Project acronym C-MORPH
Project Noninvasive cell specific morphometry in neuroinflammation and degeneration
Researcher (PI) Henrik LUNDELL
Host Institution (HI) REGION HOVEDSTADEN
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Brain structure determines function. Disentangling regional microstructural properties and understanding how these properties constitute brain function is a central goal of neuroimaging of the human brain and a key prerequisite for a mechanistic understanding of brain diseases and their treatment. Using magnetic resonance (MR) imaging, previous research has established links between regional brain microstructure and inter-individual variation in brain function, but this line of research has been limited by the non-specificity of MR-derived markers. This hampers the application of MR imaging as a tool to identify specific fingerprints of the underlying disease process.
Exploiting state-of-the-art ultra-high field MR imaging techniques, I have recently developed two independent spectroscopic MR methods that have the potential to tackle this challenge: Powder averaged diffusion weighted spectroscopy (PADWS) can provide an unbiased marker for cell specific structural degeneration, and Spectrally tuned gradient trajectories (STGT) can isolate cell shape and size. In this project, I will harness these innovations for MR-based precision medicine. I will advance PADWS and STGT methodology on state-of-the-art MR hardware and harvest the synergy of these methods to realize Cell-specific in-vivo MORPHOMETRY (C-MORPH) of the intact human brain. I will establish novel MR read-outs and analyses to derive cell-type specific tissue properties in the healthy and diseased brain and validate them with the help of a strong translational experimental framework, including histological validation. Once validated, the experimental methods and analyses will be simplified and adapted to provide clinically applicable tools. This will push the frontiers of MR-based personalized medicine, guiding therapeutic decisions by providing sensitive probes of cell-specific microstructural changes caused by inflammation, neurodegeneration or treatment response.
Summary
Brain structure determines function. Disentangling regional microstructural properties and understanding how these properties constitute brain function is a central goal of neuroimaging of the human brain and a key prerequisite for a mechanistic understanding of brain diseases and their treatment. Using magnetic resonance (MR) imaging, previous research has established links between regional brain microstructure and inter-individual variation in brain function, but this line of research has been limited by the non-specificity of MR-derived markers. This hampers the application of MR imaging as a tool to identify specific fingerprints of the underlying disease process.
Exploiting state-of-the-art ultra-high field MR imaging techniques, I have recently developed two independent spectroscopic MR methods that have the potential to tackle this challenge: Powder averaged diffusion weighted spectroscopy (PADWS) can provide an unbiased marker for cell specific structural degeneration, and Spectrally tuned gradient trajectories (STGT) can isolate cell shape and size. In this project, I will harness these innovations for MR-based precision medicine. I will advance PADWS and STGT methodology on state-of-the-art MR hardware and harvest the synergy of these methods to realize Cell-specific in-vivo MORPHOMETRY (C-MORPH) of the intact human brain. I will establish novel MR read-outs and analyses to derive cell-type specific tissue properties in the healthy and diseased brain and validate them with the help of a strong translational experimental framework, including histological validation. Once validated, the experimental methods and analyses will be simplified and adapted to provide clinically applicable tools. This will push the frontiers of MR-based personalized medicine, guiding therapeutic decisions by providing sensitive probes of cell-specific microstructural changes caused by inflammation, neurodegeneration or treatment response.
Max ERC Funding
1 498 811 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym CanCoop
Project Understanding the Proximate Mechanisms of
Canine Cooperation
Researcher (PI) Friederike Range
Host Institution (HI) VETERINAERMEDIZINISCHE UNIVERSITAET WIEN
Call Details Starting Grant (StG), SH4, ERC-2012-StG_20111124
Summary Although it is clear that human collaborative skills are exceptional, elucidating similarities and differences of proximate processes underlying cooperative interactions between non-primate and primate taxa may have important implications for our understanding of cooperation in humans and non human-animals via a profound knowledge of 1) socio-cognitive skills as adaptations to specific environments and/or 2) the evolutionary background and origin of our own skills. The closely related wolves and dogs constitute the ideal non-primate model to implement this approach, since cooperation is at the core of their social organization and they are adapted to very different environments.
I propose a series of experiments with wolves (N = 20) and identically raised and kept dogs (N= 20) that will focus on cognitive processes closely linked to the emotional system such as empathy, inequity aversion and delayed gratification that are thought to be involved in triggering and maintaining primate cooperation. In Part 1 of the project, we will investigate whether and to what extent these processes are present in canines, while in Part 2 we will elucidate how they influence partner choice in cooperative interactions. Using social network theory, we will integrate knowledge about animals’ emotional tendencies and cognitive abilities to model canine cooperation. This is an important step towards unifying theoretical and empirical approaches in animal behaviour.
CanCoop incorporates innovative methods and a novel approach that has the potential to elucidate the interactions between proximate and ultimate processes in regard to cooperation. The nature of CanCoop guarantees public and media attention needed for proper societal dissemination of the results, which will be relevant for animal behaviour, social sciences, wildlife and zoo management.
Summary
Although it is clear that human collaborative skills are exceptional, elucidating similarities and differences of proximate processes underlying cooperative interactions between non-primate and primate taxa may have important implications for our understanding of cooperation in humans and non human-animals via a profound knowledge of 1) socio-cognitive skills as adaptations to specific environments and/or 2) the evolutionary background and origin of our own skills. The closely related wolves and dogs constitute the ideal non-primate model to implement this approach, since cooperation is at the core of their social organization and they are adapted to very different environments.
I propose a series of experiments with wolves (N = 20) and identically raised and kept dogs (N= 20) that will focus on cognitive processes closely linked to the emotional system such as empathy, inequity aversion and delayed gratification that are thought to be involved in triggering and maintaining primate cooperation. In Part 1 of the project, we will investigate whether and to what extent these processes are present in canines, while in Part 2 we will elucidate how they influence partner choice in cooperative interactions. Using social network theory, we will integrate knowledge about animals’ emotional tendencies and cognitive abilities to model canine cooperation. This is an important step towards unifying theoretical and empirical approaches in animal behaviour.
CanCoop incorporates innovative methods and a novel approach that has the potential to elucidate the interactions between proximate and ultimate processes in regard to cooperation. The nature of CanCoop guarantees public and media attention needed for proper societal dissemination of the results, which will be relevant for animal behaviour, social sciences, wildlife and zoo management.
Max ERC Funding
1 295 716 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym CARAT
Project Commercial Applications for RF Arrays of Traps
Researcher (PI) Otto Rainer BLATT
Host Institution (HI) UNIVERSITAET INNSBRUCK
Call Details Proof of Concept (PoC), PC1, ERC-2012-PoC
Summary "The ERC-funded project CRYTERION has a goal of scaling up simulations and computations with trapped ions. One possible route for this is the use of a 2D array of ion traps. During the development of these 2D arrays, a novel method of being able to address the interactions was conceived, allowing addressing of individual ions and nearest-neighbour interactions between
ions in the array. A patent has been granted on the design and the ERC-POC grant is being applied for so as to develop an implementation with the goal of licensing the patent.
Technical tests of this idea with calcium ions have been performed on a mesoscale array of ion traps. Basic ideas for creating micro-scale traps are under investigation. We propose that this micro-array concept be developed, to the point where traps can be provided to potential customers for evaluation.
Besides the technical realization of the POC it is necessary to analyse the market, i.e. identify customers as well as producers and develop a strategy for how to target these two groups successfully"
Summary
"The ERC-funded project CRYTERION has a goal of scaling up simulations and computations with trapped ions. One possible route for this is the use of a 2D array of ion traps. During the development of these 2D arrays, a novel method of being able to address the interactions was conceived, allowing addressing of individual ions and nearest-neighbour interactions between
ions in the array. A patent has been granted on the design and the ERC-POC grant is being applied for so as to develop an implementation with the goal of licensing the patent.
Technical tests of this idea with calcium ions have been performed on a mesoscale array of ion traps. Basic ideas for creating micro-scale traps are under investigation. We propose that this micro-array concept be developed, to the point where traps can be provided to potential customers for evaluation.
Besides the technical realization of the POC it is necessary to analyse the market, i.e. identify customers as well as producers and develop a strategy for how to target these two groups successfully"
Max ERC Funding
144 860 €
Duration
Start date: 2013-12-01, End date: 2014-11-30
Project acronym CASINO
Project Carbohydrate signals controlling nodulation
Researcher (PI) Jens Stougaard Jensen
Host Institution (HI) AARHUS UNIVERSITET
Call Details Advanced Grant (AdG), LS3, ERC-2010-AdG_20100317
Summary Mechanisms governing interaction between multicellular organisms and microbes are central for understanding pathogenesis, symbiosis and the function of ecosystems. We propose to address these mechanisms by pioneering an interdisciplinary approach for understanding cellular signalling, response processes and organ development. The challenge is to determine factors synchronising three processes, organogenesis, infection thread formation and bacterial infection, running in parallel to build a root nodule hosting symbiotic bacteria. We aim to exploit the unique possibilities for analysing endocytosis of bacteria in model legumes and to develop genomic, genetic and biological chemistry tools to break new ground in our understanding of carbohydrates in plant development and plant-microbe interaction. Surface exposed rhizobial polysaccharides play a crucial but poorly understood role in infection thread formation and rhizobial invasion resulting in endocytosis. We will undertake an integrated functional characterisation of receptor-ligand mechanisms mediating recognition of secreted polysaccharides and subsequent signal amplification. So far progress in this field has been limited by the complex nature of carbohydrate polymers, lack of a suitable experimental model system where both partners in an interaction could be manipulated and lack of corresponding methods for carbohydrate synthesis, analysis and interaction studies. In this context our legume model system and the discovery that the legume Nod-factor receptors recognise bacterial lipochitin-oligosaccharide signals at their LysM domains provides a new opportunity. Combined with advanced bioorganic chemistry and nanobioscience approaches this proposal will engage the above mentioned limitations.
Summary
Mechanisms governing interaction between multicellular organisms and microbes are central for understanding pathogenesis, symbiosis and the function of ecosystems. We propose to address these mechanisms by pioneering an interdisciplinary approach for understanding cellular signalling, response processes and organ development. The challenge is to determine factors synchronising three processes, organogenesis, infection thread formation and bacterial infection, running in parallel to build a root nodule hosting symbiotic bacteria. We aim to exploit the unique possibilities for analysing endocytosis of bacteria in model legumes and to develop genomic, genetic and biological chemistry tools to break new ground in our understanding of carbohydrates in plant development and plant-microbe interaction. Surface exposed rhizobial polysaccharides play a crucial but poorly understood role in infection thread formation and rhizobial invasion resulting in endocytosis. We will undertake an integrated functional characterisation of receptor-ligand mechanisms mediating recognition of secreted polysaccharides and subsequent signal amplification. So far progress in this field has been limited by the complex nature of carbohydrate polymers, lack of a suitable experimental model system where both partners in an interaction could be manipulated and lack of corresponding methods for carbohydrate synthesis, analysis and interaction studies. In this context our legume model system and the discovery that the legume Nod-factor receptors recognise bacterial lipochitin-oligosaccharide signals at their LysM domains provides a new opportunity. Combined with advanced bioorganic chemistry and nanobioscience approaches this proposal will engage the above mentioned limitations.
Max ERC Funding
2 399 127 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
Project acronym CATCHIT
Project Coherently Advanced Tissue and Cell Holographic Imaging and Trapping
Researcher (PI) Monika Ritsch-Marte
Host Institution (HI) MEDIZINISCHE UNIVERSITAT INNSBRUCK
Call Details Advanced Grant (AdG), PE2, ERC-2009-AdG
Summary We envisage a new generation of dynamic holographic laser tweezers and stretching tools with unprecedented spatial control of gradient and scattering light forces, to unravel functional mysteries of cell biology and genetics: Based on our recently developed, highly successful and widely recognized amplitude and phase shaping techniques with cascaded spatial light modulators (SLM), we will create new holographic optical manipulators consisting of a line-shaped trap with balanced net scattering forces and controllable local phase-gradients. Combining these line stretchers with spiral phase contrast imaging or nonlinear optical microscopy will allow quantitative study of functional shape changes. The novel tool is hugely more versatile than standard optical tweezers, since direction and magnitude of the scattering force can be designed to precisely follow the structure. In combination with conventional multi-spot traps the line stretcher acts as a sensitive and adaptable local force sensor. In collaboration with local experts we want to tackle hot topics in Genetics, e.g. search for force profile signatures in regions with Copy Number Variations. Possibly the approach may shed light on basic physical characteristics such as, for example, chromosomal fragility in Fra(X) syndrome, the most common monogenic cause of mental retardation. The new design intrinsically offers enhanced microscopic resolution, as SLM-synthesized apertures and waveforms can enlarge the number of spatial frequencies forming the image. Ultimately, nonlinear holography can be implemented, sending phase shaped wavefronts to target samples. This can, e.g., be used to push the sensitivity of nonlinear chemical imaging, or for controlled photo-activation of targeted regions in neurons.
Summary
We envisage a new generation of dynamic holographic laser tweezers and stretching tools with unprecedented spatial control of gradient and scattering light forces, to unravel functional mysteries of cell biology and genetics: Based on our recently developed, highly successful and widely recognized amplitude and phase shaping techniques with cascaded spatial light modulators (SLM), we will create new holographic optical manipulators consisting of a line-shaped trap with balanced net scattering forces and controllable local phase-gradients. Combining these line stretchers with spiral phase contrast imaging or nonlinear optical microscopy will allow quantitative study of functional shape changes. The novel tool is hugely more versatile than standard optical tweezers, since direction and magnitude of the scattering force can be designed to precisely follow the structure. In combination with conventional multi-spot traps the line stretcher acts as a sensitive and adaptable local force sensor. In collaboration with local experts we want to tackle hot topics in Genetics, e.g. search for force profile signatures in regions with Copy Number Variations. Possibly the approach may shed light on basic physical characteristics such as, for example, chromosomal fragility in Fra(X) syndrome, the most common monogenic cause of mental retardation. The new design intrinsically offers enhanced microscopic resolution, as SLM-synthesized apertures and waveforms can enlarge the number of spatial frequencies forming the image. Ultimately, nonlinear holography can be implemented, sending phase shaped wavefronts to target samples. This can, e.g., be used to push the sensitivity of nonlinear chemical imaging, or for controlled photo-activation of targeted regions in neurons.
Max ERC Funding
1 987 428 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym CC4SOL
Project Towards chemical accuracy in computational materials science
Researcher (PI) Andreas GRÜNEIS
Host Institution (HI) TECHNISCHE UNIVERSITAET WIEN
Call Details Starting Grant (StG), PE3, ERC-2016-STG
Summary This project aims at the development of a novel toolbox of ab-initio methods that approximate the true many-electron wavefunction using systematically improvable perturbation and coupled-cluster theories. The demand and prospects for these methods are excellent given that the highly-accurate coupled-cluster theories can predict atomization- and reaction energies in a wide range of solids and molecules with chemical accuracy (≈43 meV). However, the computational cost involved inhibits their widespread use in the field of materials science so far. A multitude of suggested developments in the present proposal hold the promise to reduce the computational cost beyond what is currently considered possible by the community. These include explicit correlation methods that augment the conventional wavefunction expansion with terms that depend on the electron pair correlation factors. In contrast to the widely-used homogeneous correlation factors, this proposal aims at the investigation of inhomogeneous correlation factors that can also capture van der Waals interactions. Furthermore this proposal seeks to employ a recently developed combination of atom-centered basis functions and plane wave basis sets, maximizing the compactness in the wavefunction expansion. The combination of these ideas bears the potential to reduce the computational cost of coupled-cluster calculations in solids by three orders of magnitude, leading to a breakthrough in the field of highly-accurate ab-initio simulations. As such the study of challenging solid state physics and chemistry problems forms an important part of this proposal. We seek to investigate molecular adsorption and reactions in zeolites and on surfaces, pressure-driven solid-solid phase transitions of two dimensional layered materials and defects in solids. These problems are paradigmatic for van der Waals interactions and strong correlation, and methods that describe their electronic structure accurately are highly sought after.
Summary
This project aims at the development of a novel toolbox of ab-initio methods that approximate the true many-electron wavefunction using systematically improvable perturbation and coupled-cluster theories. The demand and prospects for these methods are excellent given that the highly-accurate coupled-cluster theories can predict atomization- and reaction energies in a wide range of solids and molecules with chemical accuracy (≈43 meV). However, the computational cost involved inhibits their widespread use in the field of materials science so far. A multitude of suggested developments in the present proposal hold the promise to reduce the computational cost beyond what is currently considered possible by the community. These include explicit correlation methods that augment the conventional wavefunction expansion with terms that depend on the electron pair correlation factors. In contrast to the widely-used homogeneous correlation factors, this proposal aims at the investigation of inhomogeneous correlation factors that can also capture van der Waals interactions. Furthermore this proposal seeks to employ a recently developed combination of atom-centered basis functions and plane wave basis sets, maximizing the compactness in the wavefunction expansion. The combination of these ideas bears the potential to reduce the computational cost of coupled-cluster calculations in solids by three orders of magnitude, leading to a breakthrough in the field of highly-accurate ab-initio simulations. As such the study of challenging solid state physics and chemistry problems forms an important part of this proposal. We seek to investigate molecular adsorption and reactions in zeolites and on surfaces, pressure-driven solid-solid phase transitions of two dimensional layered materials and defects in solids. These problems are paradigmatic for van der Waals interactions and strong correlation, and methods that describe their electronic structure accurately are highly sought after.
Max ERC Funding
1 460 826 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
Project acronym CDK6-DrugOpp
Project CDK6 in transcription - turning a foe in a friend
Researcher (PI) Veronika SEXL
Host Institution (HI) VETERINAERMEDIZINISCHE UNIVERSITAET WIEN
Call Details Advanced Grant (AdG), LS7, ERC-2015-AdG
Summary "Translational research aims at applying mechanistic understanding in the development of "precision medicine", which depends on precise diagnostic tools and therapeutic approaches. Cancer therapy is experiencing a switch from non-specific, cytotoxic agents towards molecularly targeted and rationally designed compounds with the promise of greater efficacy and fewer side effects.
The two cell-cycle kinases CDK4 and CDK6 normally facilitate cell-cycle progression but are abnormally activated in certain cancers. CDK6 is up-regulated in hematopoietic malignancies, where it is the predominant cell-cycle kinase. The importance of CDK4/6 for tumor development is underscored by the fact that the US FDA selected inhibitors of the kinase activity of CDK4/6 as "breakthrough of the year 2013". Our recent findings suggest that the effects of the inhibitors may be limited as CDK6 is not only involved in cell-cycle progression: ground-breaking research in my group and others has shown that CDK6 is involved in regulation of transcription in a kinase-independent manner thereby driving the proliferation of leukemic stem cells and tumor formation. We have now identified mutations in CDK6 that convert it from a tumor promoter into a tumor suppressor. This unexpected outcome is accompanied by a distinct transcriptional profile. Separating the tumor-promoting from the tumor suppressive functions may open a novel therapeutic avenue for drug development. We aim at understanding which domains and residues of CDK6 are involved in rewiring the transcriptional landscape to pave the way for sophisticated inhibitors. The idea of turning a cancer cell's own most potent weapon against itself is novel and would represent a new paradigm for drug design. Finally, the understanding of CDK6 functions in tumor promotion and maintenance will also result in better patient stratification and improved treatment decisions for a broad spectrum of cancer types."
Summary
"Translational research aims at applying mechanistic understanding in the development of "precision medicine", which depends on precise diagnostic tools and therapeutic approaches. Cancer therapy is experiencing a switch from non-specific, cytotoxic agents towards molecularly targeted and rationally designed compounds with the promise of greater efficacy and fewer side effects.
The two cell-cycle kinases CDK4 and CDK6 normally facilitate cell-cycle progression but are abnormally activated in certain cancers. CDK6 is up-regulated in hematopoietic malignancies, where it is the predominant cell-cycle kinase. The importance of CDK4/6 for tumor development is underscored by the fact that the US FDA selected inhibitors of the kinase activity of CDK4/6 as "breakthrough of the year 2013". Our recent findings suggest that the effects of the inhibitors may be limited as CDK6 is not only involved in cell-cycle progression: ground-breaking research in my group and others has shown that CDK6 is involved in regulation of transcription in a kinase-independent manner thereby driving the proliferation of leukemic stem cells and tumor formation. We have now identified mutations in CDK6 that convert it from a tumor promoter into a tumor suppressor. This unexpected outcome is accompanied by a distinct transcriptional profile. Separating the tumor-promoting from the tumor suppressive functions may open a novel therapeutic avenue for drug development. We aim at understanding which domains and residues of CDK6 are involved in rewiring the transcriptional landscape to pave the way for sophisticated inhibitors. The idea of turning a cancer cell's own most potent weapon against itself is novel and would represent a new paradigm for drug design. Finally, the understanding of CDK6 functions in tumor promotion and maintenance will also result in better patient stratification and improved treatment decisions for a broad spectrum of cancer types."
Max ERC Funding
2 497 520 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym CeMoMagneto
Project The Cellular and Molecular Basis of Magnetoreception
Researcher (PI) David Anthony Keays
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary Each year millions of animals undertake remarkable migratory journeys, across oceans and through hemispheres, guided by the Earth’s magnetic field. The cellular and molecular basis of this enigmatic sense, known as magnetoreception, remains an unsolved scientific mystery. One hypothesis that attempts to explain the basis of this sensory faculty is known as the magnetite theory of magnetoreception. It argues that magnetic information is transduced into a neuronal impulse by employing the iron oxide magnetite (Fe3O4). Current evidence indicates that pigeons employ a magnetoreceptor that is associated with the ophthalmic branch of the trigeminal nerve and the vestibular system, but the sensory cells remain undiscovered. The goal of this ambitious proposal is to discover the cells and molecules that mediate magnetoreception. This overall objective can be divided into three specific aims: (1) the identification of putative magnetoreceptive cells (PMCs); (2) the cellular characterisation of PMCs; and (3) the discovery and functional ablation of molecules specific to PMCs. In tackling these three aims this proposal adopts a reductionist mindset, employing and developing the latest imaging, subcellular, and molecular technologies.
Summary
Each year millions of animals undertake remarkable migratory journeys, across oceans and through hemispheres, guided by the Earth’s magnetic field. The cellular and molecular basis of this enigmatic sense, known as magnetoreception, remains an unsolved scientific mystery. One hypothesis that attempts to explain the basis of this sensory faculty is known as the magnetite theory of magnetoreception. It argues that magnetic information is transduced into a neuronal impulse by employing the iron oxide magnetite (Fe3O4). Current evidence indicates that pigeons employ a magnetoreceptor that is associated with the ophthalmic branch of the trigeminal nerve and the vestibular system, but the sensory cells remain undiscovered. The goal of this ambitious proposal is to discover the cells and molecules that mediate magnetoreception. This overall objective can be divided into three specific aims: (1) the identification of putative magnetoreceptive cells (PMCs); (2) the cellular characterisation of PMCs; and (3) the discovery and functional ablation of molecules specific to PMCs. In tackling these three aims this proposal adopts a reductionist mindset, employing and developing the latest imaging, subcellular, and molecular technologies.
Max ERC Funding
1 499 752 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym CentSatRegFunc
Project Dissecting the function and regulation of centriolar satellites: key regulators of the centrosome/cilium complex
Researcher (PI) Elif Nur Firat Karalar
Host Institution (HI) KOC UNIVERSITY
Call Details Starting Grant (StG), LS3, ERC-2015-STG
Summary Centrosomes are the main microtubule-organizing centers of animal cells. They influence the morphology of the microtubule cytoskeleton and function as the base of primary cilium, a nexus for important signaling pathways. Structural and functional defects in centrosome/cilium complex cause a variety of human diseases including cancer, ciliopathies and microcephaly. To understand the relationship between human diseases and centrosome/cilium abnormalities, it is essential to elucidate the biogenesis of centrosome/cilium complex and the control mechanisms that regulate their structure and function. To tackle these fundamental problems, we will dissect the function and regulation of centriolar satellites, the array of granules that localize around the centrosome/cilium complex in mammalian cells. Only recently interest in the satellites has grown because mutations affecting satellite components were shown to cause ciliopathies, microcephaly and schizophrenia.
Remarkably, many centrosome/cilium proteins localize to these structures and we lack understanding of when, why and how these proteins localize to satellites. The central hypothesis of this grant is that satellites ensure proper centrosome/cilium complex structure and function by acting as transit paths for modification, assembly, storage, stability and trafficking of centrosome/cilium proteins. In Aim 1, we will identify the nature of regulatory and molecular relationship between satellites and the centrosome/cilium complex. In Aim 2, we will elucidate the role of satellites in proteostasis of centrosome/cilium proteins. In Aim 3, we will investigate the functional significance of satellite-localization of centrosome/cilium proteins during processes that go awry in human disease. Using a multidisciplinary approach, the proposed research will expand our knowledge of the spatiotemporal regulation of the centrosome/cilium complex and provide new insights into pathogenesis of ciliopathies and primary microcephaly.
Summary
Centrosomes are the main microtubule-organizing centers of animal cells. They influence the morphology of the microtubule cytoskeleton and function as the base of primary cilium, a nexus for important signaling pathways. Structural and functional defects in centrosome/cilium complex cause a variety of human diseases including cancer, ciliopathies and microcephaly. To understand the relationship between human diseases and centrosome/cilium abnormalities, it is essential to elucidate the biogenesis of centrosome/cilium complex and the control mechanisms that regulate their structure and function. To tackle these fundamental problems, we will dissect the function and regulation of centriolar satellites, the array of granules that localize around the centrosome/cilium complex in mammalian cells. Only recently interest in the satellites has grown because mutations affecting satellite components were shown to cause ciliopathies, microcephaly and schizophrenia.
Remarkably, many centrosome/cilium proteins localize to these structures and we lack understanding of when, why and how these proteins localize to satellites. The central hypothesis of this grant is that satellites ensure proper centrosome/cilium complex structure and function by acting as transit paths for modification, assembly, storage, stability and trafficking of centrosome/cilium proteins. In Aim 1, we will identify the nature of regulatory and molecular relationship between satellites and the centrosome/cilium complex. In Aim 2, we will elucidate the role of satellites in proteostasis of centrosome/cilium proteins. In Aim 3, we will investigate the functional significance of satellite-localization of centrosome/cilium proteins during processes that go awry in human disease. Using a multidisciplinary approach, the proposed research will expand our knowledge of the spatiotemporal regulation of the centrosome/cilium complex and provide new insights into pathogenesis of ciliopathies and primary microcephaly.
Max ERC Funding
1 499 819 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym CeraText
Project Tailoring Microstructure and Architecture to Build Ceramic Components with Unprecedented Damage Tolerance
Researcher (PI) Raul BERMEJO
Host Institution (HI) MONTANUNIVERSITAET LEOBEN
Call Details Consolidator Grant (CoG), PE8, ERC-2018-COG
Summary Advanced ceramics are often combined with metals, polymers or other ceramics to produce structural and functional systems with exceptional properties. Examples are resistors and capacitors in microelectronics, piezo-ceramic actuators in car injection devices, and bio-implants for hip joint replacements. However, a critical issue affecting the functionality, lifetime and reliability of such systems is the initiation and uncontrolled propagation of cracks in the brittle ceramic parts, yielding in some cases rejection rates up to 70% of components production.
The remarkable “damage tolerance” found in natural materials such as wood, bone or mollusc, has yet to be achieved in technical ceramics, where incipient damage is synonymous with catastrophic failure. Novel “multilayer designs” combining microstructure and architecture could change this situation. Recent work of the PI has shown that tuning the location of “protective” layers within a 3D multilayer ceramic can increase its fracture resistance by five times (from ~3.5 to ~17 MPa∙m1/2) relative to constituent bulk ceramic layers, while retaining high strength (~500 MPa). By orienting the grain structure, similar to the textured and organized microstructure found in natural systems such as nacre, the PI has shown that crack propagation can be controlled within the textured ceramic layer. Thus, I believe tailored microstructures with controlled grain boundaries engineered in a layer-by-layer 3D architectural design hold the key to a new generation of “damage tolerant” ceramics.
This proposal outlines a research program to establish new scientific principles for the fabrication of innovative ceramic components that exhibit unprecedented damage tolerance. The successful implementation of microstructural features (e.g. texture degree, tailored internal stresses, second phases, interfaces) in a layer-by-layer architecture will provide outstanding lifetime and reliability in both structural and functional ceramic devices.
Summary
Advanced ceramics are often combined with metals, polymers or other ceramics to produce structural and functional systems with exceptional properties. Examples are resistors and capacitors in microelectronics, piezo-ceramic actuators in car injection devices, and bio-implants for hip joint replacements. However, a critical issue affecting the functionality, lifetime and reliability of such systems is the initiation and uncontrolled propagation of cracks in the brittle ceramic parts, yielding in some cases rejection rates up to 70% of components production.
The remarkable “damage tolerance” found in natural materials such as wood, bone or mollusc, has yet to be achieved in technical ceramics, where incipient damage is synonymous with catastrophic failure. Novel “multilayer designs” combining microstructure and architecture could change this situation. Recent work of the PI has shown that tuning the location of “protective” layers within a 3D multilayer ceramic can increase its fracture resistance by five times (from ~3.5 to ~17 MPa∙m1/2) relative to constituent bulk ceramic layers, while retaining high strength (~500 MPa). By orienting the grain structure, similar to the textured and organized microstructure found in natural systems such as nacre, the PI has shown that crack propagation can be controlled within the textured ceramic layer. Thus, I believe tailored microstructures with controlled grain boundaries engineered in a layer-by-layer 3D architectural design hold the key to a new generation of “damage tolerant” ceramics.
This proposal outlines a research program to establish new scientific principles for the fabrication of innovative ceramic components that exhibit unprecedented damage tolerance. The successful implementation of microstructural features (e.g. texture degree, tailored internal stresses, second phases, interfaces) in a layer-by-layer architecture will provide outstanding lifetime and reliability in both structural and functional ceramic devices.
Max ERC Funding
1 985 000 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
