Project acronym BioCircuit
Project Programmable BioMolecular Circuits: Emulating Regulatory Functions in Living Cells Using a Bottom-Up Approach
Researcher (PI) Tom Antonius Franciscus De greef
Host Institution (HI) TECHNISCHE UNIVERSITEIT EINDHOVEN
Call Details Starting Grant (StG), PE4, ERC-2015-STG
Summary Programmable biomolecular circuits have received increasing attention in recent years as the scope of chemistry expands from the synthesis of individual molecules to the construction of chemical networks that can perform sophisticated functions such as logic operations and feedback control. Rationally engineered biomolecular circuits that robustly execute higher-order spatiotemporal behaviours typically associated with intracellular regulatory functions present a unique and uncharted platform to systematically explore the molecular logic and physical design principles of the cell. The experience gained by in-vitro construction of artificial cells displaying advanced system-level functions deepens our understanding of regulatory networks in living cells and allows theoretical assumptions and models to be refined in a controlled setting. This proposal combines elements from systems chemistry, in-vitro synthetic biology and micro-engineering and explores generic strategies to investigate the molecular logic of biology’s regulatory circuits by applying a physical chemistry-driven bottom-up approach. Progress in this field requires 1) proof-of-principle systems where in-vitro biomolecular circuits are designed to emulate characteristic system-level functions of regulatory circuits in living cells and 2) novel experimental tools to operate biochemical networks under out-of-equilibrium conditions. Here, a comprehensive research program is proposed that addresses these challenges by engineering three biochemical model systems that display elementary signal transduction and information processing capabilities. In addition, an open microfluidic droplet reactor is developed that will allow, for the first time, high-throughput analysis of biomolecular circuits encapsulated in water-in-oil droplets. An integral part of the research program is to combine the computational design of in-vitro circuits with novel biochemistry and innovative micro-engineering tools.
Summary
Programmable biomolecular circuits have received increasing attention in recent years as the scope of chemistry expands from the synthesis of individual molecules to the construction of chemical networks that can perform sophisticated functions such as logic operations and feedback control. Rationally engineered biomolecular circuits that robustly execute higher-order spatiotemporal behaviours typically associated with intracellular regulatory functions present a unique and uncharted platform to systematically explore the molecular logic and physical design principles of the cell. The experience gained by in-vitro construction of artificial cells displaying advanced system-level functions deepens our understanding of regulatory networks in living cells and allows theoretical assumptions and models to be refined in a controlled setting. This proposal combines elements from systems chemistry, in-vitro synthetic biology and micro-engineering and explores generic strategies to investigate the molecular logic of biology’s regulatory circuits by applying a physical chemistry-driven bottom-up approach. Progress in this field requires 1) proof-of-principle systems where in-vitro biomolecular circuits are designed to emulate characteristic system-level functions of regulatory circuits in living cells and 2) novel experimental tools to operate biochemical networks under out-of-equilibrium conditions. Here, a comprehensive research program is proposed that addresses these challenges by engineering three biochemical model systems that display elementary signal transduction and information processing capabilities. In addition, an open microfluidic droplet reactor is developed that will allow, for the first time, high-throughput analysis of biomolecular circuits encapsulated in water-in-oil droplets. An integral part of the research program is to combine the computational design of in-vitro circuits with novel biochemistry and innovative micro-engineering tools.
Max ERC Funding
1 887 180 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym BRISC
Project Bounded Rationality in Sensorimotor Coordination
Researcher (PI) Daniel Alexander Braun
Host Institution (HI) UNIVERSITAET ULM
Call Details Starting Grant (StG), SH4, ERC-2015-STG
Summary Despite their many successes and great computational power and speed, why are machines still so blatantly outperformed by humans in uncertain environments that require flexible sensorimotor behavior like playing football or navigating a disaster zone? Answering this question requires understanding the mathematical principles of biological sensorimotor control and learning. Over the recent years Bayes-optimal actor models have widely become the gold standard in the mathematical understanding of sensorimotor processing in well-controlled laboratory tasks. However, these models quickly become intractable for real-world problems because they ignore the computational effort required to search for the Bayes-optimum. What is therefore needed is a framework of sensorimotor processing that takes the limited information-processing capacity of bounded rational actors into account and that explains their robust real-world performance. It is the aim of BRISC to establish such a framework by drawing out theoretical predictions and gathering experimental evidence in human motor control, in particular to understand (i) how single bounded rational actors deviate from Bayes-optimal behavior in motor tasks, (ii) how multiple bounded rational actors organize themselves to solve motor tasks that no individual can solve by themselves and (iii) how this drives the emergence of hierarchical control structures that simultaneously process multiple degrees of abstraction at different time scales. Understanding how abstract concepts are formed autonomously from the sensorimotor stream based on resource allocation principles will establish an essential missing link between high-level symbolic and low-level perceptual processing. These advances will provide a decisive step towards a framework for robust and flexible sensorimotor processing, which is not only essential for understanding the fundamental principles of intelligent behavior, but it is also of potentially great technological value.
Summary
Despite their many successes and great computational power and speed, why are machines still so blatantly outperformed by humans in uncertain environments that require flexible sensorimotor behavior like playing football or navigating a disaster zone? Answering this question requires understanding the mathematical principles of biological sensorimotor control and learning. Over the recent years Bayes-optimal actor models have widely become the gold standard in the mathematical understanding of sensorimotor processing in well-controlled laboratory tasks. However, these models quickly become intractable for real-world problems because they ignore the computational effort required to search for the Bayes-optimum. What is therefore needed is a framework of sensorimotor processing that takes the limited information-processing capacity of bounded rational actors into account and that explains their robust real-world performance. It is the aim of BRISC to establish such a framework by drawing out theoretical predictions and gathering experimental evidence in human motor control, in particular to understand (i) how single bounded rational actors deviate from Bayes-optimal behavior in motor tasks, (ii) how multiple bounded rational actors organize themselves to solve motor tasks that no individual can solve by themselves and (iii) how this drives the emergence of hierarchical control structures that simultaneously process multiple degrees of abstraction at different time scales. Understanding how abstract concepts are formed autonomously from the sensorimotor stream based on resource allocation principles will establish an essential missing link between high-level symbolic and low-level perceptual processing. These advances will provide a decisive step towards a framework for robust and flexible sensorimotor processing, which is not only essential for understanding the fundamental principles of intelligent behavior, but it is also of potentially great technological value.
Max ERC Funding
1 434 250 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym BROKERS
Project Participatory Urban Governance between Democracy and Clientelism: Brokers and (In)formal Politics
Researcher (PI) Martijn Koster
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Starting Grant (StG), SH2, ERC-2015-STG
Summary The emergence of participatory governance has resulted in the delegation of governmental responsibilities to citizens. Individuals position themselves as voluntary mediators, or brokers, between the government and their fellow citizens. This research asks: what are the roles of such brokers in participatory urban governance, and how do they influence democratic governance? This study will investigate ethnographically how brokers position themselves in administrative schemes, and examine the formal and informal dimensions of their performance. It will analyse the practices, discourses and networks, both in and out of officially sanctioned channels and government institutions. The research approaches brokers as ‘assemblers’, connective agents who actively bring together different governmental and citizen actors, institutions and resources.
The scholarly debate on brokerage within participatory governance is divided into two different arguments: first, an argument about neoliberal deregulation located in the Global North, which encourages the practices of active citizen-mediators, and second, a modernization argument in the Global South, which sees brokers as remnants of a clientelist political system. This research will combine these arguments to study settings in both the North and the South. It employs a comparative urbanism design to study four cities that are recognized as pioneers in democratic participatory governance, two in the North and two in the South: Rotterdam (NL), Manchester (UK), Cochabamba (Bolivia) and Recife (Brazil).
This research builds upon theories from political anthropology, urban studies, citizenship studies and public administration to develop a new framework for analysing brokerage in participatory urban governance. Understanding how the formal and informal dimensions of participatory governance are entwined will contribute to our ability to theorize the conditions under which this type of governance can give rise to more democratic cities.
Summary
The emergence of participatory governance has resulted in the delegation of governmental responsibilities to citizens. Individuals position themselves as voluntary mediators, or brokers, between the government and their fellow citizens. This research asks: what are the roles of such brokers in participatory urban governance, and how do they influence democratic governance? This study will investigate ethnographically how brokers position themselves in administrative schemes, and examine the formal and informal dimensions of their performance. It will analyse the practices, discourses and networks, both in and out of officially sanctioned channels and government institutions. The research approaches brokers as ‘assemblers’, connective agents who actively bring together different governmental and citizen actors, institutions and resources.
The scholarly debate on brokerage within participatory governance is divided into two different arguments: first, an argument about neoliberal deregulation located in the Global North, which encourages the practices of active citizen-mediators, and second, a modernization argument in the Global South, which sees brokers as remnants of a clientelist political system. This research will combine these arguments to study settings in both the North and the South. It employs a comparative urbanism design to study four cities that are recognized as pioneers in democratic participatory governance, two in the North and two in the South: Rotterdam (NL), Manchester (UK), Cochabamba (Bolivia) and Recife (Brazil).
This research builds upon theories from political anthropology, urban studies, citizenship studies and public administration to develop a new framework for analysing brokerage in participatory urban governance. Understanding how the formal and informal dimensions of participatory governance are entwined will contribute to our ability to theorize the conditions under which this type of governance can give rise to more democratic cities.
Max ERC Funding
1 497 570 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym CAT
Project Climbing the Asian Water Tower
Researcher (PI) Wouter Willem Immerzeel
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Starting Grant (StG), PE10, ERC-2015-STG
Summary The water cycle in the Himalaya is poorly understood because of its extreme topography that results in complex interactions between climate and water stored in snow and glaciers. Hydrological extremes in the greater Himalayas regularly cause great damage, e.g. the Pakistan floods in 2010, while the Himalayas also supply water to over 25% of the global population. So, the stakes are high and an accurate understanding of the Himalayan water cycle is imperative. The discovery of the monumental error on the future of the Himalayan glaciers in the fourth assessment report of the IPCC is exemplary for the scientific misconceptions which are associated to the Himalayan glaciers and its water supplying function. The underlying reason is the huge scale gap that exists between studies for individual glaciers that are not representative of the entire region and hydrological modelling studies that represent the variability in Himalayan climates. In CAT, I will bridge this knowledge gap and explain spatial differences in Himalayan glacio-hydrology at an unprecedented level of detail by combining high-altitude observations, the latest remote sensing technology and state-of-the-art atmospheric and hydrological models. I will generate a high-altitude meteorological observations and will employ drones to monitor glacier dynamics. The data will be used to parameterize key processes in hydro-meteorological models such as cloud resolving mechanisms, glacier dynamics and the ice and snow energy balance. The results will be integrated into atmospheric and glacio-hyrological models for two representative, but contrasting catchments using in combination with the systematic inclusion of the newly developed algorithms. CAT will unambiguously reveal spatial differences in Himalayan glacio-hydrology necessary to project future changes in water availability and extreme events. As such, CAT may provide the scientific base for climate change adaptation policies in this vulnerable region.
Summary
The water cycle in the Himalaya is poorly understood because of its extreme topography that results in complex interactions between climate and water stored in snow and glaciers. Hydrological extremes in the greater Himalayas regularly cause great damage, e.g. the Pakistan floods in 2010, while the Himalayas also supply water to over 25% of the global population. So, the stakes are high and an accurate understanding of the Himalayan water cycle is imperative. The discovery of the monumental error on the future of the Himalayan glaciers in the fourth assessment report of the IPCC is exemplary for the scientific misconceptions which are associated to the Himalayan glaciers and its water supplying function. The underlying reason is the huge scale gap that exists between studies for individual glaciers that are not representative of the entire region and hydrological modelling studies that represent the variability in Himalayan climates. In CAT, I will bridge this knowledge gap and explain spatial differences in Himalayan glacio-hydrology at an unprecedented level of detail by combining high-altitude observations, the latest remote sensing technology and state-of-the-art atmospheric and hydrological models. I will generate a high-altitude meteorological observations and will employ drones to monitor glacier dynamics. The data will be used to parameterize key processes in hydro-meteorological models such as cloud resolving mechanisms, glacier dynamics and the ice and snow energy balance. The results will be integrated into atmospheric and glacio-hyrological models for two representative, but contrasting catchments using in combination with the systematic inclusion of the newly developed algorithms. CAT will unambiguously reveal spatial differences in Himalayan glacio-hydrology necessary to project future changes in water availability and extreme events. As such, CAT may provide the scientific base for climate change adaptation policies in this vulnerable region.
Max ERC Funding
1 499 631 €
Duration
Start date: 2016-02-01, End date: 2021-01-31
Project acronym CatASus
Project Cleave and couple: Fully sustainable catalytic conversion of renewable resources to amines
Researcher (PI) Katalin Barta Weissert
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Call Details Starting Grant (StG), PE5, ERC-2015-STG
Summary Amines are crucially important classes of chemicals, widely present in pharmaceuticals, agrochemicals and surfactants. Yet, surprisingly, a systematic approach to obtaining this essential class of compounds from renewables has not been realized to date.
The aim of this proposal is to enable chemical pathways for the production of amines through alcohols from renewable resources, preferably lignocellulose waste. Two key scientific challenges will be addressed: The development of efficient cleavage reactions of complex renewable resources by novel heterogeneous catalysts; and finding new homogeneous catalyst based on earth-abundant metals for the atom-economic coupling of the derived alcohol building blocks directly with ammonia as well as possible further functionalization reactions. The program is divided into 3 interrelated but not mutually dependent work packages, each research addressing a key challenge in their respective fields, these are:
WP1: Lignin conversion to aromatics; WP2: Cellulose-derived platform chemicals to aromatic and aliphatic diols and solvents. WP3: New iron-based homogeneous catalysts for the direct, atom-economic C-O to C-N transformations.
The approach taken will embrace the inherent complexity present in the renewable feedstock. A unique balance between cleavage and coupling pathways will allow to access chemical diversity in products that is necessary to achieve economic competitiveness with current fossil fuel-based pathways and will permit rapid conversion to higher value products such as functionalized amines that can enter the chemical supply chain at a much later stage than bulk chemicals derived from petroleum. The proposed high risk-high gain research will push the frontiers of sustainable and green chemistry and reach well beyond state of the art in this area. This universal, flexible and iterative approach is anticipated to give rise to a variety of similar systems targeting diverse product outcomes starting from renewables.
Summary
Amines are crucially important classes of chemicals, widely present in pharmaceuticals, agrochemicals and surfactants. Yet, surprisingly, a systematic approach to obtaining this essential class of compounds from renewables has not been realized to date.
The aim of this proposal is to enable chemical pathways for the production of amines through alcohols from renewable resources, preferably lignocellulose waste. Two key scientific challenges will be addressed: The development of efficient cleavage reactions of complex renewable resources by novel heterogeneous catalysts; and finding new homogeneous catalyst based on earth-abundant metals for the atom-economic coupling of the derived alcohol building blocks directly with ammonia as well as possible further functionalization reactions. The program is divided into 3 interrelated but not mutually dependent work packages, each research addressing a key challenge in their respective fields, these are:
WP1: Lignin conversion to aromatics; WP2: Cellulose-derived platform chemicals to aromatic and aliphatic diols and solvents. WP3: New iron-based homogeneous catalysts for the direct, atom-economic C-O to C-N transformations.
The approach taken will embrace the inherent complexity present in the renewable feedstock. A unique balance between cleavage and coupling pathways will allow to access chemical diversity in products that is necessary to achieve economic competitiveness with current fossil fuel-based pathways and will permit rapid conversion to higher value products such as functionalized amines that can enter the chemical supply chain at a much later stage than bulk chemicals derived from petroleum. The proposed high risk-high gain research will push the frontiers of sustainable and green chemistry and reach well beyond state of the art in this area. This universal, flexible and iterative approach is anticipated to give rise to a variety of similar systems targeting diverse product outcomes starting from renewables.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym CHEMCHECK
Project CHECKPOINTS IN CHECK: Novel Chemical Toolbox for Local Cancer Immunotherapy
Researcher (PI) Martijn Verdoes
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Cancer evades the immune system by generating an immunosuppressive tumour-microenvironment through various mechanisms to enable unhampered growth. Recent breakthroughs in blocking one of these mechanisms – the so called ‘immune checkpoints’ – put cancer immunotherapy back in the spotlights. Although promising, clinical benefits of these checkpoint inhibitors as single treatment has been limited to a subset of patients and goes along with unwanted systemic autoimmune toxicity. I hypostasize, that attacking the tumour microenvironment from multiple immunological angles simultaneously by local, conditional, and multimodal immunomodulation will greatly improve success of cancer immunotherapy and patient wellbeing. To achieve this, I will develop a highly defined synergistic chemistry-based molecular therapeutic toolbox to specifically attack cancer, acting on effector T cells, macrophages as well as tumour cells simultaneously. In this highly multidisciplinary endeavour I will (i) generate novel multifunctional dendritic cell targeted anti-cancer vaccines to ‘educate’ the patient’s immune system to recognise the tumour, (ii) I will develop conditional, targeted immune checkpoint inhibitors to release the immunosuppressive break specifically within the tumour microenvironment without the risk of autoimmunity and (iii) I will generate chemical tools to locally eliminate the tumour-associated macrophages to tear down a major immunosuppressive barrier. I will do so utilizing the novel ModimAb technology which I developed to obtain functionalized antibody fragments. These individual therapeutic tools will allow me and my research team to explore uncharted tumour immunological territories in vitro as well as in vivo, greatly advancing the field of cancer immunotherapy. But above all, together they will form a highly dedicated symbiotic immunotherapeutic regime which will be extremely effective without systemic side effects, dramatically improving patient care.
Summary
Cancer evades the immune system by generating an immunosuppressive tumour-microenvironment through various mechanisms to enable unhampered growth. Recent breakthroughs in blocking one of these mechanisms – the so called ‘immune checkpoints’ – put cancer immunotherapy back in the spotlights. Although promising, clinical benefits of these checkpoint inhibitors as single treatment has been limited to a subset of patients and goes along with unwanted systemic autoimmune toxicity. I hypostasize, that attacking the tumour microenvironment from multiple immunological angles simultaneously by local, conditional, and multimodal immunomodulation will greatly improve success of cancer immunotherapy and patient wellbeing. To achieve this, I will develop a highly defined synergistic chemistry-based molecular therapeutic toolbox to specifically attack cancer, acting on effector T cells, macrophages as well as tumour cells simultaneously. In this highly multidisciplinary endeavour I will (i) generate novel multifunctional dendritic cell targeted anti-cancer vaccines to ‘educate’ the patient’s immune system to recognise the tumour, (ii) I will develop conditional, targeted immune checkpoint inhibitors to release the immunosuppressive break specifically within the tumour microenvironment without the risk of autoimmunity and (iii) I will generate chemical tools to locally eliminate the tumour-associated macrophages to tear down a major immunosuppressive barrier. I will do so utilizing the novel ModimAb technology which I developed to obtain functionalized antibody fragments. These individual therapeutic tools will allow me and my research team to explore uncharted tumour immunological territories in vitro as well as in vivo, greatly advancing the field of cancer immunotherapy. But above all, together they will form a highly dedicated symbiotic immunotherapeutic regime which will be extremely effective without systemic side effects, dramatically improving patient care.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym CONTEXTVISION
Project Visual perception in Context
Researcher (PI) Floris Pieter De lange
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Starting Grant (StG), SH4, ERC-2015-STG
Summary Everything occurs in a context. We see a car in the context of a street scene and a stove in the context of a kitchen. Context greatly helps the processing of individual objects. Surprisingly however, context hardly plays a role in most models of visual perception, which treat perception as a largely bottom-up categorization process.
In this research proposal, I will examine how context changes the cortical computations that give rise to visual perception, focusing on contextual modulations in space and time. Moreover, I will translate this research to a clinical condition that is marked by aberrant context modulations in perception.
Firstly, I will examine the influence of spatial context from the surround on cortical processing of individual elements. I aim to uncover the neural mechanisms responsible for the contextual facilitation of features and objects. I hypothesize that spatial context constrains sensory input by changing sensory representations at earlier stages in line with expectations at higher-order stages of perceptual analysis.
Secondly, I will examine the influence of temporal context from past history. I hypothesize that temporal contexts trigger cortical waves of neural ‘preplay’ activity, setting up time-varying templates of expected incoming visual input.
Thirdly, I will test the clinical significance of this framework to understand perceptual atypicalities in Autism Spectrum Disorder (ASD). I will empirically test the hypothesis that ASD is marked by deficient processing of contextual information, in both the spatial and temporal domain.
This integrative approach has the potential to significantly advance theoretical models of perception, based on underlying neurobiology, and underline the importance of context for understanding perception. Moreover, the knowledge gleaned can have significant societal and clinical impact.
Summary
Everything occurs in a context. We see a car in the context of a street scene and a stove in the context of a kitchen. Context greatly helps the processing of individual objects. Surprisingly however, context hardly plays a role in most models of visual perception, which treat perception as a largely bottom-up categorization process.
In this research proposal, I will examine how context changes the cortical computations that give rise to visual perception, focusing on contextual modulations in space and time. Moreover, I will translate this research to a clinical condition that is marked by aberrant context modulations in perception.
Firstly, I will examine the influence of spatial context from the surround on cortical processing of individual elements. I aim to uncover the neural mechanisms responsible for the contextual facilitation of features and objects. I hypothesize that spatial context constrains sensory input by changing sensory representations at earlier stages in line with expectations at higher-order stages of perceptual analysis.
Secondly, I will examine the influence of temporal context from past history. I hypothesize that temporal contexts trigger cortical waves of neural ‘preplay’ activity, setting up time-varying templates of expected incoming visual input.
Thirdly, I will test the clinical significance of this framework to understand perceptual atypicalities in Autism Spectrum Disorder (ASD). I will empirically test the hypothesis that ASD is marked by deficient processing of contextual information, in both the spatial and temporal domain.
This integrative approach has the potential to significantly advance theoretical models of perception, based on underlying neurobiology, and underline the importance of context for understanding perception. Moreover, the knowledge gleaned can have significant societal and clinical impact.
Max ERC Funding
1 499 421 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym COSI
Project Cerebellar modules and the Ontogeny of Sensorimotor Integration
Researcher (PI) Martijn Schonewille
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Starting Grant (StG), LS5, ERC-2015-STG
Summary The perfect execution of a voluntary movement requires the appropriate integration of current bodily state, sensory input and desired outcome. To assure that this motor output becomes and remains appropriate, the brain needs to learn from the result of previous outputs. The cerebellum plays a central role in sensorimotor integration, yet -despite decades of studies- there is no generally excepted theory for cerebellar functioning. I recently demonstrated that cerebellar modules, identified based on anatomical connectivity and gene expression, differ distinctly in spike activity properties. It is my long-term goal to identify the ontogeny of anatomical and physiological differences between modules, and their functional consequences. My hypothesis is that these differences can explain existing controversies, and unify contradicting results into one central theory.
To this end, I have designed three key objectives. First, I will identify the development of connectivity and activity patterns at the input stage of the cerebellar cortex in relation to the cerebellar modules (key objective A). Next, I will relate the differences in gene expression levels between modules to differences in basal activity and strength of plasticity mechanisms in juvenile mice (key objective B). Finally, I will determine how module specific output develops in relation to behavior and what the effect of module specific mutations is on cerebellum-dependent motor tasks and higher order functions (key objective C).
Ultimately, the combined results of all key objectives will reveal how distinct difference between cerebellar modules develop, and how this ensemble ensures proper cerebellar information processing for optimal coordination of timing and force of movements. Combined with the growing body of evidence for a cerebellar role in higher order brain functions and neurodevelopmental disorders, a unifying theory would be fundamental for understanding how the juvenile brain develops.
Summary
The perfect execution of a voluntary movement requires the appropriate integration of current bodily state, sensory input and desired outcome. To assure that this motor output becomes and remains appropriate, the brain needs to learn from the result of previous outputs. The cerebellum plays a central role in sensorimotor integration, yet -despite decades of studies- there is no generally excepted theory for cerebellar functioning. I recently demonstrated that cerebellar modules, identified based on anatomical connectivity and gene expression, differ distinctly in spike activity properties. It is my long-term goal to identify the ontogeny of anatomical and physiological differences between modules, and their functional consequences. My hypothesis is that these differences can explain existing controversies, and unify contradicting results into one central theory.
To this end, I have designed three key objectives. First, I will identify the development of connectivity and activity patterns at the input stage of the cerebellar cortex in relation to the cerebellar modules (key objective A). Next, I will relate the differences in gene expression levels between modules to differences in basal activity and strength of plasticity mechanisms in juvenile mice (key objective B). Finally, I will determine how module specific output develops in relation to behavior and what the effect of module specific mutations is on cerebellum-dependent motor tasks and higher order functions (key objective C).
Ultimately, the combined results of all key objectives will reveal how distinct difference between cerebellar modules develop, and how this ensemble ensures proper cerebellar information processing for optimal coordination of timing and force of movements. Combined with the growing body of evidence for a cerebellar role in higher order brain functions and neurodevelopmental disorders, a unifying theory would be fundamental for understanding how the juvenile brain develops.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym CoupledIceClim
Project Coupled climate and Greenland ice sheet evolution:past, present and future
Researcher (PI) Miren Vizcaino Trueba
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Starting Grant (StG), PE10, ERC-2015-STG
Summary The Greenland ice sheet (GrIS) is losing mass at an increasing pace, in response to atmospheric and ocean forcing. The mechanisms leading to the observed mass loss are poorly understood. It is not clear whether the current trends will be sustained into the future, and how they are affected by regional and global climate variability. In addition, the impacts of Greenland deglaciation on the local and global climate are not well known. This project aims to explain the relationship between GrIS surface melt trends and climate variability, to determine the timing and impacts of multi-century deglaciation of Greenland, and to explain the relationship between ongoing and previous deglaciations during the last interglacial and the Holocene. For this purpose, we will use the Community Earth System Model (CESM), the first full-complexity global climate model to include interactive ice sheet flow and a realistic and physical-based simulation of surface mass balance (the difference between surface accumulation and losses from runoff and sublimation). This tool will include for the first time a large range of temporal and spatial scales of ice sheet-climate interaction in the same model. Previous work has been done with oversimplified and/or uncoupled representations of ice sheet and climate processes, for instance with simplified ocean and/or atmospheric dynamics in Earth System Models of Intermediate Complexity, with fixed topography and prescribed ocean components in Regional Climate Models, or with highly parameterized snow albedo and/or melt schemes in General Circulation Models. This project will provide new insights into the coupling between the GrIS and climate change, will lead widespread integration of ice sheets as a new and indispensable component of complex Earth System Models, and will advance our understanding of present and past climate dynamics.
Summary
The Greenland ice sheet (GrIS) is losing mass at an increasing pace, in response to atmospheric and ocean forcing. The mechanisms leading to the observed mass loss are poorly understood. It is not clear whether the current trends will be sustained into the future, and how they are affected by regional and global climate variability. In addition, the impacts of Greenland deglaciation on the local and global climate are not well known. This project aims to explain the relationship between GrIS surface melt trends and climate variability, to determine the timing and impacts of multi-century deglaciation of Greenland, and to explain the relationship between ongoing and previous deglaciations during the last interglacial and the Holocene. For this purpose, we will use the Community Earth System Model (CESM), the first full-complexity global climate model to include interactive ice sheet flow and a realistic and physical-based simulation of surface mass balance (the difference between surface accumulation and losses from runoff and sublimation). This tool will include for the first time a large range of temporal and spatial scales of ice sheet-climate interaction in the same model. Previous work has been done with oversimplified and/or uncoupled representations of ice sheet and climate processes, for instance with simplified ocean and/or atmospheric dynamics in Earth System Models of Intermediate Complexity, with fixed topography and prescribed ocean components in Regional Climate Models, or with highly parameterized snow albedo and/or melt schemes in General Circulation Models. This project will provide new insights into the coupling between the GrIS and climate change, will lead widespread integration of ice sheets as a new and indispensable component of complex Earth System Models, and will advance our understanding of present and past climate dynamics.
Max ERC Funding
1 677 282 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym CureCKDHeart
Project Targeting perivascular myofibroblast progenitors to treat cardiac fibrosis and heart failure in chronic kidney disease
Researcher (PI) Rafael Johannes Thomas Kramann
Host Institution (HI) UNIVERSITAETSKLINIKUM AACHEN
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary Chronic kidney disease (CKD) is a growing public health problem with a massively increased cardiovascular mortality. Patients with advanced CKD mostly die from sudden cardiac death and recurrent heart failure due to premature cardiac aging with hypertrophy, fibrosis, and capillary rarefaction. I have recently identified the long sought key cardiac myofibroblast progenitor population, an emerging breakthrough that carries the potential to develop novel targeted therapeutics. Genetic ablation of these Gli1+ perivascular progenitors ameliorates fibrosis, cardiac hypertrophy and rescues left-ventricular function. I propose that Gli1+ cells are critically involved in all major pathophysiologic changes in cardiac aging and uremic cardiomyopathy including fibrosis, hypertrophy and capillary rarefaction. I will perform state of the art genetic fate tracing, ablation and in vivo CRISPR/Cas9 genome editing experiments to untangle their complex mechanism of activation and communication with endothelial cells and cardiomyocytes promoting fibrosis, capillary rarefaction, cardiac hypertrophy and heart failure. To identify novel druggable targets I will utilize new mouse models that allow comparative transcript and proteasome profiling assays of these critical myofibroblast precusors in homeostasis, aging and premature aging in CKD. Novel assays with immortalized cardiac Gli1+ cells will allow high throughput screens to identify uremia associated factors of cell activation and inhibitory compounds to facilitate the development of novel therapeutics.
This ambitious interdisciplinary project requires the expertise of chemists, physiologists, biomedical researchers and physician scientists to develop novel targeted therapies in cardiac remodeling during aging and CKD. The passion that drives this project results from a simple emerging hypothesis: It is possible to treat heart failure and sudden cardiac death in aging and CKD by targeting perivascular myofibroblast progenitors.
Summary
Chronic kidney disease (CKD) is a growing public health problem with a massively increased cardiovascular mortality. Patients with advanced CKD mostly die from sudden cardiac death and recurrent heart failure due to premature cardiac aging with hypertrophy, fibrosis, and capillary rarefaction. I have recently identified the long sought key cardiac myofibroblast progenitor population, an emerging breakthrough that carries the potential to develop novel targeted therapeutics. Genetic ablation of these Gli1+ perivascular progenitors ameliorates fibrosis, cardiac hypertrophy and rescues left-ventricular function. I propose that Gli1+ cells are critically involved in all major pathophysiologic changes in cardiac aging and uremic cardiomyopathy including fibrosis, hypertrophy and capillary rarefaction. I will perform state of the art genetic fate tracing, ablation and in vivo CRISPR/Cas9 genome editing experiments to untangle their complex mechanism of activation and communication with endothelial cells and cardiomyocytes promoting fibrosis, capillary rarefaction, cardiac hypertrophy and heart failure. To identify novel druggable targets I will utilize new mouse models that allow comparative transcript and proteasome profiling assays of these critical myofibroblast precusors in homeostasis, aging and premature aging in CKD. Novel assays with immortalized cardiac Gli1+ cells will allow high throughput screens to identify uremia associated factors of cell activation and inhibitory compounds to facilitate the development of novel therapeutics.
This ambitious interdisciplinary project requires the expertise of chemists, physiologists, biomedical researchers and physician scientists to develop novel targeted therapies in cardiac remodeling during aging and CKD. The passion that drives this project results from a simple emerging hypothesis: It is possible to treat heart failure and sudden cardiac death in aging and CKD by targeting perivascular myofibroblast progenitors.
Max ERC Funding
1 497 888 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
