Project acronym 3DPROTEINPUZZLES
Project Shape-directed protein assembly design
Researcher (PI) Lars Ingemar ANDRÉ
Host Institution (HI) LUNDS UNIVERSITET
Call Details Consolidator Grant (CoG), LS9, ERC-2017-COG
Summary Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.
Summary
Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.
Max ERC Funding
2 325 292 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym 3Ps
Project 3Ps
Plastic-Antibodies, Plasmonics and Photovoltaic-Cells: on-site screening of cancer biomarkers made possible
Researcher (PI) Maria Goreti Ferreira Sales
Host Institution (HI) INSTITUTO SUPERIOR DE ENGENHARIA DO PORTO
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary This project presents a new concept for the detection, diagnosis and monitoring of cancer biomarker patterns in point-of-care. The device under development will make use of the selectivity of the plastic antibodies as sensing materials and the interference they will play on the normal operation of a photovoltaic cell.
Plastic antibodies will be designed by surface imprinting procedures. Self-assembled monolayer and molecular imprinting techniques will be merged in this process because they allow the self-assembly of nanostructured materials on a “bottom-up” nanofabrication approach. A dye-sensitized solar cell will be used as photovoltaic cell. It includes a liquid interface in the cell circuit, which allows the introduction of the sample (also in liquid phase) without disturbing the normal cell operation. Furthermore, it works well with rather low cost materials and requires mild and easy processing conditions. The cell will be equipped with plasmonic structures to enhance light absorption and cell efficiency.
The device under development will be easily operated by any clinician or patient. It will require ambient light and a regular multimeter. Eye detection will be also tried out.
Summary
This project presents a new concept for the detection, diagnosis and monitoring of cancer biomarker patterns in point-of-care. The device under development will make use of the selectivity of the plastic antibodies as sensing materials and the interference they will play on the normal operation of a photovoltaic cell.
Plastic antibodies will be designed by surface imprinting procedures. Self-assembled monolayer and molecular imprinting techniques will be merged in this process because they allow the self-assembly of nanostructured materials on a “bottom-up” nanofabrication approach. A dye-sensitized solar cell will be used as photovoltaic cell. It includes a liquid interface in the cell circuit, which allows the introduction of the sample (also in liquid phase) without disturbing the normal cell operation. Furthermore, it works well with rather low cost materials and requires mild and easy processing conditions. The cell will be equipped with plasmonic structures to enhance light absorption and cell efficiency.
The device under development will be easily operated by any clinician or patient. It will require ambient light and a regular multimeter. Eye detection will be also tried out.
Max ERC Funding
998 584 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym 3S-BTMUC
Project Soft, Slimy, Sliding Interfaces: Biotribological Properties of Mucins and Mucus gels
Researcher (PI) Seunghwan Lee
Host Institution (HI) DANMARKS TEKNISKE UNIVERSITET
Call Details Starting Grant (StG), LS9, ERC-2010-StG_20091118
Summary Mucins are a family of high-molecular-weight glycoproteins and a major macromolecular constituent in slimy mucus gels that are covering the surface of internal biological tissues. A primary role of mucus gels in biological systems is known to be the protection and lubrication of underlying epithelial cell surfaces. This is intuitively well appreciated by both science community and the public, and yet detailed lubrication properties of mucins and mucus gels have remained largely unexplored to date. Detailed and systematic understanding of the lubrication mechanism of mucus gels is significant from many angles; firstly, lubricity of mucus gels is closely related with fundamental functions of various human organs, such as eye blinking, mastication in oral cavity, swallowing through esophagus, digestion in stomach, breathing through air way and respiratory organs, and thus often indicates the health state of those organs. Furthermore, for the application of various tissue-contacting devices or personal care products, e.g. catheters, endoscopes, and contact lenses, mucus gel layer is the first counter surface that comes into the mechanical and tribological contacts with them. Finally, remarkable lubricating performance by mucins and mucus gels in biological systems may provide many useful and possibly innovative hints in utilizing water as base lubricant for man-made engineering systems. This project thus proposes to carry out a 5 year research program focusing on exploring the lubricity of mucins and mucus gels by combining a broad range of experimental approaches in biology and tribology.
Summary
Mucins are a family of high-molecular-weight glycoproteins and a major macromolecular constituent in slimy mucus gels that are covering the surface of internal biological tissues. A primary role of mucus gels in biological systems is known to be the protection and lubrication of underlying epithelial cell surfaces. This is intuitively well appreciated by both science community and the public, and yet detailed lubrication properties of mucins and mucus gels have remained largely unexplored to date. Detailed and systematic understanding of the lubrication mechanism of mucus gels is significant from many angles; firstly, lubricity of mucus gels is closely related with fundamental functions of various human organs, such as eye blinking, mastication in oral cavity, swallowing through esophagus, digestion in stomach, breathing through air way and respiratory organs, and thus often indicates the health state of those organs. Furthermore, for the application of various tissue-contacting devices or personal care products, e.g. catheters, endoscopes, and contact lenses, mucus gel layer is the first counter surface that comes into the mechanical and tribological contacts with them. Finally, remarkable lubricating performance by mucins and mucus gels in biological systems may provide many useful and possibly innovative hints in utilizing water as base lubricant for man-made engineering systems. This project thus proposes to carry out a 5 year research program focusing on exploring the lubricity of mucins and mucus gels by combining a broad range of experimental approaches in biology and tribology.
Max ERC Funding
1 432 920 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym 4D-PET
Project Innovative PET scanner for dynamic imaging
Researcher (PI) José María BENLLOCH BAVIERA
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Call Details Advanced Grant (AdG), LS7, ERC-2015-AdG
Summary The main objective of 4D-PET is to develop an innovative whole-body PET scanner based in a new detector concept that stores 3D position and time of every single gamma interaction with unprecedented resolution. The combination of scanner geometrical design and high timing resolution will enable developing a full sequence of all gamma-ray interactions inside the scanner, including Compton interactions, like in a 3D movie. 4D-PET fully exploits Time Of Flight (TOF) information to obtain a better image quality and to increase scanner sensitivity, through the inclusion in the image formation of all Compton events occurring inside the detector, which are always rejected in state-of-the-art PET scanners. The new PET design will radically improve state-of-the-art PET performance features, overcoming limitations of current PET technology and opening up new diagnostic venues and very valuable physiological information
Summary
The main objective of 4D-PET is to develop an innovative whole-body PET scanner based in a new detector concept that stores 3D position and time of every single gamma interaction with unprecedented resolution. The combination of scanner geometrical design and high timing resolution will enable developing a full sequence of all gamma-ray interactions inside the scanner, including Compton interactions, like in a 3D movie. 4D-PET fully exploits Time Of Flight (TOF) information to obtain a better image quality and to increase scanner sensitivity, through the inclusion in the image formation of all Compton events occurring inside the detector, which are always rejected in state-of-the-art PET scanners. The new PET design will radically improve state-of-the-art PET performance features, overcoming limitations of current PET technology and opening up new diagnostic venues and very valuable physiological information
Max ERC Funding
2 048 386 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
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
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 5HT-OPTOGENETICS
Project Optogenetic Analysis of Serotonin Function in the Mammalian Brain
Researcher (PI) Zachary Mainen
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary Serotonin (5-HT) is implicated in a wide spectrum of brain functions and disorders. However, its functions remain controversial and enigmatic. We suggest that past work on the 5-HT system have been significantly hampered by technical limitations in the selectivity and temporal resolution of the conventional pharmacological and electrophysiological methods that have been applied. We therefore propose to apply novel optogenetic methods that will allow us to overcome these limitations and thereby gain new insight into the biological functions of this important molecule. In preliminary studies, we have demonstrated that we can deliver exogenous proteins specifically to 5-HT neurons using viral vectors. Our objectives are to (1) record, (2) stimulate and (3) silence the activity of 5-HT neurons with high molecular selectivity and temporal precision by using genetically-encoded sensors, activators and inhibitors of neural function. These tools will allow us to monitor and control the 5-HT system in real-time in freely-behaving animals and thereby to establish causal links between information processing in 5-HT neurons and specific behaviors. In combination with quantitative behavioral assays, we will use this approach to define the role of 5-HT in sensory, motor and cognitive functions. The significance of the work is three-fold. First, we will establish a new arsenal of tools for probing the physiological and behavioral functions of 5-HT neurons. Second, we will make definitive tests of major hypotheses of 5-HT function. Third, we will have possible therapeutic applications. In this way, the proposed work has the potential for a major impact in research on the role of 5-HT in brain function and dysfunction.
Summary
Serotonin (5-HT) is implicated in a wide spectrum of brain functions and disorders. However, its functions remain controversial and enigmatic. We suggest that past work on the 5-HT system have been significantly hampered by technical limitations in the selectivity and temporal resolution of the conventional pharmacological and electrophysiological methods that have been applied. We therefore propose to apply novel optogenetic methods that will allow us to overcome these limitations and thereby gain new insight into the biological functions of this important molecule. In preliminary studies, we have demonstrated that we can deliver exogenous proteins specifically to 5-HT neurons using viral vectors. Our objectives are to (1) record, (2) stimulate and (3) silence the activity of 5-HT neurons with high molecular selectivity and temporal precision by using genetically-encoded sensors, activators and inhibitors of neural function. These tools will allow us to monitor and control the 5-HT system in real-time in freely-behaving animals and thereby to establish causal links between information processing in 5-HT neurons and specific behaviors. In combination with quantitative behavioral assays, we will use this approach to define the role of 5-HT in sensory, motor and cognitive functions. The significance of the work is three-fold. First, we will establish a new arsenal of tools for probing the physiological and behavioral functions of 5-HT neurons. Second, we will make definitive tests of major hypotheses of 5-HT function. Third, we will have possible therapeutic applications. In this way, the proposed work has the potential for a major impact in research on the role of 5-HT in brain function and dysfunction.
Max ERC Funding
2 318 636 €
Duration
Start date: 2010-07-01, End date: 2015-12-31
Project acronym 5HTCircuits
Project Modulation of cortical circuits and predictive neural coding by serotonin
Researcher (PI) Zachary Mainen
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Advanced Grant (AdG), LS5, ERC-2014-ADG
Summary Serotonin (5-HT) is a central neuromodulator and a major target of therapeutic psychoactive drugs, but relatively little is known about how it modulates information processing in neural circuits. The theory of predictive coding postulates that the brain combines raw bottom-up sensory information with top-down information from internal models to make perceptual inferences about the world. We hypothesize, based on preliminary data and prior literature, that a role of 5-HT in this process is to report prediction errors and promote the suppression and weakening of erroneous internal models. We propose that it does this by inhibiting top-down relative to bottom-up cortical information flow. To test this hypothesis, we propose a set of experiments in mice performing olfactory perceptual tasks. Our specific aims are: (1) We will test whether 5-HT neurons encode sensory prediction errors. (2) We will test their causal role in using predictive cues to guide perceptual decisions. (3) We will characterize how 5-HT influences the encoding of sensory information by neuronal populations in the olfactory cortex and identify the underlying circuitry. (4) Finally, we will map the effects of 5-HT across the whole brain and use this information to target further causal manipulations to specific 5-HT projections. We accomplish these aims using state-of-the-art optogenetic, electrophysiological and imaging techniques (including 9.4T small-animal functional magnetic resonance imaging) as well as psychophysical tasks amenable to quantitative analysis and computational theory. Together, these experiments will tackle multiple facets of an important general computational question, bringing to bear an array of cutting-edge technologies to address with unprecedented mechanistic detail how 5-HT impacts neural coding and perceptual decision-making.
Summary
Serotonin (5-HT) is a central neuromodulator and a major target of therapeutic psychoactive drugs, but relatively little is known about how it modulates information processing in neural circuits. The theory of predictive coding postulates that the brain combines raw bottom-up sensory information with top-down information from internal models to make perceptual inferences about the world. We hypothesize, based on preliminary data and prior literature, that a role of 5-HT in this process is to report prediction errors and promote the suppression and weakening of erroneous internal models. We propose that it does this by inhibiting top-down relative to bottom-up cortical information flow. To test this hypothesis, we propose a set of experiments in mice performing olfactory perceptual tasks. Our specific aims are: (1) We will test whether 5-HT neurons encode sensory prediction errors. (2) We will test their causal role in using predictive cues to guide perceptual decisions. (3) We will characterize how 5-HT influences the encoding of sensory information by neuronal populations in the olfactory cortex and identify the underlying circuitry. (4) Finally, we will map the effects of 5-HT across the whole brain and use this information to target further causal manipulations to specific 5-HT projections. We accomplish these aims using state-of-the-art optogenetic, electrophysiological and imaging techniques (including 9.4T small-animal functional magnetic resonance imaging) as well as psychophysical tasks amenable to quantitative analysis and computational theory. Together, these experiments will tackle multiple facets of an important general computational question, bringing to bear an array of cutting-edge technologies to address with unprecedented mechanistic detail how 5-HT impacts neural coding and perceptual decision-making.
Max ERC Funding
2 486 074 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym A-DIET
Project Metabolomics based biomarkers of dietary intake- new tools for nutrition research
Researcher (PI) Lorraine Brennan
Host Institution (HI) UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary In todays advanced technological world, we can track the exact movement of individuals, analyse their genetic makeup and predict predisposition to certain diseases. However, we are unable to accurately assess an individual’s dietary intake. This is without a doubt one of the main stumbling blocks in assessing the link between diet and disease/health. The present proposal (A-DIET) will address this issue with the overarching objective to develop novel strategies for assessment of dietary intake.
Using approaches to (1) identify biomarkers of specific foods (2) classify people into dietary patterns (nutritypes) and (3) develop a tool for integration of dietary and biomarker data, A-DIET has the potential to dramatically enhance our ability to accurately assess dietary intake. The ultimate output from A-DIET will be a dietary assessment tool which can be used to obtain an accurate assessment of dietary intake by combining dietary and biomarker data which in turn will allow investigations into relationships between diet, health and disease. New biomarkers of specific foods will be identified and validated using intervention studies and metabolomic analyses. Methods will be developed to classify individuals into dietary patterns based on biomarker/metabolomic profiles thus demonstrating the novel concept of nutritypes. Strategies for integration of dietary and biomarker data will be developed and translated into a tool that will be made available to the wider scientific community.
Advances made in A-DIET will enable nutrition epidemiologist’s to properly examine the relationship between diet and disease and develop clear public health messages with regard to diet and health. Additionally results from A-DIET will allow researchers to accurately assess people’s diet and implement health promotion strategies and enable dieticians in a clinical environment to assess compliance to therapeutic diets such as adherence to a high fibre diet or a gluten free diet.
Summary
In todays advanced technological world, we can track the exact movement of individuals, analyse their genetic makeup and predict predisposition to certain diseases. However, we are unable to accurately assess an individual’s dietary intake. This is without a doubt one of the main stumbling blocks in assessing the link between diet and disease/health. The present proposal (A-DIET) will address this issue with the overarching objective to develop novel strategies for assessment of dietary intake.
Using approaches to (1) identify biomarkers of specific foods (2) classify people into dietary patterns (nutritypes) and (3) develop a tool for integration of dietary and biomarker data, A-DIET has the potential to dramatically enhance our ability to accurately assess dietary intake. The ultimate output from A-DIET will be a dietary assessment tool which can be used to obtain an accurate assessment of dietary intake by combining dietary and biomarker data which in turn will allow investigations into relationships between diet, health and disease. New biomarkers of specific foods will be identified and validated using intervention studies and metabolomic analyses. Methods will be developed to classify individuals into dietary patterns based on biomarker/metabolomic profiles thus demonstrating the novel concept of nutritypes. Strategies for integration of dietary and biomarker data will be developed and translated into a tool that will be made available to the wider scientific community.
Advances made in A-DIET will enable nutrition epidemiologist’s to properly examine the relationship between diet and disease and develop clear public health messages with regard to diet and health. Additionally results from A-DIET will allow researchers to accurately assess people’s diet and implement health promotion strategies and enable dieticians in a clinical environment to assess compliance to therapeutic diets such as adherence to a high fibre diet or a gluten free diet.
Max ERC Funding
1 995 548 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
Project acronym A-FRO
Project Actively Frozen - contextual modulation of freezing and its neuronal basis
Researcher (PI) Marta de Aragão Pacheco Moita
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Summary
When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Max ERC Funding
1 969 750 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym A-HERO
Project Anthelmintic Research and Optimization
Researcher (PI) Jennifer Irene Keiser
Host Institution (HI) SCHWEIZERISCHES TROPEN- UND PUBLIC HEALTH-INSTITUT
Call Details Consolidator Grant (CoG), LS7, ERC-2013-CoG
Summary "I propose an ambitious, yet feasible 5-year research project that will fill an important gap in global health. Specifically, I will develop and validate novel approaches for anthelmintic drug discovery and development. My proposal pursues the following five research questions: (i) Is a chip calorimeter suitable for high-throughput screening in anthelmintic drug discovery? (ii) Is combination chemotherapy safe and more efficacious than monotherapy against strongyloidiasis and trichuriasis? (iii) What are the key pharmacokinetic parameters of praziquantel in preschool-aged children and school-aged children infected with Schistosoma mansoni and S. haematobium using a novel and validated technology based on dried blood spotting? (iv) What are the metabolic consequences and clearance of praziquantel treatment in S. mansoni-infected mice and S. mansoni- and S. haematobium-infected children? (v) Which is the ideal compartment to study pharmacokinetic parameters for intestinal nematode infections and does age, nutrition, co-infection and infection intensity influence the efficacy of anthelmintic drugs?
My proposed research is of considerable public health relevance since it will ultimately result in improved treatments for soil-transmitted helminthiasis and pediatric schistosomiasis. Additionally, at the end of this project, I have generated comprehensive information on drug disposition of anthelmintics. A comprehensive database of metabolite profiles following praziquantel treatment will be available. Finally, the proof-of-concept of chip calorimetry in anthelmintic drug discovery has been established and broadly validated."
Summary
"I propose an ambitious, yet feasible 5-year research project that will fill an important gap in global health. Specifically, I will develop and validate novel approaches for anthelmintic drug discovery and development. My proposal pursues the following five research questions: (i) Is a chip calorimeter suitable for high-throughput screening in anthelmintic drug discovery? (ii) Is combination chemotherapy safe and more efficacious than monotherapy against strongyloidiasis and trichuriasis? (iii) What are the key pharmacokinetic parameters of praziquantel in preschool-aged children and school-aged children infected with Schistosoma mansoni and S. haematobium using a novel and validated technology based on dried blood spotting? (iv) What are the metabolic consequences and clearance of praziquantel treatment in S. mansoni-infected mice and S. mansoni- and S. haematobium-infected children? (v) Which is the ideal compartment to study pharmacokinetic parameters for intestinal nematode infections and does age, nutrition, co-infection and infection intensity influence the efficacy of anthelmintic drugs?
My proposed research is of considerable public health relevance since it will ultimately result in improved treatments for soil-transmitted helminthiasis and pediatric schistosomiasis. Additionally, at the end of this project, I have generated comprehensive information on drug disposition of anthelmintics. A comprehensive database of metabolite profiles following praziquantel treatment will be available. Finally, the proof-of-concept of chip calorimetry in anthelmintic drug discovery has been established and broadly validated."
Max ERC Funding
1 927 350 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
