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 AuxinER
Project Mechanisms of Auxin-dependent Signaling in the Endoplasmic Reticulum
Researcher (PI) Jürgen Kleine-Vehn
Host Institution (HI) UNIVERSITAET FUER BODENKULTUR WIEN
Call Details Starting Grant (StG), LS3, ERC-2014-STG
Summary The phytohormone auxin has profound importance for plant development. The extracellular AUXIN BINDING PROTEIN1 (ABP1) and the nuclear AUXIN F-BOX PROTEINs (TIR1/AFBs) auxin receptors perceive fast, non-genomic and slow, genomic auxin responses, respectively. Despite the fact that ABP1 mainly localizes to the endoplasmic reticulum (ER), until now it has been proposed to be active only in the extracellular matrix (reviewed in Sauer and Kleine-Vehn, 2011). Just recently, ABP1 function was also linked to genomic responses, modulating TIR1/AFB-dependent processes (Tromas et al., 2013). Intriguingly, the genomic effect of ABP1 appears to be at least partially independent of the endogenous auxin indole 3-acetic acid (IAA) (Paque et al., 2014).
In this proposal my main research objective is to unravel the importance of the ER for genomic auxin responses. The PIN-LIKES (PILS) putative carriers for auxinic compounds also localize to the ER and determine the cellular sensitivity to auxin. PILS5 gain-of-function reduces canonical auxin signaling (Barbez et al., 2012) and phenocopies abp1 knock down lines (Barbez et al., 2012, Paque et al., 2014). Accordingly, a PILS-dependent substrate could be a negative regulator of ABP1 function in the ER. Based on our unpublished data, an IAA metabolite could play a role in ABP1-dependent processes in the ER, possibly providing feedback on the canonical nuclear IAA-signaling.
I hypothesize that the genomic auxin response may be an integration of auxin- and auxin-metabolite-dependent nuclear and ER localized signaling, respectively. This proposed project aims to characterize a novel auxin-signaling paradigm in plants. We will employ state of the art interdisciplinary (biochemical, biophysical, computational modeling, molecular, and genetic) methods to assess the projected research. The identification of the proposed auxin conjugate-dependent signal could have far reaching plant developmental and biotechnological importance.
Summary
The phytohormone auxin has profound importance for plant development. The extracellular AUXIN BINDING PROTEIN1 (ABP1) and the nuclear AUXIN F-BOX PROTEINs (TIR1/AFBs) auxin receptors perceive fast, non-genomic and slow, genomic auxin responses, respectively. Despite the fact that ABP1 mainly localizes to the endoplasmic reticulum (ER), until now it has been proposed to be active only in the extracellular matrix (reviewed in Sauer and Kleine-Vehn, 2011). Just recently, ABP1 function was also linked to genomic responses, modulating TIR1/AFB-dependent processes (Tromas et al., 2013). Intriguingly, the genomic effect of ABP1 appears to be at least partially independent of the endogenous auxin indole 3-acetic acid (IAA) (Paque et al., 2014).
In this proposal my main research objective is to unravel the importance of the ER for genomic auxin responses. The PIN-LIKES (PILS) putative carriers for auxinic compounds also localize to the ER and determine the cellular sensitivity to auxin. PILS5 gain-of-function reduces canonical auxin signaling (Barbez et al., 2012) and phenocopies abp1 knock down lines (Barbez et al., 2012, Paque et al., 2014). Accordingly, a PILS-dependent substrate could be a negative regulator of ABP1 function in the ER. Based on our unpublished data, an IAA metabolite could play a role in ABP1-dependent processes in the ER, possibly providing feedback on the canonical nuclear IAA-signaling.
I hypothesize that the genomic auxin response may be an integration of auxin- and auxin-metabolite-dependent nuclear and ER localized signaling, respectively. This proposed project aims to characterize a novel auxin-signaling paradigm in plants. We will employ state of the art interdisciplinary (biochemical, biophysical, computational modeling, molecular, and genetic) methods to assess the projected research. The identification of the proposed auxin conjugate-dependent signal could have far reaching plant developmental and biotechnological importance.
Max ERC Funding
1 441 125 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
Project acronym Big Splash
Project Big Splash: Efficient Simulation of Natural Phenomena at Extremely Large Scales
Researcher (PI) Christopher John Wojtan
Host Institution (HI) Institute of Science and Technology Austria
Call Details Starting Grant (StG), PE6, ERC-2014-STG
Summary Computational simulations of natural phenomena are essential in science, engineering, product design, architecture, and computer graphics applications. However, despite progress in numerical algorithms and computational power, it is still unfeasible to compute detailed simulations at large scales. To make matters worse, important phenomena like turbulent splashing liquids and fracturing solids rely on delicate coupling between small-scale details and large-scale behavior. Brute-force computation of such phenomena is intractable, and current adaptive techniques are too fragile, too costly, or too crude to capture subtle instabilities at small scales. Increases in computational power and parallel algorithms will improve the situation, but progress will only be incremental until we address the problem at its source.
I propose two main approaches to this problem of efficiently simulating large-scale liquid and solid dynamics. My first avenue of research combines numerics and shape: I will investigate a careful de-coupling of dynamics from geometry, allowing essential shape details to be preserved and retrieved without wasting computation. I will also develop methods for merging small-scale analytical solutions with large-scale numerical algorithms. (These ideas show particular promise for phenomena like splashing liquids and fracturing solids, whose small-scale behaviors are poorly captured by standard finite element methods.) My second main research direction is the manipulation of large-scale simulation data: Given the redundant and parallel nature of physics computation, we will drastically speed up computation with novel dimension reduction and data compression approaches. We can also minimize unnecessary computation by re-using existing simulation data. The novel approaches resulting from this work will undoubtedly synergize to enable the simulation and understanding of complicated natural and biological processes that are presently unfeasible to compute.
Summary
Computational simulations of natural phenomena are essential in science, engineering, product design, architecture, and computer graphics applications. However, despite progress in numerical algorithms and computational power, it is still unfeasible to compute detailed simulations at large scales. To make matters worse, important phenomena like turbulent splashing liquids and fracturing solids rely on delicate coupling between small-scale details and large-scale behavior. Brute-force computation of such phenomena is intractable, and current adaptive techniques are too fragile, too costly, or too crude to capture subtle instabilities at small scales. Increases in computational power and parallel algorithms will improve the situation, but progress will only be incremental until we address the problem at its source.
I propose two main approaches to this problem of efficiently simulating large-scale liquid and solid dynamics. My first avenue of research combines numerics and shape: I will investigate a careful de-coupling of dynamics from geometry, allowing essential shape details to be preserved and retrieved without wasting computation. I will also develop methods for merging small-scale analytical solutions with large-scale numerical algorithms. (These ideas show particular promise for phenomena like splashing liquids and fracturing solids, whose small-scale behaviors are poorly captured by standard finite element methods.) My second main research direction is the manipulation of large-scale simulation data: Given the redundant and parallel nature of physics computation, we will drastically speed up computation with novel dimension reduction and data compression approaches. We can also minimize unnecessary computation by re-using existing simulation data. The novel approaches resulting from this work will undoubtedly synergize to enable the simulation and understanding of complicated natural and biological processes that are presently unfeasible to compute.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-03-01, End date: 2020-02-29
Project acronym CAFES
Project Causal Analysis of Feedback Systems
Researcher (PI) Joris Marten Mooij
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), PE6, ERC-2014-STG
Summary Many questions in science, policy making and everyday life are of a causal nature: how would changing A influence B? Causal inference, a branch of statistics and machine learning, studies how cause-effect relationships can be discovered from data and how these can be used for making predictions in situations where a system has been perturbed by an external intervention. The ability to reliably make such causal predictions is of great value for practical applications in a variety of disciplines. Over the last two decades, remarkable progress has been made in the field. However, even though state-of-the-art causal inference algorithms work well on simulated data when all their assumptions are met, there is still a considerable gap between theory and practice. The goal of CAFES is to bridge that gap by developing theory and algorithms that will enable large-scale applications of causal inference in various challenging domains in science, industry and decision making.
The key challenge that will be addressed is how to deal with cyclic causal relationships ("feedback loops"). Feedback loops are very common in many domains (e.g., biology, economy and climatology), but have mostly been ignored so far in the field. Building on recently established connections between dynamical systems and causal models, CAFES will develop theory and algorithms for causal modeling, reasoning, discovery and prediction for cyclic causal systems. Extensions to stationary and non-stationary processes will be developed to advance the state-of-the-art in causal analysis of time-series data. In order to optimally use available resources, computationally efficient and statistically robust algorithms for causal inference from observational and interventional data in the context of confounders and feedback will be developed. The work will be done with a strong focus on applications in molecular biology, one of the most promising areas for automated causal inference from data.
Summary
Many questions in science, policy making and everyday life are of a causal nature: how would changing A influence B? Causal inference, a branch of statistics and machine learning, studies how cause-effect relationships can be discovered from data and how these can be used for making predictions in situations where a system has been perturbed by an external intervention. The ability to reliably make such causal predictions is of great value for practical applications in a variety of disciplines. Over the last two decades, remarkable progress has been made in the field. However, even though state-of-the-art causal inference algorithms work well on simulated data when all their assumptions are met, there is still a considerable gap between theory and practice. The goal of CAFES is to bridge that gap by developing theory and algorithms that will enable large-scale applications of causal inference in various challenging domains in science, industry and decision making.
The key challenge that will be addressed is how to deal with cyclic causal relationships ("feedback loops"). Feedback loops are very common in many domains (e.g., biology, economy and climatology), but have mostly been ignored so far in the field. Building on recently established connections between dynamical systems and causal models, CAFES will develop theory and algorithms for causal modeling, reasoning, discovery and prediction for cyclic causal systems. Extensions to stationary and non-stationary processes will be developed to advance the state-of-the-art in causal analysis of time-series data. In order to optimally use available resources, computationally efficient and statistically robust algorithms for causal inference from observational and interventional data in the context of confounders and feedback will be developed. The work will be done with a strong focus on applications in molecular biology, one of the most promising areas for automated causal inference from data.
Max ERC Funding
1 405 652 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym CELL HYBRIDGE
Project 3D Scaffolds as a Stem Cell Delivery System for Musculoskeletal Regenerative Medicine
Researcher (PI) Lorenzo Moroni
Host Institution (HI) UNIVERSITEIT MAASTRICHT
Call Details Starting Grant (StG), PE8, ERC-2014-STG
Summary Aging worldwide population demands new solutions to permanently restore damaged tissues, thus reducing healthcare costs. Regenerative medicine offers alternative therapies for tissue repair. Although first clinical trials revealed excellent initial response after implantation of these engineered tissues, long-term follow-ups demonstrated that degeneration and lack of integration with the surrounding tissues occur. Causes are related to insufficient cell-material interactions and loss of cell potency when cultured in two-dimensional substrates, among others.
Stem cells are a promising alternative due to their differentiation potential into multiple lineages. Yet, better control over cell-material interactions is necessary to maintain tissue engineered constructs in time. It is crucial to control stem cell quiescence, proliferation and differentiation in three-dimensional scaffolds while maintaining cells viable in situ. Stem cell activity is controlled by a complex cascade of signals called “niche”, where the extra-cellular matrix (ECM) surrounding the cells play a major role. Designing scaffolds inspired by this cellular niche and its ECM may lead to engineered tissues with instructive properties characterized by enhanced homeostasis, stability and integration with the surrounding milieu.
This research proposal aims at engineering constructs where scaffolds work as stem cell delivery systems actively controlling cell quiescence, proliferation, and differentiation. This challenge will be approached through a biomimetic design inspired by the mesenchymal stem cell niche. Three different scaffolds will be combined to achieve this purpose: (i) a scaffold designed to maintain cell quiescence; (ii) a scaffold designed to promote cell proliferation; and (iii) a scaffold designed to control cell differentiation. To prove the design criteria the evaluation of stem cell quiescence, proliferation, and differentiation will be assessed for musculoskeletal regenerative therapies.
Summary
Aging worldwide population demands new solutions to permanently restore damaged tissues, thus reducing healthcare costs. Regenerative medicine offers alternative therapies for tissue repair. Although first clinical trials revealed excellent initial response after implantation of these engineered tissues, long-term follow-ups demonstrated that degeneration and lack of integration with the surrounding tissues occur. Causes are related to insufficient cell-material interactions and loss of cell potency when cultured in two-dimensional substrates, among others.
Stem cells are a promising alternative due to their differentiation potential into multiple lineages. Yet, better control over cell-material interactions is necessary to maintain tissue engineered constructs in time. It is crucial to control stem cell quiescence, proliferation and differentiation in three-dimensional scaffolds while maintaining cells viable in situ. Stem cell activity is controlled by a complex cascade of signals called “niche”, where the extra-cellular matrix (ECM) surrounding the cells play a major role. Designing scaffolds inspired by this cellular niche and its ECM may lead to engineered tissues with instructive properties characterized by enhanced homeostasis, stability and integration with the surrounding milieu.
This research proposal aims at engineering constructs where scaffolds work as stem cell delivery systems actively controlling cell quiescence, proliferation, and differentiation. This challenge will be approached through a biomimetic design inspired by the mesenchymal stem cell niche. Three different scaffolds will be combined to achieve this purpose: (i) a scaffold designed to maintain cell quiescence; (ii) a scaffold designed to promote cell proliferation; and (iii) a scaffold designed to control cell differentiation. To prove the design criteria the evaluation of stem cell quiescence, proliferation, and differentiation will be assessed for musculoskeletal regenerative therapies.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym Con Espressione
Project Getting at the Heart of Things: Towards Expressivity-aware Computer Systems in Music
Researcher (PI) Gerhard Widmer
Host Institution (HI) UNIVERSITAT LINZ
Call Details Advanced Grant (AdG), PE6, ERC-2014-ADG
Summary What makes music so important, what can make a performance so special and stirring? It is the things the music expresses, the emotions it induces, the associations it evokes, the drama and characters it portrays. The sources of this expressivity are manifold: the music itself, its structure, orchestration, personal associations, social settings, but also – and very importantly – the act of performance, the interpretation and expressive intentions made explicit by the musicians through nuances in timing, dynamics etc.
Thanks to research in fields like Music Information Research (MIR), computers can do many useful things with music, from beat and rhythm detection to song identification and tracking. However, they are still far from grasping the essence of music: they cannot tell whether a performance expresses playfulness or ennui, solemnity or gaiety, determination or uncertainty; they cannot produce music with a desired expressive quality; they cannot interact with human musicians in a truly musical way, recognising and responding to the expressive intentions implied in their playing.
The project is about developing machines that are aware of certain dimensions of expressivity, specifically in the domain of (classical) music, where expressivity is both essential and – at least as far as it relates to the act of performance – can be traced back to well-defined and measurable parametric dimensions (such as timing, dynamics, articulation). We will develop systems that can recognise, characterise, search music by expressive aspects, generate, modify, and react to expressive qualities in music. To do so, we will (1) bring together the fields of AI, Machine Learning, MIR and Music Performance Research; (2) integrate theories from Musicology to build more well-founded models of music understanding; (3) support model learning and validation with massive musical corpora of a size and quality unprecedented in computational music research.
Summary
What makes music so important, what can make a performance so special and stirring? It is the things the music expresses, the emotions it induces, the associations it evokes, the drama and characters it portrays. The sources of this expressivity are manifold: the music itself, its structure, orchestration, personal associations, social settings, but also – and very importantly – the act of performance, the interpretation and expressive intentions made explicit by the musicians through nuances in timing, dynamics etc.
Thanks to research in fields like Music Information Research (MIR), computers can do many useful things with music, from beat and rhythm detection to song identification and tracking. However, they are still far from grasping the essence of music: they cannot tell whether a performance expresses playfulness or ennui, solemnity or gaiety, determination or uncertainty; they cannot produce music with a desired expressive quality; they cannot interact with human musicians in a truly musical way, recognising and responding to the expressive intentions implied in their playing.
The project is about developing machines that are aware of certain dimensions of expressivity, specifically in the domain of (classical) music, where expressivity is both essential and – at least as far as it relates to the act of performance – can be traced back to well-defined and measurable parametric dimensions (such as timing, dynamics, articulation). We will develop systems that can recognise, characterise, search music by expressive aspects, generate, modify, and react to expressive qualities in music. To do so, we will (1) bring together the fields of AI, Machine Learning, MIR and Music Performance Research; (2) integrate theories from Musicology to build more well-founded models of music understanding; (3) support model learning and validation with massive musical corpora of a size and quality unprecedented in computational music research.
Max ERC Funding
2 318 750 €
Duration
Start date: 2016-01-01, End date: 2021-12-31
Project acronym CoordinatedDopamine
Project Coordination of regional dopamine release in the striatum during habit formation and compulsive behaviour
Researcher (PI) Ingo Willuhn
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary The basal ganglia consist of a set of neuroanatomical structures that participate in the representation and execution of action sequences. Dopamine neurotransmission in the striatum, the main input nucleus of the basal ganglia, is a fundamental mechanism involved in learning and regulation of such actions. The striatum has multiple functional units, where the limbic striatum is thought to mediate motivational aspects of actions (e.g., goal-directedness) and the sensorimotor striatum their automation (e.g., habit formation). A long-standing question in the field is how limbic and sensorimotor domains communicate with each other, and specifically if they do so during the automation of action sequences. It has been suggested that such coordination is implemented by reciprocal loop connections between striatal projection neurons and the dopaminergic midbrain. Although very influential in theory the effectiveness of this limbic-sensorimotor “bridging” principle has yet to be verified. I hypothesize that during the automation of behaviour regional dopamine signalling is governed by a striatal hierarchy and that dysregulation of this coordination leads to compulsive execution of automatic actions characteristic of several psychiatric disorders. To test this hypothesis, we will conduct electrochemical measurements with real-time resolution simultaneously in limbic and sensorimotor striatum to assess the regional coordination of dopamine release in behaving animals. We developed novel chronically implantable electrodes to enable monitoring of dopamine dynamics throughout the development of habitual behaviour and its compulsive execution in transgenic rats - a species suitable for our complex behavioural assays. Novel rabies virus-mediated gene delivery for in vivo optogenetics in these rats will give us the unique opportunity to test whether specific loop pathways govern striatal dopamine transmission and are causally involved in habit formation and compulsive behaviour.
Summary
The basal ganglia consist of a set of neuroanatomical structures that participate in the representation and execution of action sequences. Dopamine neurotransmission in the striatum, the main input nucleus of the basal ganglia, is a fundamental mechanism involved in learning and regulation of such actions. The striatum has multiple functional units, where the limbic striatum is thought to mediate motivational aspects of actions (e.g., goal-directedness) and the sensorimotor striatum their automation (e.g., habit formation). A long-standing question in the field is how limbic and sensorimotor domains communicate with each other, and specifically if they do so during the automation of action sequences. It has been suggested that such coordination is implemented by reciprocal loop connections between striatal projection neurons and the dopaminergic midbrain. Although very influential in theory the effectiveness of this limbic-sensorimotor “bridging” principle has yet to be verified. I hypothesize that during the automation of behaviour regional dopamine signalling is governed by a striatal hierarchy and that dysregulation of this coordination leads to compulsive execution of automatic actions characteristic of several psychiatric disorders. To test this hypothesis, we will conduct electrochemical measurements with real-time resolution simultaneously in limbic and sensorimotor striatum to assess the regional coordination of dopamine release in behaving animals. We developed novel chronically implantable electrodes to enable monitoring of dopamine dynamics throughout the development of habitual behaviour and its compulsive execution in transgenic rats - a species suitable for our complex behavioural assays. Novel rabies virus-mediated gene delivery for in vivo optogenetics in these rats will give us the unique opportunity to test whether specific loop pathways govern striatal dopamine transmission and are causally involved in habit formation and compulsive behaviour.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym CUTTINGBUBBLES
Project Bubbles on the Cutting Edge
Researcher (PI) Niels Gerbrand Deen
Host Institution (HI) TECHNISCHE UNIVERSITEIT EINDHOVEN
Call Details Starting Grant (StG), PE8, ERC-2010-StG_20091028
Summary Many processes in the chemical, petrochemical and/or biological industries involve three phase gas-liquidsolid flows, where the solid material acts as a catalyst carrier, the gas phase supplies the reactants for the (bio-)chemical transformations and the liquid phase carries the product. In these processes the performance and operation of the reactor is mostly constrained by the interfacial mass transfer rate and the achievable insitu heat removal rate. A micro-structured bubble column reactor that significantly improves these crucial properties is proposed in this project. This novel type of reactor takes advantage of micro-structuring of the catalyst carrier in the form of a wire-mesh (see Figure 1).
The aim of the wire-mesh is i) to cut bubbles into smaller pieces leading to a larger interfacial area, ii) to enhance the bubble interface dynamics and mass transfer due to the interaction between the bubbles and the wires, and iii) to save costs in practical operation due to the smaller required reactor volume and the fact that
there is no need for an external filtration unit.
Cutting edge three-phase direct numerical simulation (DNS) tools and novel non-invasive optical (highspeed camera) techniques are used to study the micro-scale interaction between bubbles and a wire-mesh to gain understanding of the splitting and merging of bubbles and associated mass transfer characteristics. Furthermore, a proof-of-principle of the micro-structured reactor will be given through lab-scale experiments and macroscopic Euler-Lagrange numerical simulations, employing bubble-wire interaction closures based on the DNS simulations.
In addition to the novel reactor type, the project will generate a broad set of fundamental numerical and experimental research tools that can be used for the improvement of various gas-liquid-solid processes.
Several large companies (AkzoNobel, DSM, Sabic and Shell) have indicated their interest in the proposed
project and would like to be involved in a users committee.
Summary
Many processes in the chemical, petrochemical and/or biological industries involve three phase gas-liquidsolid flows, where the solid material acts as a catalyst carrier, the gas phase supplies the reactants for the (bio-)chemical transformations and the liquid phase carries the product. In these processes the performance and operation of the reactor is mostly constrained by the interfacial mass transfer rate and the achievable insitu heat removal rate. A micro-structured bubble column reactor that significantly improves these crucial properties is proposed in this project. This novel type of reactor takes advantage of micro-structuring of the catalyst carrier in the form of a wire-mesh (see Figure 1).
The aim of the wire-mesh is i) to cut bubbles into smaller pieces leading to a larger interfacial area, ii) to enhance the bubble interface dynamics and mass transfer due to the interaction between the bubbles and the wires, and iii) to save costs in practical operation due to the smaller required reactor volume and the fact that
there is no need for an external filtration unit.
Cutting edge three-phase direct numerical simulation (DNS) tools and novel non-invasive optical (highspeed camera) techniques are used to study the micro-scale interaction between bubbles and a wire-mesh to gain understanding of the splitting and merging of bubbles and associated mass transfer characteristics. Furthermore, a proof-of-principle of the micro-structured reactor will be given through lab-scale experiments and macroscopic Euler-Lagrange numerical simulations, employing bubble-wire interaction closures based on the DNS simulations.
In addition to the novel reactor type, the project will generate a broad set of fundamental numerical and experimental research tools that can be used for the improvement of various gas-liquid-solid processes.
Several large companies (AkzoNobel, DSM, Sabic and Shell) have indicated their interest in the proposed
project and would like to be involved in a users committee.
Max ERC Funding
1 500 000 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym DROSOPIRNAS
Project The piRNA pathway in the Drosophila germline a small RNA based genome immune system
Researcher (PI) Julius Brennecke
Host Institution (HI) INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Call Details Starting Grant (StG), LS3, ERC-2010-StG_20091118
Summary The discovery of RNA interference (RNAi) has revolutionized biology. As a technology it opened up new experimental and therapeutic avenues. As a biological phenomenon it changed our view on a diverse array of cellular processes. Among those are the control of gene expression, the suppression of viral replication, the formation of heterochromatin and the protection of the genome against selfish genetic elements such as transposons.
I propose to study the molecular mechanism and the biological impact of a recently discovered RNAi pathway, the Piwi interacting RNA pathway (piRNA pathway).
The piRNA pathway is an evolutionarily conserved small RNA pathway acting in the animal germline. It is the key genome surveillance system that suppresses the activity of transposons. Recent work has provided a conceptual framework for this pathway: According to this, the genome stores transposon sequences in heterochromatic loci called piRNA clusters. These provide the RNA substrates for the biogenesis of 23-29 nt long piRNAs. An amplification cycle steers piRNA production predominantly to those cluster regions that are complementary to transposons being active at a given time. Finally, piRNAs guide a protein complex centered on Piwi-proteins to complementary transposon RNAs in the cell, leading to their silencing.
In contrast to other RNAi pathways, the mechanistic framework of the piRNA pathway is largely unknown. Moreover, the spectrum of biological processes impacted by it is only poorly understood. piRNAs are for example not only derived from transposon sequences but also from various other genomic repeats that are enriched at telomeres and in heterochromatin.
We will systematically dissect the piRNA pathway regarding its molecular architecture as well as its biological functions in Drosophila. Our studies will be a combination of fly genetics, proteomics and genomics approaches. Throughout we aim at linking our results back to the underlying biology of germline development.
Summary
The discovery of RNA interference (RNAi) has revolutionized biology. As a technology it opened up new experimental and therapeutic avenues. As a biological phenomenon it changed our view on a diverse array of cellular processes. Among those are the control of gene expression, the suppression of viral replication, the formation of heterochromatin and the protection of the genome against selfish genetic elements such as transposons.
I propose to study the molecular mechanism and the biological impact of a recently discovered RNAi pathway, the Piwi interacting RNA pathway (piRNA pathway).
The piRNA pathway is an evolutionarily conserved small RNA pathway acting in the animal germline. It is the key genome surveillance system that suppresses the activity of transposons. Recent work has provided a conceptual framework for this pathway: According to this, the genome stores transposon sequences in heterochromatic loci called piRNA clusters. These provide the RNA substrates for the biogenesis of 23-29 nt long piRNAs. An amplification cycle steers piRNA production predominantly to those cluster regions that are complementary to transposons being active at a given time. Finally, piRNAs guide a protein complex centered on Piwi-proteins to complementary transposon RNAs in the cell, leading to their silencing.
In contrast to other RNAi pathways, the mechanistic framework of the piRNA pathway is largely unknown. Moreover, the spectrum of biological processes impacted by it is only poorly understood. piRNAs are for example not only derived from transposon sequences but also from various other genomic repeats that are enriched at telomeres and in heterochromatin.
We will systematically dissect the piRNA pathway regarding its molecular architecture as well as its biological functions in Drosophila. Our studies will be a combination of fly genetics, proteomics and genomics approaches. Throughout we aim at linking our results back to the underlying biology of germline development.
Max ERC Funding
1 500 000 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym ENCODING IN AXONS
Project Identifying mechanisms of information encoding in myelinated single axons
Researcher (PI) Maarten Kole
Host Institution (HI) KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary A major challenge in neuroscience is to understand how information is stored and coded within single nerve cells (neurons) and across neuron populations in the brain. Nerve cell fibres (axons) are thought to provide the wiring to connect neurons and conduct the electrical nerve impulse (action potential; AP). Recent discoveries, however, show that the initial part of axons actively participates in modulating APs and providing a means to enhance the computational repertoire of neurons in the central nervous system. To decrease the temporal delay in information transmission over long distances most axons are myelinated. Here, we will test the hypothesis that the degree of myelination of single axons directly and indirectly influences the mechanisms of AP generation and neural coding. We will use a novel approach of patch-clamp recording combined with immunohistochemical and ultrastructural identification to develop a detailed model of single myelinated neocortical axons. We also will investigate the neuron-glia interactions responsible for the myelination process and measure whether their development follows an activity-dependent process. Finally, we will elucidate the physiological and molecular similarities and discrepancies between myelinated and experimentally demyelinated single neocortical axons. These studies will provide a novel methodological framework to study central nervous system axons and yield basic insights into myelin physiology and pathophysiology.
Summary
A major challenge in neuroscience is to understand how information is stored and coded within single nerve cells (neurons) and across neuron populations in the brain. Nerve cell fibres (axons) are thought to provide the wiring to connect neurons and conduct the electrical nerve impulse (action potential; AP). Recent discoveries, however, show that the initial part of axons actively participates in modulating APs and providing a means to enhance the computational repertoire of neurons in the central nervous system. To decrease the temporal delay in information transmission over long distances most axons are myelinated. Here, we will test the hypothesis that the degree of myelination of single axons directly and indirectly influences the mechanisms of AP generation and neural coding. We will use a novel approach of patch-clamp recording combined with immunohistochemical and ultrastructural identification to develop a detailed model of single myelinated neocortical axons. We also will investigate the neuron-glia interactions responsible for the myelination process and measure whether their development follows an activity-dependent process. Finally, we will elucidate the physiological and molecular similarities and discrepancies between myelinated and experimentally demyelinated single neocortical axons. These studies will provide a novel methodological framework to study central nervous system axons and yield basic insights into myelin physiology and pathophysiology.
Max ERC Funding
1 994 640 €
Duration
Start date: 2011-04-01, End date: 2016-03-31