Project acronym ChromatinTargets
Project Systematic in-vivo analysis of chromatin-associated targets in leukemia
Researcher (PI) Johannes Zuber
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary Recent advances in genome sequencing illustrate the complexity, heterogeneity and plasticity of cancer genomes. In leukemia - a group of blood cancers affecting 300,000 new patients every year – we know over 100 driver mutations. This genetic complexity poses a daunting challenge for the development of targeted therapies and highlights the urgent need for evaluating them in combination. One gene class that has recently emerged as highly promising target space are chromatin regulators, which maintain aberrant cell fate programs in leukemia. The dependency on altered chromatin states is thought to provide great therapeutic opportunities, since epigenetic aberrations are reversible and controlled by a machinery that is amenable to drug modulation. However, the precise mechanisms underlying these dependencies and the most effective and safe targets to exploit them therapeutically remain unknown.
Here we propose an innovative approach combining genetically engineered leukemia mouse models and advanced in-vivo RNAi technologies to explore chromatin-associated vulnerabilities at an unprecedented level of depth. Following a first screen in MLL-AF9;Nras-driven AML, which led to the discovery of BRD4 as a promising therapeutic target, we aim to (1) construct a knockdown-validated shRNA library targeting 520 chromatin regulators and use it to comparatively probe chromatin-associated dependencies in diverse leukemia subtypes; (2) explore the mechanistic basis of response and resistance to suppression of BRD4 and new chromatin-associated targets; and (3) pioneer a system for multiplexed combinatorial RNAi screening and use it to identify synergies between established and new chromatin-associated targets. We envision that this ERC-funded project will generate a comprehensive functional-genetic dataset that will greatly complement ongoing genome and epigenome profiling studies and ultimately guide the development of targeted therapies for leukemia and, potentially, other cancers.
Summary
Recent advances in genome sequencing illustrate the complexity, heterogeneity and plasticity of cancer genomes. In leukemia - a group of blood cancers affecting 300,000 new patients every year – we know over 100 driver mutations. This genetic complexity poses a daunting challenge for the development of targeted therapies and highlights the urgent need for evaluating them in combination. One gene class that has recently emerged as highly promising target space are chromatin regulators, which maintain aberrant cell fate programs in leukemia. The dependency on altered chromatin states is thought to provide great therapeutic opportunities, since epigenetic aberrations are reversible and controlled by a machinery that is amenable to drug modulation. However, the precise mechanisms underlying these dependencies and the most effective and safe targets to exploit them therapeutically remain unknown.
Here we propose an innovative approach combining genetically engineered leukemia mouse models and advanced in-vivo RNAi technologies to explore chromatin-associated vulnerabilities at an unprecedented level of depth. Following a first screen in MLL-AF9;Nras-driven AML, which led to the discovery of BRD4 as a promising therapeutic target, we aim to (1) construct a knockdown-validated shRNA library targeting 520 chromatin regulators and use it to comparatively probe chromatin-associated dependencies in diverse leukemia subtypes; (2) explore the mechanistic basis of response and resistance to suppression of BRD4 and new chromatin-associated targets; and (3) pioneer a system for multiplexed combinatorial RNAi screening and use it to identify synergies between established and new chromatin-associated targets. We envision that this ERC-funded project will generate a comprehensive functional-genetic dataset that will greatly complement ongoing genome and epigenome profiling studies and ultimately guide the development of targeted therapies for leukemia and, potentially, other cancers.
Max ERC Funding
1 498 985 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym CombaTCancer
Project Rational combination therapies for metastatic cancer
Researcher (PI) Anna Obenauf
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS4, ERC-2017-STG
Summary Targeted therapy (TT) is frequently used to treat metastatic cancer. Although TT can achieve effective tumor control for several months, durable treatment responses are rare, due to emergence of aggressive, drug-resistant clones (RCs) with high metastatic competence. Tumor heterogeneity and plasticity result in multifaceted resistance mechanisms and targeting RCs poses a daunting challenge.
To better understand the clinical emergence of RCs, my work focuses on the poorly understood events during TT-induced tumor regression. We recently reported that during this phase drug-responsive cancer cells release a therapy-induced secretome, which remodels the tumor microenvironment (TME) and propagates disease relapse by promoting the survival of drug-sensitive cells and stimulating the outgrowth of RCs. Consequently, intervening with combination therapies during the tumor regression period has the potential to prevent the clinical emergence of RCs in the first place.
Here, we outline strategies to (1) understand how RCs emerge and (2) to leverage our findings on the TME remodeling for combination therapies. First, we will develop a novel and innovative parental clone-lookup method, that will allow us to identify and isolate treatment-naïve, parental clones (PCs) that gave rise to RCs. In functional experiments, we will assess (i) whether PCs were already resistant before or developed resistance during TT, (ii) whether PCs have a higher susceptibility to develop resistance than random clones, and (iii) the mechanistic basis for metastatic competence in different clones. Second, we will study the TT-induced TME remodeling, focusing on the effects on tumor vasculature and immune cells. We will utilize our results to target PCs and RCs by combining TT in the phase of tumor regression with other therapies, such as immunotherapies. Our study will provide new mechanistic insights into the biological processes during tumor regression and aims for novel therapeutic strategies.
Summary
Targeted therapy (TT) is frequently used to treat metastatic cancer. Although TT can achieve effective tumor control for several months, durable treatment responses are rare, due to emergence of aggressive, drug-resistant clones (RCs) with high metastatic competence. Tumor heterogeneity and plasticity result in multifaceted resistance mechanisms and targeting RCs poses a daunting challenge.
To better understand the clinical emergence of RCs, my work focuses on the poorly understood events during TT-induced tumor regression. We recently reported that during this phase drug-responsive cancer cells release a therapy-induced secretome, which remodels the tumor microenvironment (TME) and propagates disease relapse by promoting the survival of drug-sensitive cells and stimulating the outgrowth of RCs. Consequently, intervening with combination therapies during the tumor regression period has the potential to prevent the clinical emergence of RCs in the first place.
Here, we outline strategies to (1) understand how RCs emerge and (2) to leverage our findings on the TME remodeling for combination therapies. First, we will develop a novel and innovative parental clone-lookup method, that will allow us to identify and isolate treatment-naïve, parental clones (PCs) that gave rise to RCs. In functional experiments, we will assess (i) whether PCs were already resistant before or developed resistance during TT, (ii) whether PCs have a higher susceptibility to develop resistance than random clones, and (iii) the mechanistic basis for metastatic competence in different clones. Second, we will study the TT-induced TME remodeling, focusing on the effects on tumor vasculature and immune cells. We will utilize our results to target PCs and RCs by combining TT in the phase of tumor regression with other therapies, such as immunotherapies. Our study will provide new mechanistic insights into the biological processes during tumor regression and aims for novel therapeutic strategies.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym EVOLOR
Project Cognitive Ageing in Dogs
Researcher (PI) Eniko Kubinyi
Host Institution (HI) EOTVOS LORAND TUDOMANYEGYETEM
Call Details Starting Grant (StG), LS9, ERC-2015-STG
Summary The aim of this project is to understand the causal factors contributing to the cognitive decline during senescence and to develop sensitive and standardized behaviour tests for early detection in order to increase the welfare of affected species. With the rapidly ageing population of Europe, related research is a priority in the European Union.
We will focus both on characterising the ageing phenotype and the underlying biological processes in dogs as a well-established natural animal model. We develop a reliable and valid test battery applying innovative multidisciplinary methods (e.g. eye-tracking, motion path analysis, identification of behaviour using inertial sensors, EEG, fMRI, candidate gene, and epigenetics) in both longitudinal and cross-sectional studies. We expect to reveal specific environmental risk factors which hasten ageing and also protective factors which may postpone it. We aim to provide objective criteria (behavioural, physiological and genetic biomarkers) to assess and predict the ageing trajectory for specific individual dogs. This would help veterinarians to recognise the symptoms early, and initiate necessary counter actions.
This approach establishes the framework for answering the broad question that how we can extend the healthy life of ageing dogs which indirectly also contributes to the welfare of the owner and decreases veterinary expenses. The detailed description of the ageing phenotype may also facilitate the use of dogs as a natural model for human senescence, including the development and application of pharmaceutical interventions.
We expect that our approach offers the scientific foundation to delay the onset of cognitive ageing in dog populations by 1-2 years, and also increase the proportion of dogs that enjoy healthy ageing.
Summary
The aim of this project is to understand the causal factors contributing to the cognitive decline during senescence and to develop sensitive and standardized behaviour tests for early detection in order to increase the welfare of affected species. With the rapidly ageing population of Europe, related research is a priority in the European Union.
We will focus both on characterising the ageing phenotype and the underlying biological processes in dogs as a well-established natural animal model. We develop a reliable and valid test battery applying innovative multidisciplinary methods (e.g. eye-tracking, motion path analysis, identification of behaviour using inertial sensors, EEG, fMRI, candidate gene, and epigenetics) in both longitudinal and cross-sectional studies. We expect to reveal specific environmental risk factors which hasten ageing and also protective factors which may postpone it. We aim to provide objective criteria (behavioural, physiological and genetic biomarkers) to assess and predict the ageing trajectory for specific individual dogs. This would help veterinarians to recognise the symptoms early, and initiate necessary counter actions.
This approach establishes the framework for answering the broad question that how we can extend the healthy life of ageing dogs which indirectly also contributes to the welfare of the owner and decreases veterinary expenses. The detailed description of the ageing phenotype may also facilitate the use of dogs as a natural model for human senescence, including the development and application of pharmaceutical interventions.
We expect that our approach offers the scientific foundation to delay the onset of cognitive ageing in dog populations by 1-2 years, and also increase the proportion of dogs that enjoy healthy ageing.
Max ERC Funding
1 202 500 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym FEAR-SAP
Project Function and Evolution of Attack and Response Strategies during Allelopathy in Plants
Researcher (PI) Claude BECKER
Host Institution (HI) GREGOR MENDEL INSTITUT FUR MOLEKULARE PFLANZENBIOLOGIE GMBH
Call Details Starting Grant (StG), LS9, ERC-2016-STG
Summary In natural and agricultural habitats, plants grow in organismal communities and therefore have to compete for limited resources. Competition between different crop plants and between crops and weeds leads to losses of potential agricultural product and requires heavy use of fertilizer and herbicides, with negative effects for the environment and human health. Plants have evolved various strategies to outcompete their neighbours and to secure their access to resources; one of them is the release of toxic chemical compounds into the soil that interfere with the growth of neighbouring plants. Many of today’s major crops, such as wheat, rye and maize, produce phytotoxins. Conversely, crop species also suffer from chemical attack by other plants growing in their vicinity. Although many of the chemical compounds applied in this biochemical warfare have been identified, we know little about how they act in the target plant; neither do we understand how some plant species are able to tolerate this chemical attack.
FEAR-SAP studies the genetic architecture that underlies biochemical plant-plant interference and the evolution of weed resistance to crop-released phytotoxins. To this end it employs a comprehensive array of molecular genetics, genomics and metagenomics analyses, unprecedented in the research on plant-plant competition. The aims of FEAR-SAP are to uncover the molecular targets of plant-derived phytotoxins and to identify the genetic components that are essential for tolerance to these substances. Moreover, FEAR-SAP investigates how the microbial community that is associated with the plant might enhance efficiency of the donor and/or mediate tolerance of the target plant. Ultimately, we will use this information to explore intelligent engineering of more refined and competitive crops, which will be at the foundation of efficient and ecologically responsible weed control and improved crop rotation strategies.
Summary
In natural and agricultural habitats, plants grow in organismal communities and therefore have to compete for limited resources. Competition between different crop plants and between crops and weeds leads to losses of potential agricultural product and requires heavy use of fertilizer and herbicides, with negative effects for the environment and human health. Plants have evolved various strategies to outcompete their neighbours and to secure their access to resources; one of them is the release of toxic chemical compounds into the soil that interfere with the growth of neighbouring plants. Many of today’s major crops, such as wheat, rye and maize, produce phytotoxins. Conversely, crop species also suffer from chemical attack by other plants growing in their vicinity. Although many of the chemical compounds applied in this biochemical warfare have been identified, we know little about how they act in the target plant; neither do we understand how some plant species are able to tolerate this chemical attack.
FEAR-SAP studies the genetic architecture that underlies biochemical plant-plant interference and the evolution of weed resistance to crop-released phytotoxins. To this end it employs a comprehensive array of molecular genetics, genomics and metagenomics analyses, unprecedented in the research on plant-plant competition. The aims of FEAR-SAP are to uncover the molecular targets of plant-derived phytotoxins and to identify the genetic components that are essential for tolerance to these substances. Moreover, FEAR-SAP investigates how the microbial community that is associated with the plant might enhance efficiency of the donor and/or mediate tolerance of the target plant. Ultimately, we will use this information to explore intelligent engineering of more refined and competitive crops, which will be at the foundation of efficient and ecologically responsible weed control and improved crop rotation strategies.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym GEL-SYS
Project Smart HydroGEL SYStems – From Bioinspired Design to Soft Electronics and Machines
Researcher (PI) Martin KALTENBRUNNER
Host Institution (HI) UNIVERSITAT LINZ
Call Details Starting Grant (StG), PE8, ERC-2017-STG
Summary Hydrogels evolved as versatile building blocks of life – we all are in essence gel-embodied soft machines. Drawing inspiration from the diversity found in living creatures, GEL-SYS will develop a set of concepts, materials approaches and design rules for wide ranging classes of soft, hydrogel-based electronic, ionic and photonic devices in three core aims.
Aim (A) will pursue a high level of complexity in soft, yet tough biomimetic devices and machines by introducing nature-inspired instant strong bonds between hydrogels and antagonistic materials – from soft and elastic to hard and brittle. Building on these newly developed interfaces, aim (B) will pursue biocompatible hydrogel electronics with iontronic transducers and large area multimodal sensor arrays for a new class of medical tools and health monitors. Aim (C) will foster the current soft revolution of robotics with self-sensing, transparent grippers not occluding objects and workspace. A soft robotic visual system with hydrogel-based adaptive optical elements and ultraflexible photosensor arrays will allow robots to see while grasping. Autonomous operation will be a central question in soft systems, tackled with tough stretchable batteries and energy harvesting from mechanical motion on small and large scales with soft membranes. GEL-SYS will use our experience on soft, “imperceptible” electronics and devices. By fusing this technology platform with tough hydrogels - nature’s most pluripotent ingredient of soft machines - we aim to create the next generation of bionic systems. The envisioned hybrids promise new discoveries in the nonlinear mechanical responses of soft systems, and may allow exploiting triggered elastic instabilities for unconventional locomotion. Exploring soft matter, intimately united with solid materials, will trigger novel concepts for medical equipment, healthcare, consumer electronics, energy harvesting from renewable sources and in robotics, with imminent impact on our society.
Summary
Hydrogels evolved as versatile building blocks of life – we all are in essence gel-embodied soft machines. Drawing inspiration from the diversity found in living creatures, GEL-SYS will develop a set of concepts, materials approaches and design rules for wide ranging classes of soft, hydrogel-based electronic, ionic and photonic devices in three core aims.
Aim (A) will pursue a high level of complexity in soft, yet tough biomimetic devices and machines by introducing nature-inspired instant strong bonds between hydrogels and antagonistic materials – from soft and elastic to hard and brittle. Building on these newly developed interfaces, aim (B) will pursue biocompatible hydrogel electronics with iontronic transducers and large area multimodal sensor arrays for a new class of medical tools and health monitors. Aim (C) will foster the current soft revolution of robotics with self-sensing, transparent grippers not occluding objects and workspace. A soft robotic visual system with hydrogel-based adaptive optical elements and ultraflexible photosensor arrays will allow robots to see while grasping. Autonomous operation will be a central question in soft systems, tackled with tough stretchable batteries and energy harvesting from mechanical motion on small and large scales with soft membranes. GEL-SYS will use our experience on soft, “imperceptible” electronics and devices. By fusing this technology platform with tough hydrogels - nature’s most pluripotent ingredient of soft machines - we aim to create the next generation of bionic systems. The envisioned hybrids promise new discoveries in the nonlinear mechanical responses of soft systems, and may allow exploiting triggered elastic instabilities for unconventional locomotion. Exploring soft matter, intimately united with solid materials, will trigger novel concepts for medical equipment, healthcare, consumer electronics, energy harvesting from renewable sources and in robotics, with imminent impact on our society.
Max ERC Funding
1 499 975 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym HelixMold
Project Computational design of novel functions in helical proteins by deviating from ideal geometries
Researcher (PI) Gustav OBERDORFER
Host Institution (HI) TECHNISCHE UNIVERSITAET GRAZ
Call Details Starting Grant (StG), LS9, ERC-2018-STG
Summary We propose to computationally design novel ligand binding and catalytically active proteins by harnessing the high thermodynamic stability of de novo helical proteins. Tremendous progress has been made in protein design. However, the ability to robustly introduce function into genetically encodable de novo proteins is an unsolved problem. We will follow a highly interdisciplinary computational-experimental approach to address this challenge and aim to:
-Characterize to which extent we can harness the stability of parametrically designed helical bundles to introduce deviations from ideal geometry. Ensembles of idealized de novo helix bundle backbones will be generated using our established parametric design code and designed with constraints accounting for an envisioned functional site. This will be followed by detailed computational, biophysical, crystallographic and site-saturation mutagenesis analysis to isolate critical design features.
-Develop a new computational design strategy, which expands on the Crick coiled-coil parametrization and allows to rationally build non-ideal helical protein backbones at specified regions in the desired structure. This will enable us to model backbones around binding/active sites. We will design sites to bind glyphosate, for which remediation is highly needed. By using non-ideal geometries and not relying on classic heptad repeating units, we will be able to access a much larger sequence to structure space than is usually available to nature, enabling us to build more specific and more stable binding/catalytically active proteins.
-Investigate new strategies to design the first cascade reactions into de novo designs.
This research will allow functionalization of de novo designed proteins with high thermostability, extraordinary resistance to harsh chemical environments and high tolerance for organic solvents and has the potential to revolutionize how proteins for biotechnological and biomedical applications are generated.
Summary
We propose to computationally design novel ligand binding and catalytically active proteins by harnessing the high thermodynamic stability of de novo helical proteins. Tremendous progress has been made in protein design. However, the ability to robustly introduce function into genetically encodable de novo proteins is an unsolved problem. We will follow a highly interdisciplinary computational-experimental approach to address this challenge and aim to:
-Characterize to which extent we can harness the stability of parametrically designed helical bundles to introduce deviations from ideal geometry. Ensembles of idealized de novo helix bundle backbones will be generated using our established parametric design code and designed with constraints accounting for an envisioned functional site. This will be followed by detailed computational, biophysical, crystallographic and site-saturation mutagenesis analysis to isolate critical design features.
-Develop a new computational design strategy, which expands on the Crick coiled-coil parametrization and allows to rationally build non-ideal helical protein backbones at specified regions in the desired structure. This will enable us to model backbones around binding/active sites. We will design sites to bind glyphosate, for which remediation is highly needed. By using non-ideal geometries and not relying on classic heptad repeating units, we will be able to access a much larger sequence to structure space than is usually available to nature, enabling us to build more specific and more stable binding/catalytically active proteins.
-Investigate new strategies to design the first cascade reactions into de novo designs.
This research will allow functionalization of de novo designed proteins with high thermostability, extraordinary resistance to harsh chemical environments and high tolerance for organic solvents and has the potential to revolutionize how proteins for biotechnological and biomedical applications are generated.
Max ERC Funding
1 499 414 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym InterAct-MemNP
Project Interaction and actuation of lipid membranes with magnetic nanoparticles
Researcher (PI) Erik Reimhult
Host Institution (HI) UNIVERSITAET FUER BODENKULTUR WIEN
Call Details Starting Grant (StG), LS9, ERC-2012-StG_20111109
Summary Cell membranes contain a large part of the delicate machinery of life and comprise the barriers controlling access to and from the interior of the cell. With the increasing use of nanoparticles (NPs) in medical imaging, drug delivery, cosmetics and materials the need is great and increasing to understand how NPs physically interact with cell membranes. On the one hand it is important to understand mechanisms to control risks of novel nanomaterials and to design therapeutic agents which can enter cells specifically and non-destructively. On the other hand, the structure and function of biological membranes inspire development of biomimetic smart materials for biotechnological applications which exploit or are modeled on biological membranes, but given enhanced functionality and external control of properties through incorporation of functional NPs.
The aim of the proposed work is to develop understanding of the biophysical interaction of functional NPs with lipid membranes, in particular NP incorporation into and penetration through lipid membranes. Further, the aim is, based on that knowledge, to understand and control the self-assembly of superparamagnetic NPs into synthetic and cell lipid membranes to actuate them and control their physical properties in pursuit of novel biomimetic smart materials and cell analytical methods.
The required level of control for this research has until recently been beyond the reach of existing NP systems (lack of synthetic control, stability and characterization) and methodology (lipid membrane models and high resolution techniques for their investigation). However, it can now be achieved using the Fe3O4 NP platform and surface-based and vesicular membrane model systems of tuned composition that I have developed. Using the same platform, breakthrough magneto-responsive biomimetic smart materials with application in drug delivery and cell manipulation with novel mechanisms of actuation will be self-assembled and investigated.
Summary
Cell membranes contain a large part of the delicate machinery of life and comprise the barriers controlling access to and from the interior of the cell. With the increasing use of nanoparticles (NPs) in medical imaging, drug delivery, cosmetics and materials the need is great and increasing to understand how NPs physically interact with cell membranes. On the one hand it is important to understand mechanisms to control risks of novel nanomaterials and to design therapeutic agents which can enter cells specifically and non-destructively. On the other hand, the structure and function of biological membranes inspire development of biomimetic smart materials for biotechnological applications which exploit or are modeled on biological membranes, but given enhanced functionality and external control of properties through incorporation of functional NPs.
The aim of the proposed work is to develop understanding of the biophysical interaction of functional NPs with lipid membranes, in particular NP incorporation into and penetration through lipid membranes. Further, the aim is, based on that knowledge, to understand and control the self-assembly of superparamagnetic NPs into synthetic and cell lipid membranes to actuate them and control their physical properties in pursuit of novel biomimetic smart materials and cell analytical methods.
The required level of control for this research has until recently been beyond the reach of existing NP systems (lack of synthetic control, stability and characterization) and methodology (lipid membrane models and high resolution techniques for their investigation). However, it can now be achieved using the Fe3O4 NP platform and surface-based and vesicular membrane model systems of tuned composition that I have developed. Using the same platform, breakthrough magneto-responsive biomimetic smart materials with application in drug delivery and cell manipulation with novel mechanisms of actuation will be self-assembled and investigated.
Max ERC Funding
1 483 487 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym LEBMEC
Project Laser-engineered Biomimetic Matrices with Embedded Cells
Researcher (PI) Aleksandr Ovsianikov
Host Institution (HI) TECHNISCHE UNIVERSITAET WIEN
Call Details Starting Grant (StG), PE8, ERC-2012-StG_20111012
Summary Traditional 2D cell culture systems used in biology do not accurately reproduce the 3D structure, function, or physiology of living tissue. Resulting behaviour and responses of cells are substantially different from those observed within natural extracellular matrices (ECM). The early designs of 3D cell-culture matrices focused on their bulk properties, while disregarding individual cell environment. However, recent findings indicate that the role of the ECM extends beyond a simple structural support to regulation of cell and tissue function. So far the mechanisms of this regulation are not fully understood, due to technical limitations of available research tools, diversity of tissues and complexity of cell-matrix interactions.
The main goal of this project is to develop a versatile and straightforward method, enabling systematic studies of cell-matrix interactions. 3D CAD matrices will be produced by femtosecond laser-induced polymerization of hydrogels with cells in them. Cell embedment results in a tissue-like intimate cell-matrix contact and appropriate cell densities right from the start.
A unique advantage of the LeBMEC is its capability to alter on demand a multitude of individual properties of produced 3D matrices, including: geometry, stiffness, and cell adhesion properties. It allows us systematically reconstruct and identify the key biomimetic properties of the ECM in vitro. The particular focus of this project is on the role of local mechanical properties of produced hydrogel constructs. It is known that, stem cells on soft 2D substrates differentiate into neurons, stiffer substrates induce bone cells, and intermediate ones result in myoblasts. With LeBMEC, a controlled distribution of site-specific stiffness within the same hydrogel matrix can be achieved in 3D. This way, by rational design of cell-culture matrices initially embedding only stem cells, for realisation of precisely defined 3D multi-tissue constructs, is possible for the first time.
Summary
Traditional 2D cell culture systems used in biology do not accurately reproduce the 3D structure, function, or physiology of living tissue. Resulting behaviour and responses of cells are substantially different from those observed within natural extracellular matrices (ECM). The early designs of 3D cell-culture matrices focused on their bulk properties, while disregarding individual cell environment. However, recent findings indicate that the role of the ECM extends beyond a simple structural support to regulation of cell and tissue function. So far the mechanisms of this regulation are not fully understood, due to technical limitations of available research tools, diversity of tissues and complexity of cell-matrix interactions.
The main goal of this project is to develop a versatile and straightforward method, enabling systematic studies of cell-matrix interactions. 3D CAD matrices will be produced by femtosecond laser-induced polymerization of hydrogels with cells in them. Cell embedment results in a tissue-like intimate cell-matrix contact and appropriate cell densities right from the start.
A unique advantage of the LeBMEC is its capability to alter on demand a multitude of individual properties of produced 3D matrices, including: geometry, stiffness, and cell adhesion properties. It allows us systematically reconstruct and identify the key biomimetic properties of the ECM in vitro. The particular focus of this project is on the role of local mechanical properties of produced hydrogel constructs. It is known that, stem cells on soft 2D substrates differentiate into neurons, stiffer substrates induce bone cells, and intermediate ones result in myoblasts. With LeBMEC, a controlled distribution of site-specific stiffness within the same hydrogel matrix can be achieved in 3D. This way, by rational design of cell-culture matrices initially embedding only stem cells, for realisation of precisely defined 3D multi-tissue constructs, is possible for the first time.
Max ERC Funding
1 440 594 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym MICROBONE
Project Multiscale poro-micromechanics of bone materials, with links to biology and medicine
Researcher (PI) Christian Hellmich
Host Institution (HI) TECHNISCHE UNIVERSITAET WIEN
Call Details Starting Grant (StG), PE8, ERC-2010-StG_20091028
Summary "Modern computational engineering science allows for reliable design of the most breathtaking high-rise buildings, but it has hardly entered the fracture risk assessment of biological structures like bones. Is it only an engineering scientist's dream to decipher mathematically the origins and the evolution of the astonishingly varying mechanical properties of hierarchical biological materials? Not quite: By means of micromechanical theories, we could recently show in a quantitative fashion how ""universal"" elementary building blocks (being independent of tissue type, species, age, or anatomical location) govern the elastic properties of bone materials across the entire vertebrate kingdom, from the super-molecular to the centimetre scale. Now is the time to drive forward these developments beyond elasticity, striving for scientific breakthroughs in multiscale bone strength. Through novel, experimentally validated micromechanical theories, we will aim at predicting tissue-specific inelastic
properties of bone materials, from the ""universal"" mechanical properties of the nanoscaled elementary components (hydroxyapatite, collagen, water), their tissue-specific dosages, and the ""universal"" organizational patterns they build up. Moreover, we will extend cell population models of contemporary systems biology, towards biomineralization kinetics,in
order to quantify evolutions of bone mass and composition in living organisms. When using these evolutions as input for the aforementioned micromechanics models, the latter will predict the mechanical implications of biological processes. This will open unprecedented avenues in bone disease therapies, including patient-specific bone fracture risk assessment relying on micromechanics-based Finite Element analyses."
Summary
"Modern computational engineering science allows for reliable design of the most breathtaking high-rise buildings, but it has hardly entered the fracture risk assessment of biological structures like bones. Is it only an engineering scientist's dream to decipher mathematically the origins and the evolution of the astonishingly varying mechanical properties of hierarchical biological materials? Not quite: By means of micromechanical theories, we could recently show in a quantitative fashion how ""universal"" elementary building blocks (being independent of tissue type, species, age, or anatomical location) govern the elastic properties of bone materials across the entire vertebrate kingdom, from the super-molecular to the centimetre scale. Now is the time to drive forward these developments beyond elasticity, striving for scientific breakthroughs in multiscale bone strength. Through novel, experimentally validated micromechanical theories, we will aim at predicting tissue-specific inelastic
properties of bone materials, from the ""universal"" mechanical properties of the nanoscaled elementary components (hydroxyapatite, collagen, water), their tissue-specific dosages, and the ""universal"" organizational patterns they build up. Moreover, we will extend cell population models of contemporary systems biology, towards biomineralization kinetics,in
order to quantify evolutions of bone mass and composition in living organisms. When using these evolutions as input for the aforementioned micromechanics models, the latter will predict the mechanical implications of biological processes. This will open unprecedented avenues in bone disease therapies, including patient-specific bone fracture risk assessment relying on micromechanics-based Finite Element analyses."
Max ERC Funding
1 493 399 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym PhytoTrace
Project Wanted: Micronutrients! Phytosiderophore-mediated acquisition strategies in grass crops
Researcher (PI) Eva OBURGER
Host Institution (HI) UNIVERSITAET FUER BODENKULTUR WIEN
Call Details Starting Grant (StG), LS9, ERC-2018-STG
Summary Understanding how plants respond to micronutrient deficiency and which biogeochemical processes are induced at the root-soil interface, i.e. the rhizosphere, is crucial to improve crop yield and micronutrient grain content for high quality food and feed. Iron nutrition by grass species relies on the release and re-uptake of phytosiderophores, which are root exudates that form stable complexes with Fe but also other trace metals such as Zn and Cu. However, neither the importance of phytosiderophores under Zn and Cu deficient conditions nor the interplay of plant responses and rhizosphere processes are well understood as the majority of studies in the past was carried out under ‘soil-free’ hydroponic conditions. In this project, I aim to elucidate the mechanisms controlling phytosiderophore-mediated micronutrient acquisition of barley (Hordeum vulgare) under Zn, Cu, and as reference, Fe deficient conditions, with particular emphasis on soil environments. Barley is the fifth most produced crop worldwide and of great importance in regions that are characterized by harsh living conditions. In a holistic approach, my team and I will apply innovative soil-based and traditional hydroponic root exudation sampling approaches in combination with advanced plant molecular techniques to study the phytosiderophore release and uptake system under different experimental conditions. The chemical synthesis of otherwise commercially unavailable phytosiderophores in their natural and 13C-labelled form will allow us to trace their decomposition and metal solubilizing efficiency in the plant-microbe-soil system to uncover the interplay of plant genetic responses and rhizosphere processes affecting the time-window of PS-mediated MN acquisition. Moving beyond ‘soil-free’ experimental designs of the past, this project will generate key knowledge to improve selection of crops with highly efficient micronutrient acquisition traits to alleviate micronutrient malnutrition of people world-wide.
Summary
Understanding how plants respond to micronutrient deficiency and which biogeochemical processes are induced at the root-soil interface, i.e. the rhizosphere, is crucial to improve crop yield and micronutrient grain content for high quality food and feed. Iron nutrition by grass species relies on the release and re-uptake of phytosiderophores, which are root exudates that form stable complexes with Fe but also other trace metals such as Zn and Cu. However, neither the importance of phytosiderophores under Zn and Cu deficient conditions nor the interplay of plant responses and rhizosphere processes are well understood as the majority of studies in the past was carried out under ‘soil-free’ hydroponic conditions. In this project, I aim to elucidate the mechanisms controlling phytosiderophore-mediated micronutrient acquisition of barley (Hordeum vulgare) under Zn, Cu, and as reference, Fe deficient conditions, with particular emphasis on soil environments. Barley is the fifth most produced crop worldwide and of great importance in regions that are characterized by harsh living conditions. In a holistic approach, my team and I will apply innovative soil-based and traditional hydroponic root exudation sampling approaches in combination with advanced plant molecular techniques to study the phytosiderophore release and uptake system under different experimental conditions. The chemical synthesis of otherwise commercially unavailable phytosiderophores in their natural and 13C-labelled form will allow us to trace their decomposition and metal solubilizing efficiency in the plant-microbe-soil system to uncover the interplay of plant genetic responses and rhizosphere processes affecting the time-window of PS-mediated MN acquisition. Moving beyond ‘soil-free’ experimental designs of the past, this project will generate key knowledge to improve selection of crops with highly efficient micronutrient acquisition traits to alleviate micronutrient malnutrition of people world-wide.
Max ERC Funding
1 498 628 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
