Project acronym DCVFUSION
Project Telling the full story: how neurons send other signals than by classical synaptic transmission
Researcher (PI) Matthijs Verhage
Host Institution (HI) STICHTING VUMC
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary The regulated secretion of chemical signals in the brain occurs principally from two organelles, synaptic vesicles and dense core vesicles (DCVs). Synaptic vesicle secretion accounts for the well characterized local, fast signalling in synapses. DCVs contain a diverse collection of cargo, including many neuropeptides that trigger a multitude of modulatory effects with quite robust impact, for instance on memory, mood, pain, appetite or social behavior. Disregulation of neuropeptide secretion is firmly associated with many diseases such as cognitive and mood disorders, obesity and diabetes. In addition, many other signals depend on DCVs, for instance trophic factors and proteolytic enzymes, but also signals that typically do not diffuse like guidance cues and pre-assembled active zones. Hence, it is beyond doubt that DCV signalling is a central factor in brain communication. However, many fundamental questions remain open on DCV trafficking and secretion. Therefore, the aim of this proposal is to characterize the molecular principles that account for DCV delivery at release sites and their secretion. I will address 4 fundamental questions: What are the molecular factors that drive DCV fusion in mammalian CNS neurons? How does Ca2+ trigger DCV fusion? What are the requirements of DCV release sites and where do they occur? Can DCV fusion be targeted to synthetic release sites in vivo? I will exploit >30 mutant mouse lines and new cell biological and photonic approaches that allow for the first time a quantitative assessment of DCV-trafficking and fusion of many cargo types, in living neurons with a single vesicle resolution. Preliminary data suggest that DCV secretion is quite different from synaptic vesicle and chromaffin granule secretion. Together, these studies will produce the first systematic evaluation of the molecular identity of the core machinery that drives DCV fusion in neurons, the Ca2+-affinity of DCV fusion and the characteristics of DCV release sites.
Summary
The regulated secretion of chemical signals in the brain occurs principally from two organelles, synaptic vesicles and dense core vesicles (DCVs). Synaptic vesicle secretion accounts for the well characterized local, fast signalling in synapses. DCVs contain a diverse collection of cargo, including many neuropeptides that trigger a multitude of modulatory effects with quite robust impact, for instance on memory, mood, pain, appetite or social behavior. Disregulation of neuropeptide secretion is firmly associated with many diseases such as cognitive and mood disorders, obesity and diabetes. In addition, many other signals depend on DCVs, for instance trophic factors and proteolytic enzymes, but also signals that typically do not diffuse like guidance cues and pre-assembled active zones. Hence, it is beyond doubt that DCV signalling is a central factor in brain communication. However, many fundamental questions remain open on DCV trafficking and secretion. Therefore, the aim of this proposal is to characterize the molecular principles that account for DCV delivery at release sites and their secretion. I will address 4 fundamental questions: What are the molecular factors that drive DCV fusion in mammalian CNS neurons? How does Ca2+ trigger DCV fusion? What are the requirements of DCV release sites and where do they occur? Can DCV fusion be targeted to synthetic release sites in vivo? I will exploit >30 mutant mouse lines and new cell biological and photonic approaches that allow for the first time a quantitative assessment of DCV-trafficking and fusion of many cargo types, in living neurons with a single vesicle resolution. Preliminary data suggest that DCV secretion is quite different from synaptic vesicle and chromaffin granule secretion. Together, these studies will produce the first systematic evaluation of the molecular identity of the core machinery that drives DCV fusion in neurons, the Ca2+-affinity of DCV fusion and the characteristics of DCV release sites.
Max ERC Funding
2 439 315 €
Duration
Start date: 2013-05-01, End date: 2019-04-30
Project acronym iGEO
Project Integrated geodynamics: Reconciling geophysics and geochemistry
Researcher (PI) Jeannot Alphonse Trampert
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Advanced Grant (AdG), PE10, ERC-2012-ADG_20120216
Summary How are deep mantle processes related to the mapped geological record? How can we reconcile geochemical observations with geophysical inferences? These are first order unanswered questions despite our steady progress in imaging the Earth's internal structure and understanding the high temperature and pressure properties of minerals. To make a breakthrough, we have to understand solid-state convection in the Earth's mantle in much greater detail. Much is known about the physical processes, such as melting and the delicate interaction between thermal and chemical buoyancy, but the parameters that enter their mathematical description are not very well known. Once these parameters are determined, the thermo-chemical evolution of our planet can self-consistently be modelled. The state-of-the-art is to roughly estimate these parameters and qualitatively compare the modelling to some relevant geophysical, geochemical or geological observations. This comparison is not comprehensive and never explains all observables. We propose a radically new approach, where all observables are used together to infer these parameters directly, using a fully non-linear Bayesian inference technique based on neural networks. This will determine for the first time the initial conditions at the Earth's formation, the Earth-like flow parameters essential to model the thermo-chemical evolution of our planet and produce models that are simultaneously consistent with the main different geophysical and geochemical datasets.
Summary
How are deep mantle processes related to the mapped geological record? How can we reconcile geochemical observations with geophysical inferences? These are first order unanswered questions despite our steady progress in imaging the Earth's internal structure and understanding the high temperature and pressure properties of minerals. To make a breakthrough, we have to understand solid-state convection in the Earth's mantle in much greater detail. Much is known about the physical processes, such as melting and the delicate interaction between thermal and chemical buoyancy, but the parameters that enter their mathematical description are not very well known. Once these parameters are determined, the thermo-chemical evolution of our planet can self-consistently be modelled. The state-of-the-art is to roughly estimate these parameters and qualitatively compare the modelling to some relevant geophysical, geochemical or geological observations. This comparison is not comprehensive and never explains all observables. We propose a radically new approach, where all observables are used together to infer these parameters directly, using a fully non-linear Bayesian inference technique based on neural networks. This will determine for the first time the initial conditions at the Earth's formation, the Earth-like flow parameters essential to model the thermo-chemical evolution of our planet and produce models that are simultaneously consistent with the main different geophysical and geochemical datasets.
Max ERC Funding
3 480 600 €
Duration
Start date: 2013-05-01, End date: 2018-04-30
Project acronym NPW
Project Novel Process Windows - Boosted Micro Process Technology
Researcher (PI) Volker Hessel
Host Institution (HI) TECHNISCHE UNIVERSITEIT EINDHOVEN
Call Details Advanced Grant (AdG), PE8, ERC-2010-AdG_20100224
Summary Novel Process Windows (NPW) is an entirely new way of process design to boost micro process technology for the production of high-added value fine chemicals. Such process intensification demands for microstructured reactors with their excellent capabilities on mass and heat transfer and short residence times with prime constructional and functional features. This proposal is truly comprehensive and holistic as it includes four projects with different NPW facets; starting from a molecular-mechanistic- (New Chemical Trans¬formations) and kinetic-scale (High-Temperature / Pressure Processing) via the scale of reaction environment (Solvent-free Operation and Tuneable / Reactive Solvents) up to a process scale (Process Simplification and Integration). These four individual measures are bundled and directed by a generic project for cross-cutting insight, evaluation through cost and life-cycle analysis, and transfer to a large number of reactions.
High-p,T processing will enable for the Claisen rearrangement to shrink reaction times by orders of magnitude and to increase space-time yields consequently. Substantial selectivity increases are targeted for this reaction and the hydroformylation. The latter reaction will make use of tuneable solvents and near-critical water processing. As new chemical transformations with process simplification and integration, the direct oxidation of cyclohexene to adipic acid as one-step synthesis and the copper-catalysed triazole Click Chemistry as one-flow multi-step synthesis will be tested.
These new and challenging processing technologies provide highly promising perspectives for future ‘green’ chemical factories to boost sustainability, covering the whole manufacturing chain in one system and providing a multi-purpose infrastructure.
Summary
Novel Process Windows (NPW) is an entirely new way of process design to boost micro process technology for the production of high-added value fine chemicals. Such process intensification demands for microstructured reactors with their excellent capabilities on mass and heat transfer and short residence times with prime constructional and functional features. This proposal is truly comprehensive and holistic as it includes four projects with different NPW facets; starting from a molecular-mechanistic- (New Chemical Trans¬formations) and kinetic-scale (High-Temperature / Pressure Processing) via the scale of reaction environment (Solvent-free Operation and Tuneable / Reactive Solvents) up to a process scale (Process Simplification and Integration). These four individual measures are bundled and directed by a generic project for cross-cutting insight, evaluation through cost and life-cycle analysis, and transfer to a large number of reactions.
High-p,T processing will enable for the Claisen rearrangement to shrink reaction times by orders of magnitude and to increase space-time yields consequently. Substantial selectivity increases are targeted for this reaction and the hydroformylation. The latter reaction will make use of tuneable solvents and near-critical water processing. As new chemical transformations with process simplification and integration, the direct oxidation of cyclohexene to adipic acid as one-step synthesis and the copper-catalysed triazole Click Chemistry as one-flow multi-step synthesis will be tested.
These new and challenging processing technologies provide highly promising perspectives for future ‘green’ chemical factories to boost sustainability, covering the whole manufacturing chain in one system and providing a multi-purpose infrastructure.
Max ERC Funding
2 496 100 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym TOPCHEM
Project Towards Perfect Chemical Reactors:
Engineering the Enhanced Control of Reaction Pathways at Molecular Level via Fundamental Concepts of Process Intensification
Researcher (PI) Andrzej Ignacy Stankiewicz
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Advanced Grant (AdG), PE8, ERC-2010-AdG_20100224
Summary Molecular-level control of chemical reactions presents undoubtedly the most important scientific challenge on the way to fully sustainable processes. Factors responsible for the effectiveness of a reaction include number/frequency of molecular collisions, orientation of molecules at the moment of collisions and their energy. Current reactors offer a very limited control of the above factors. Reactions usually take place in random geometries and the energy is brought to molecules by conductive heating which is non-selective and thermodynamically inefficient.
A groundbreaking solution here can only be achieved by creating a “perfect” reaction environment, in which the geometry of molecular collisions is fully controlled while energy is transferred selectively from the source to the required molecules in the required form, in the required amount, at the required moment, and at the required position. The current proposal aims at the first of its kind development of structured reactors using electric and electromagnetic fields for alignment, orientation and selective activation of targeted molecules. To engineer such “perfect” reaction environment the fundamental concepts of Process Intensification are applied. We build here on the Nobel Prize-awarded fundamental works in the area of the reaction dynamics and molecular reaction control that were not considered in chemical engineering thus far. Chemistries studied are mono- and bi-molecular reactions using CO2, CH4 and H2O, which are of paramount importance for clean fuel production and carbon dioxide management.
The proposal bridges chemical physics and chemical engineering incorporating the knowledge domains of chemistry, catalysis, materials science, electronics, computer modelling and micromechanical engineering.
Summary
Molecular-level control of chemical reactions presents undoubtedly the most important scientific challenge on the way to fully sustainable processes. Factors responsible for the effectiveness of a reaction include number/frequency of molecular collisions, orientation of molecules at the moment of collisions and their energy. Current reactors offer a very limited control of the above factors. Reactions usually take place in random geometries and the energy is brought to molecules by conductive heating which is non-selective and thermodynamically inefficient.
A groundbreaking solution here can only be achieved by creating a “perfect” reaction environment, in which the geometry of molecular collisions is fully controlled while energy is transferred selectively from the source to the required molecules in the required form, in the required amount, at the required moment, and at the required position. The current proposal aims at the first of its kind development of structured reactors using electric and electromagnetic fields for alignment, orientation and selective activation of targeted molecules. To engineer such “perfect” reaction environment the fundamental concepts of Process Intensification are applied. We build here on the Nobel Prize-awarded fundamental works in the area of the reaction dynamics and molecular reaction control that were not considered in chemical engineering thus far. Chemistries studied are mono- and bi-molecular reactions using CO2, CH4 and H2O, which are of paramount importance for clean fuel production and carbon dioxide management.
The proposal bridges chemical physics and chemical engineering incorporating the knowledge domains of chemistry, catalysis, materials science, electronics, computer modelling and micromechanical engineering.
Max ERC Funding
2 298 789 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
