Project acronym 2O2ACTIVATION
Project Development of Direct Dehydrogenative Couplings mediated by Dioxygen
Researcher (PI) Frederic William Patureau
Host Institution (HI) RHEINISCH-WESTFAELISCHE TECHNISCHE HOCHSCHULE AACHEN
Country Germany
Call Details Starting Grant (StG), PE5, ERC-2016-STG
Summary The field of C-H bond activation has evolved at an exponential pace in the last 15 years. What appeals most in those novel synthetic techniques is clear: they bypass the pre-activation steps usually required in traditional cross-coupling chemistry by directly metalating C-H bonds. Many C-H bond functionalizations today however, rely on poorly atom and step efficient oxidants, leading to significant and costly chemical waste, thereby seriously undermining the overall sustainability of those methods. As restrictions in sustainability regulations will further increase, and the cost of certain chemical commodities will rise, atom efficiency in organic synthesis remains a top priority for research.
The aim of 2O2ACTIVATION is to develop novel technologies utilizing O2 as sole terminal oxidant in order to allow useful, extremely sustainable, thermodynamically challenging, dehydrogenative C-N and C-O bond forming coupling reactions. However, the moderate reactivity of O2 towards many catalysts constitutes a major challenge. 2O2ACTIVATION will pioneer the design of new catalysts based on the ultra-simple propene motive, capable of direct activation of O2 for C-H activation based cross-couplings. The project is divided into 3 major lines: O2 activation using propene and its analogues (propenoids), 1) without metal or halide, 2) with hypervalent halide catalysis, 3) with metal catalyzed C-H activation.
The philosophy of 2O2ACTIVATION is to focus C-H functionalization method development on the oxidative event.
Consequently, 2O2ACTIVATION breakthroughs will dramatically shortcut synthetic routes through the use of inactivated, unprotected, and readily available building blocks; and thus should be easily scalable. This will lead to a strong decrease in the costs related to the production of many essential chemicals, while preserving the environment (water as terminal by-product). The resulting novels coupling methods will thus have a lasting impact on the chemical industry.
Summary
The field of C-H bond activation has evolved at an exponential pace in the last 15 years. What appeals most in those novel synthetic techniques is clear: they bypass the pre-activation steps usually required in traditional cross-coupling chemistry by directly metalating C-H bonds. Many C-H bond functionalizations today however, rely on poorly atom and step efficient oxidants, leading to significant and costly chemical waste, thereby seriously undermining the overall sustainability of those methods. As restrictions in sustainability regulations will further increase, and the cost of certain chemical commodities will rise, atom efficiency in organic synthesis remains a top priority for research.
The aim of 2O2ACTIVATION is to develop novel technologies utilizing O2 as sole terminal oxidant in order to allow useful, extremely sustainable, thermodynamically challenging, dehydrogenative C-N and C-O bond forming coupling reactions. However, the moderate reactivity of O2 towards many catalysts constitutes a major challenge. 2O2ACTIVATION will pioneer the design of new catalysts based on the ultra-simple propene motive, capable of direct activation of O2 for C-H activation based cross-couplings. The project is divided into 3 major lines: O2 activation using propene and its analogues (propenoids), 1) without metal or halide, 2) with hypervalent halide catalysis, 3) with metal catalyzed C-H activation.
The philosophy of 2O2ACTIVATION is to focus C-H functionalization method development on the oxidative event.
Consequently, 2O2ACTIVATION breakthroughs will dramatically shortcut synthetic routes through the use of inactivated, unprotected, and readily available building blocks; and thus should be easily scalable. This will lead to a strong decrease in the costs related to the production of many essential chemicals, while preserving the environment (water as terminal by-product). The resulting novels coupling methods will thus have a lasting impact on the chemical industry.
Max ERC Funding
1 489 823 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym 3D_Tryps
Project The role of three-dimensional genome architecture in antigenic variation
Researcher (PI) Tim Nicolai SIEGEL
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Country Germany
Call Details Starting Grant (StG), LS6, ERC-2016-STG
Summary Antigenic variation is a widely employed strategy to evade the host immune response. It has similar functional requirements even in evolutionarily divergent pathogens. These include the mutually exclusive expression of antigens and the periodic, nonrandom switching in the expression of different antigens during the course of an infection. Despite decades of research the mechanisms of antigenic variation are not fully understood in any organism.
The recent development of high-throughput sequencing-based assays to probe the 3D genome architecture (Hi-C) has revealed the importance of the spatial organization of DNA inside the nucleus. 3D genome architecture plays a critical role in the regulation of mutually exclusive gene expression and the frequency of translocation between different genomic loci in many eukaryotes. Thus, genome architecture may also be a key regulator of antigenic variation, yet the causal links between genome architecture and the expression of antigens have not been studied systematically. In addition, the development of CRISPR-Cas9-based approaches to perform nucleotide-specific genome editing has opened unprecedented opportunities to study the influence of DNA sequence elements on the spatial organization of DNA and how this impacts antigen expression.
I have adapted both Hi-C and CRISPR-Cas9 technology to the protozoan parasite Trypanosoma brucei, one of the most important model organisms to study antigenic variation. These techniques will enable me to bridge the field of antigenic variation research with that of genome architecture. I will perform the first systematic analysis of the role of genome architecture in the mutually exclusive and hierarchical expression of antigens in any pathogen.
The experiments outlined in this proposal will provide new insight, facilitating a new view of antigenic variation and may eventually help medical intervention in T. brucei and in other pathogens relying on antigenic variation for their survival.
Summary
Antigenic variation is a widely employed strategy to evade the host immune response. It has similar functional requirements even in evolutionarily divergent pathogens. These include the mutually exclusive expression of antigens and the periodic, nonrandom switching in the expression of different antigens during the course of an infection. Despite decades of research the mechanisms of antigenic variation are not fully understood in any organism.
The recent development of high-throughput sequencing-based assays to probe the 3D genome architecture (Hi-C) has revealed the importance of the spatial organization of DNA inside the nucleus. 3D genome architecture plays a critical role in the regulation of mutually exclusive gene expression and the frequency of translocation between different genomic loci in many eukaryotes. Thus, genome architecture may also be a key regulator of antigenic variation, yet the causal links between genome architecture and the expression of antigens have not been studied systematically. In addition, the development of CRISPR-Cas9-based approaches to perform nucleotide-specific genome editing has opened unprecedented opportunities to study the influence of DNA sequence elements on the spatial organization of DNA and how this impacts antigen expression.
I have adapted both Hi-C and CRISPR-Cas9 technology to the protozoan parasite Trypanosoma brucei, one of the most important model organisms to study antigenic variation. These techniques will enable me to bridge the field of antigenic variation research with that of genome architecture. I will perform the first systematic analysis of the role of genome architecture in the mutually exclusive and hierarchical expression of antigens in any pathogen.
The experiments outlined in this proposal will provide new insight, facilitating a new view of antigenic variation and may eventually help medical intervention in T. brucei and in other pathogens relying on antigenic variation for their survival.
Max ERC Funding
1 498 175 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym 5D Heart Patch
Project A Functional, Mature In vivo Human Ventricular Muscle Patch for Cardiomyopathy
Researcher (PI) Kenneth Randall Chien
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy
Summary
Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy
Max ERC Funding
2 149 228 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
Project acronym AAA
Project Adaptive Actin Architectures
Researcher (PI) Laurent Blanchoin
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Advanced Grant (AdG), LS3, ERC-2016-ADG
Summary Although we have extensive knowledge of many important processes in cell biology, including information on many of the molecules involved and the physical interactions among them, we still do not understand most of the dynamical features that are the essence of living systems. This is particularly true for the actin cytoskeleton, a major component of the internal architecture of eukaryotic cells. In living cells, actin networks constantly assemble and disassemble filaments while maintaining an apparent stable structure, suggesting a perfect balance between the two processes. Such behaviors are called “dynamic steady states”. They confer upon actin networks a high degree of plasticity allowing them to adapt in response to external changes and enable cells to adjust to their environments. Despite their fundamental importance in the regulation of cell physiology, the basic mechanisms that control the coordinated dynamics of co-existing actin networks are poorly understood. In the AAA project, first, we will characterize the parameters that allow the coupling among co-existing actin networks at steady state. In vitro reconstituted systems will be used to control the actin nucleation patterns, the closed volume of the reaction chamber and the physical interaction of the networks. We hope to unravel the mechanism allowing the global coherence of a dynamic actin cytoskeleton. Second, we will use our unique capacity to perform dynamic micropatterning, to add or remove actin nucleation sites in real time, in order to investigate the ability of dynamic networks to adapt to changes and the role of coupled network dynamics in this emergent property. In this part, in vitro experiments will be complemented by the analysis of actin network remodeling in living cells. In the end, our project will provide a comprehensive understanding of how the adaptive response of the cytoskeleton derives from the complex interplay between its biochemical, structural and mechanical properties.
Summary
Although we have extensive knowledge of many important processes in cell biology, including information on many of the molecules involved and the physical interactions among them, we still do not understand most of the dynamical features that are the essence of living systems. This is particularly true for the actin cytoskeleton, a major component of the internal architecture of eukaryotic cells. In living cells, actin networks constantly assemble and disassemble filaments while maintaining an apparent stable structure, suggesting a perfect balance between the two processes. Such behaviors are called “dynamic steady states”. They confer upon actin networks a high degree of plasticity allowing them to adapt in response to external changes and enable cells to adjust to their environments. Despite their fundamental importance in the regulation of cell physiology, the basic mechanisms that control the coordinated dynamics of co-existing actin networks are poorly understood. In the AAA project, first, we will characterize the parameters that allow the coupling among co-existing actin networks at steady state. In vitro reconstituted systems will be used to control the actin nucleation patterns, the closed volume of the reaction chamber and the physical interaction of the networks. We hope to unravel the mechanism allowing the global coherence of a dynamic actin cytoskeleton. Second, we will use our unique capacity to perform dynamic micropatterning, to add or remove actin nucleation sites in real time, in order to investigate the ability of dynamic networks to adapt to changes and the role of coupled network dynamics in this emergent property. In this part, in vitro experiments will be complemented by the analysis of actin network remodeling in living cells. In the end, our project will provide a comprehensive understanding of how the adaptive response of the cytoskeleton derives from the complex interplay between its biochemical, structural and mechanical properties.
Max ERC Funding
2 349 898 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym ACCENT
Project Unravelling the architecture and the cartography of the human centriole
Researcher (PI) Paul, Philippe, Desire GUICHARD
Host Institution (HI) UNIVERSITE DE GENEVE
Country Switzerland
Call Details Starting Grant (StG), LS1, ERC-2016-STG
Summary The centriole is the largest evolutionary conserved macromolecular structure responsible for building centrosomes and cilia or flagella in many eukaryotes. Centrioles are critical for the proper execution of important biological processes ranging from cell division to cell signaling. Moreover, centriolar defects have been associated to several human pathologies including ciliopathies and cancer. This state of facts emphasizes the importance of understanding centriole biogenesis. The study of centriole formation is a deep-rooted question, however our current knowledge on its molecular organization at high resolution remains fragmented and limited. In particular, exquisite details of the overall molecular architecture of the human centriole and in particular of its central core region are lacking to understand the basis of centriole organization and function. Resolving this important question represents a challenge that needs to be undertaken and will undoubtedly lead to groundbreaking advances. Another important question to tackle next is to develop innovative methods to enable the nanometric molecular mapping of centriolar proteins within distinct architectural elements of the centriole. This missing information will be key to unravel the molecular mechanisms behind centriolar organization.
This research proposal aims at building a cartography of the human centriole by elucidating its molecular composition and architecture. To this end, we will combine the use of innovative and multidisciplinary techniques encompassing spatial proteomics, cryo-electron tomography, state-of-the-art microscopy and in vitro assays and to achieve a comprehensive molecular and structural view of the human centriole. All together, we expect that these advances will help understand basic principles underlying centriole and cilia formation as well as might have further relevance for human health.
Summary
The centriole is the largest evolutionary conserved macromolecular structure responsible for building centrosomes and cilia or flagella in many eukaryotes. Centrioles are critical for the proper execution of important biological processes ranging from cell division to cell signaling. Moreover, centriolar defects have been associated to several human pathologies including ciliopathies and cancer. This state of facts emphasizes the importance of understanding centriole biogenesis. The study of centriole formation is a deep-rooted question, however our current knowledge on its molecular organization at high resolution remains fragmented and limited. In particular, exquisite details of the overall molecular architecture of the human centriole and in particular of its central core region are lacking to understand the basis of centriole organization and function. Resolving this important question represents a challenge that needs to be undertaken and will undoubtedly lead to groundbreaking advances. Another important question to tackle next is to develop innovative methods to enable the nanometric molecular mapping of centriolar proteins within distinct architectural elements of the centriole. This missing information will be key to unravel the molecular mechanisms behind centriolar organization.
This research proposal aims at building a cartography of the human centriole by elucidating its molecular composition and architecture. To this end, we will combine the use of innovative and multidisciplinary techniques encompassing spatial proteomics, cryo-electron tomography, state-of-the-art microscopy and in vitro assays and to achieve a comprehensive molecular and structural view of the human centriole. All together, we expect that these advances will help understand basic principles underlying centriole and cilia formation as well as might have further relevance for human health.
Max ERC Funding
1 498 965 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym ACETOGENS
Project Acetogenic bacteria: from basic physiology via gene regulation to application in industrial biotechnology
Researcher (PI) Volker MueLLER
Host Institution (HI) JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN
Country Germany
Call Details Advanced Grant (AdG), LS9, ERC-2016-ADG
Summary Demand for biofuels and other biologically derived commodities is growing worldwide as efforts increase to reduce reliance on fossil fuels and to limit climate change. Most commercial approaches rely on fermentations of organic matter with its inherent problems in producing CO2 and being in conflict with the food supply of humans. These problems are avoided if CO2 can be used as feedstock. Autotrophic organisms can fix CO2 by producing chemicals that are used as building blocks for the synthesis of cellular components (Biomass). Acetate-forming bacteria (acetogens) do neither require light nor oxygen for this and they can be used in bioreactors to reduce CO2 with hydrogen gas, carbon monoxide or an organic substrate. Gas fermentation using these bacteria has already been realized on an industrial level in two pre-commercial 100,000 gal/yr demonstration facilities to produce fuel ethanol from abundant waste gas resources (by LanzaTech). Acetogens can metabolise a wide variety of substrates that could be used for the production of biocommodities. However, their broad use to produce biofuels and platform chemicals from substrates other than gases or together with gases is hampered by our very limited knowledge about their metabolism and ability to use different substrates simultaneously. Nearly nothing is known about regulatory processes involved in substrate utilization or product formation but this is an absolute requirement for metabolic engineering approaches. The aim of this project is to provide this basic knowledge about metabolic routes in the acetogenic model strain Acetobacterium woodii and their regulation. We will unravel the function of “organelles” found in this bacterium and explore their potential as bio-nanoreactors for the production of biocommodities and pave the road for the industrial use of A. woodii in energy (hydrogen) storage. Thus, this project creates cutting-edge opportunities for the development of biosustainable technologies in Europe.
Summary
Demand for biofuels and other biologically derived commodities is growing worldwide as efforts increase to reduce reliance on fossil fuels and to limit climate change. Most commercial approaches rely on fermentations of organic matter with its inherent problems in producing CO2 and being in conflict with the food supply of humans. These problems are avoided if CO2 can be used as feedstock. Autotrophic organisms can fix CO2 by producing chemicals that are used as building blocks for the synthesis of cellular components (Biomass). Acetate-forming bacteria (acetogens) do neither require light nor oxygen for this and they can be used in bioreactors to reduce CO2 with hydrogen gas, carbon monoxide or an organic substrate. Gas fermentation using these bacteria has already been realized on an industrial level in two pre-commercial 100,000 gal/yr demonstration facilities to produce fuel ethanol from abundant waste gas resources (by LanzaTech). Acetogens can metabolise a wide variety of substrates that could be used for the production of biocommodities. However, their broad use to produce biofuels and platform chemicals from substrates other than gases or together with gases is hampered by our very limited knowledge about their metabolism and ability to use different substrates simultaneously. Nearly nothing is known about regulatory processes involved in substrate utilization or product formation but this is an absolute requirement for metabolic engineering approaches. The aim of this project is to provide this basic knowledge about metabolic routes in the acetogenic model strain Acetobacterium woodii and their regulation. We will unravel the function of “organelles” found in this bacterium and explore their potential as bio-nanoreactors for the production of biocommodities and pave the road for the industrial use of A. woodii in energy (hydrogen) storage. Thus, this project creates cutting-edge opportunities for the development of biosustainable technologies in Europe.
Max ERC Funding
2 497 140 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym ADJUV-ANT VACCINES
Project Elucidating the Molecular Mechanisms of Synthetic Saponin Adjuvants and Development of Novel Self-Adjuvanting Vaccines
Researcher (PI) Alberto FERNANDEZ TEJADA
Host Institution (HI) ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOCIENCIAS
Country Spain
Call Details Starting Grant (StG), PE5, ERC-2016-STG
Summary The clinical success of anticancer and antiviral vaccines often requires the use of an adjuvant, a substance that helps stimulate the body’s immune response to the vaccine, making it work better. However, few adjuvants are sufficiently potent and non-toxic for clinical use; moreover, it is not really known how they work. Current vaccine approaches based on weak carbohydrate and glycopeptide antigens are not being particularly effective to induce the human immune system to mount an effective fight against cancer. Despite intensive research and several clinical trials, no such carbohydrate-based antitumor vaccine has yet been approved for public use. In this context, the proposed project has a double, ultimate goal based on applying chemistry to address the above clear gaps in the adjuvant-vaccine field. First, I will develop new improved adjuvants and novel chemical strategies towards more effective, self-adjuvanting synthetic vaccines. Second, I will probe deeply into the molecular mechanisms of the synthetic constructs by combining extensive immunological evaluations with molecular target identification and detailed conformational studies. Thus, the singularity of this multidisciplinary proposal stems from the integration of its main objectives and approaches connecting chemical synthesis and chemical/structural biology with cellular and molecular immunology. This ground-breaking project at the chemistry-biology frontier will allow me to establish my own independent research group and explore key unresolved mechanistic questions in the adjuvant/vaccine arena with extraordinary chemical precision. Therefore, with this transformative and timely research program I aim to (a) develop novel synthetic antitumor and antiviral vaccines with improved properties and efficacy for their prospective translation into the clinic and (b) gain new critical insights into the molecular basis and three-dimensional structure underlying the biological activity of these constructs.
Summary
The clinical success of anticancer and antiviral vaccines often requires the use of an adjuvant, a substance that helps stimulate the body’s immune response to the vaccine, making it work better. However, few adjuvants are sufficiently potent and non-toxic for clinical use; moreover, it is not really known how they work. Current vaccine approaches based on weak carbohydrate and glycopeptide antigens are not being particularly effective to induce the human immune system to mount an effective fight against cancer. Despite intensive research and several clinical trials, no such carbohydrate-based antitumor vaccine has yet been approved for public use. In this context, the proposed project has a double, ultimate goal based on applying chemistry to address the above clear gaps in the adjuvant-vaccine field. First, I will develop new improved adjuvants and novel chemical strategies towards more effective, self-adjuvanting synthetic vaccines. Second, I will probe deeply into the molecular mechanisms of the synthetic constructs by combining extensive immunological evaluations with molecular target identification and detailed conformational studies. Thus, the singularity of this multidisciplinary proposal stems from the integration of its main objectives and approaches connecting chemical synthesis and chemical/structural biology with cellular and molecular immunology. This ground-breaking project at the chemistry-biology frontier will allow me to establish my own independent research group and explore key unresolved mechanistic questions in the adjuvant/vaccine arena with extraordinary chemical precision. Therefore, with this transformative and timely research program I aim to (a) develop novel synthetic antitumor and antiviral vaccines with improved properties and efficacy for their prospective translation into the clinic and (b) gain new critical insights into the molecular basis and three-dimensional structure underlying the biological activity of these constructs.
Max ERC Funding
1 499 219 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym AgeConsolidate
Project The Missing Link of Episodic Memory Decline in Aging: The Role of Inefficient Systems Consolidation
Researcher (PI) Anders Martin FJELL
Host Institution (HI) UNIVERSITETET I OSLO
Country Norway
Call Details Consolidator Grant (CoG), SH4, ERC-2016-COG
Summary Which brain mechanisms are responsible for the faith of the memories we make with age, whether they wither or stay, and in what form? Episodic memory function does decline with age. While this decline can have multiple causes, research has focused almost entirely on encoding and retrieval processes, largely ignoring a third critical process– consolidation. The objective of AgeConsolidate is to provide this missing link, by combining novel experimental cognitive paradigms with neuroimaging in a longitudinal large-scale attempt to directly test how age-related changes in consolidation processes in the brain impact episodic memory decline. The ambitious aims of the present proposal are two-fold:
(1) Use recent advances in memory consolidation theory to achieve an elaborate model of episodic memory deficits in aging
(2) Use aging as a model to uncover how structural and functional brain changes affect episodic memory consolidation in general
The novelty of the project lies in the synthesis of recent methodological advances and theoretical models for episodic memory consolidation to explain age-related decline, by employing a unique combination of a range of different techniques and approaches. This is ground-breaking, in that it aims at taking our understanding of the brain processes underlying episodic memory decline in aging to a new level, while at the same time advancing our theoretical understanding of how episodic memories are consolidated in the human brain. To obtain this outcome, I will test the main hypothesis of the project: Brain processes of episodic memory consolidation are less effective in older adults, and this can account for a significant portion of the episodic memory decline in aging. This will be answered by six secondary hypotheses, with 1-3 experiments or tasks designated to address each hypothesis, focusing on functional and structural MRI, positron emission tomography data and sleep experiments to target consolidation from different angles.
Summary
Which brain mechanisms are responsible for the faith of the memories we make with age, whether they wither or stay, and in what form? Episodic memory function does decline with age. While this decline can have multiple causes, research has focused almost entirely on encoding and retrieval processes, largely ignoring a third critical process– consolidation. The objective of AgeConsolidate is to provide this missing link, by combining novel experimental cognitive paradigms with neuroimaging in a longitudinal large-scale attempt to directly test how age-related changes in consolidation processes in the brain impact episodic memory decline. The ambitious aims of the present proposal are two-fold:
(1) Use recent advances in memory consolidation theory to achieve an elaborate model of episodic memory deficits in aging
(2) Use aging as a model to uncover how structural and functional brain changes affect episodic memory consolidation in general
The novelty of the project lies in the synthesis of recent methodological advances and theoretical models for episodic memory consolidation to explain age-related decline, by employing a unique combination of a range of different techniques and approaches. This is ground-breaking, in that it aims at taking our understanding of the brain processes underlying episodic memory decline in aging to a new level, while at the same time advancing our theoretical understanding of how episodic memories are consolidated in the human brain. To obtain this outcome, I will test the main hypothesis of the project: Brain processes of episodic memory consolidation are less effective in older adults, and this can account for a significant portion of the episodic memory decline in aging. This will be answered by six secondary hypotheses, with 1-3 experiments or tasks designated to address each hypothesis, focusing on functional and structural MRI, positron emission tomography data and sleep experiments to target consolidation from different angles.
Max ERC Funding
1 999 482 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym AlCat
Project Bond activation and catalysis with low-valent aluminium
Researcher (PI) Michael James COWLEY
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Country United Kingdom
Call Details Starting Grant (StG), PE5, ERC-2016-STG
Summary This project will develop the principles required to enable bond-modifying redox catalysis based on aluminium by preparing and studying new Al(I) compounds capable of reversible oxidative addition.
Catalytic processes are involved in the synthesis of 75 % of all industrially produced chemicals, but most catalysts involved are based on precious metals such as rhodium, palladium or platinum. These metals are expensive and their supply limited and unstable; there is a significant need to develop the chemistry of non-precious metals as alternatives. On toxicity and abundance alone, aluminium is an attractive candidate. Furthermore, recent work, including in our group, has demonstrated that Al(I) compounds can perform a key step in catalytic cycles - the oxidative addition of E-H bonds.
In order to realise the significant potential of Al(I) for transition-metal style catalysis we urgently need to:
- establish the principles governing oxidative addition and reductive elimination reactivity in aluminium systems.
- know how the reactivity of Al(I) compounds can be controlled by varying properties of ligand frameworks.
- understand the onward reactivity of oxidative addition products of Al(I) to enable applications in catalysis.
In this project we will:
- Study mechanisms of oxidative addition and reductive elimination of a range of synthetically relevant bonds at Al(I) centres, establishing the principles governing this fundamental reactivity.
- Develop new ligand frameworks to support of Al(I) centres and evaluate the effect of the ligand on oxidative addition/reductive elimination at Al centres.
- Investigate methods for Al-mediated functionalisation of organic compounds by exploring the reactivity of E-H oxidative addition products with unsaturated organic compounds.
Summary
This project will develop the principles required to enable bond-modifying redox catalysis based on aluminium by preparing and studying new Al(I) compounds capable of reversible oxidative addition.
Catalytic processes are involved in the synthesis of 75 % of all industrially produced chemicals, but most catalysts involved are based on precious metals such as rhodium, palladium or platinum. These metals are expensive and their supply limited and unstable; there is a significant need to develop the chemistry of non-precious metals as alternatives. On toxicity and abundance alone, aluminium is an attractive candidate. Furthermore, recent work, including in our group, has demonstrated that Al(I) compounds can perform a key step in catalytic cycles - the oxidative addition of E-H bonds.
In order to realise the significant potential of Al(I) for transition-metal style catalysis we urgently need to:
- establish the principles governing oxidative addition and reductive elimination reactivity in aluminium systems.
- know how the reactivity of Al(I) compounds can be controlled by varying properties of ligand frameworks.
- understand the onward reactivity of oxidative addition products of Al(I) to enable applications in catalysis.
In this project we will:
- Study mechanisms of oxidative addition and reductive elimination of a range of synthetically relevant bonds at Al(I) centres, establishing the principles governing this fundamental reactivity.
- Develop new ligand frameworks to support of Al(I) centres and evaluate the effect of the ligand on oxidative addition/reductive elimination at Al centres.
- Investigate methods for Al-mediated functionalisation of organic compounds by exploring the reactivity of E-H oxidative addition products with unsaturated organic compounds.
Max ERC Funding
1 493 679 €
Duration
Start date: 2017-03-01, End date: 2022-08-31
Project acronym ALFA
Project Shaping a European Scientific Scene : Alfonsine Astronomy
Researcher (PI) Matthieu Husson
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Consolidator Grant (CoG), SH6, ERC-2016-COG
Summary Alfonsine astronomy is arguably among the first European scientific achievements. It shaped a scene for actors like Regiomontanus or Copernicus. There is however little detailed historical analysis encompassing its development in its full breadth. ALFA addresses this issue by studying tables, instruments, mathematical and theoretical texts in a methodologically innovative way relying on approaches from the history of manuscript cultures, history of mathematics, and history of astronomy.
ALFA integrates these approaches not only to benefit from different perspectives but also to build new questions from their interactions. For instance the analysis of mathematical practices in astral sciences manuscripts induces new ways to analyse the documents and to think about astronomical questions.
Relying on these approaches the main objectives of ALFA are thus to:
- Retrace the development of the corpus of Alfonsine texts from its origin in the second half of the 13th century to the end of the 15th century by following, on the manuscript level, the milieus fostering it;
- Analyse the Alfonsine astronomers’ practices, their relations to mathematics, to the natural world, to proofs and justification, their intellectual context and audiences;
- Build a meaningful narrative showing how astronomers in different milieus with diverse practices shaped, also from Arabic materials, an original scientific scene in Europe.
ALFA will shed new light on the intellectual history of the late medieval period as a whole and produce a better understanding of its relations to related scientific periods in Europe and beyond. It will also produce methodological breakthroughs impacting the ways history of knowledge is practiced outside the field of ancient and medieval sciences. Efforts will be devoted to bring these results not only to the relevant scholarly communities but also to a wider audience as a resource in the public debates around science, knowledge and culture.
Summary
Alfonsine astronomy is arguably among the first European scientific achievements. It shaped a scene for actors like Regiomontanus or Copernicus. There is however little detailed historical analysis encompassing its development in its full breadth. ALFA addresses this issue by studying tables, instruments, mathematical and theoretical texts in a methodologically innovative way relying on approaches from the history of manuscript cultures, history of mathematics, and history of astronomy.
ALFA integrates these approaches not only to benefit from different perspectives but also to build new questions from their interactions. For instance the analysis of mathematical practices in astral sciences manuscripts induces new ways to analyse the documents and to think about astronomical questions.
Relying on these approaches the main objectives of ALFA are thus to:
- Retrace the development of the corpus of Alfonsine texts from its origin in the second half of the 13th century to the end of the 15th century by following, on the manuscript level, the milieus fostering it;
- Analyse the Alfonsine astronomers’ practices, their relations to mathematics, to the natural world, to proofs and justification, their intellectual context and audiences;
- Build a meaningful narrative showing how astronomers in different milieus with diverse practices shaped, also from Arabic materials, an original scientific scene in Europe.
ALFA will shed new light on the intellectual history of the late medieval period as a whole and produce a better understanding of its relations to related scientific periods in Europe and beyond. It will also produce methodological breakthroughs impacting the ways history of knowledge is practiced outside the field of ancient and medieval sciences. Efforts will be devoted to bring these results not only to the relevant scholarly communities but also to a wider audience as a resource in the public debates around science, knowledge and culture.
Max ERC Funding
1 871 250 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
