capable of producing pulp cells and odontoblasts.
WE PROPOSE TO ADDRESS THE ROLE OF A SENSORY NERVE AS A PROVIDER OF DENTAL STEM CELLS DURING THE DEVELOPMENT, ADULTHOOD AND REGENERATION.
To experimentally address our hypothesis we developed innovative and powerful approaches: we will use advanced genetics tracing with multicolor reporters, completely novel unconventional individual cell transcriptome analysis, transgenic mice with cell type-specific modifications in signaling, microsurgery and grafting, and, finally, 3D-imaging of developing tooth structures.
This project is interesting to a wide community of scientists because it addresses a novel function of peripheral nervous system which is contributing stem cells as building blocks to local tissues in development and regeneration.
The MEDICAL IMPLICATION of this project will include better understanding of tooth regeneration providing new approaches to dentin recovery and tooth restoration following trauma.
Max ERC Funding
1 964 338 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
Project acronym TotipotentZygotChrom
Project Mechanisms of chromatin organization and reprogramming in totipotent mammalian zygotes
Researcher (PI) Kikue Tachibana
Host Institution (HI) INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Call Details Consolidator Grant (CoG), LS3, ERC-2018-COG
Summary Totipotency, the developmental potential of a cell to give rise to all cell types, is naturally achieved when differentiated egg and sperm fuse to form the one-cell zygote. How chromatin is epigenetically reprogrammed to totipotency within hours after fertilisation remains a central question in biology. We aim to address this by investigating the mechanisms of reprogramming and the spatial reorganisation of chromatin in mammalian zygotes. Our interdisciplinary approach combines mechanistic cell biology with genetics and genomics to understand how chromatin reorganisation promotes totipotency and to identify key regulators of this process in zygotes. Molecular insights into reprogramming to totipotency are crucial to understand the essential zygotic stage of sexually reproducing species. A better understanding of how cells naturally reprogram chromatin to totipotency, a state upstream of pluripotency, has the potential to improve induced reprogramming technology and revolutionize regenerative medicine.
Our aim is to understand how chromatin is reprogrammed to totipotency. To reach this ambitious goal: 1) We will discover new general concepts of genome organization, as well as reprogramming-specific aspects, by capitalising on our recently developed single-nucleus Hi-C method to dissect spatial reorganisation of chromatin in zygotes. We will investigate the relationship between chromatin reorganisation and transcription. 2) We will uncover mechanisms of zygotic reprogramming by elucidating the loci and factors that support active DNA demethylation during reprogramming of the paternal genome. 3) We will illuminate the origins and contributions of the oocyte since the factors responsible for reprogramming likely reside as proteins or RNA in the unfertilized egg. Overall, these studies will provide novel insights into how chromatin is reprogrammed and spatially reorganised towards a totipotent state that facilitates zygotic genome activation.
Summary
Totipotency, the developmental potential of a cell to give rise to all cell types, is naturally achieved when differentiated egg and sperm fuse to form the one-cell zygote. How chromatin is epigenetically reprogrammed to totipotency within hours after fertilisation remains a central question in biology. We aim to address this by investigating the mechanisms of reprogramming and the spatial reorganisation of chromatin in mammalian zygotes. Our interdisciplinary approach combines mechanistic cell biology with genetics and genomics to understand how chromatin reorganisation promotes totipotency and to identify key regulators of this process in zygotes. Molecular insights into reprogramming to totipotency are crucial to understand the essential zygotic stage of sexually reproducing species. A better understanding of how cells naturally reprogram chromatin to totipotency, a state upstream of pluripotency, has the potential to improve induced reprogramming technology and revolutionize regenerative medicine.
Our aim is to understand how chromatin is reprogrammed to totipotency. To reach this ambitious goal: 1) We will discover new general concepts of genome organization, as well as reprogramming-specific aspects, by capitalising on our recently developed single-nucleus Hi-C method to dissect spatial reorganisation of chromatin in zygotes. We will investigate the relationship between chromatin reorganisation and transcription. 2) We will uncover mechanisms of zygotic reprogramming by elucidating the loci and factors that support active DNA demethylation during reprogramming of the paternal genome. 3) We will illuminate the origins and contributions of the oocyte since the factors responsible for reprogramming likely reside as proteins or RNA in the unfertilized egg. Overall, these studies will provide novel insights into how chromatin is reprogrammed and spatially reorganised towards a totipotent state that facilitates zygotic genome activation.
Max ERC Funding
2 000 000 €
Duration
Start date: 2020-02-01, End date: 2025-01-31
