Project acronym 2-HIT
Project Genetic interaction networks: From C. elegans to human disease
Researcher (PI) Ben Lehner
Host Institution (HI) FUNDACIO CENTRE DE REGULACIO GENOMICA
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary Most hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.
Summary
Most hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.
Max ERC Funding
1 100 000 €
Duration
Start date: 2008-09-01, End date: 2014-04-30
Project acronym 2DNANOPTICA
Project Nano-optics on flatland: from quantum nanotechnology to nano-bio-photonics
Researcher (PI) Pablo Alonso-González
Host Institution (HI) UNIVERSIDAD DE OVIEDO
Call Details Starting Grant (StG), PE3, ERC-2016-STG
Summary Ubiquitous in nature, light-matter interactions are of fundamental importance in science and all optical technologies. Understanding and controlling them has been a long-pursued objective in modern physics. However, so far, related experiments have relied on traditional optical schemes where, owing to the classical diffraction limit, control of optical fields to length scales below the wavelength of light is prevented. Importantly, this limitation impedes to exploit the extraordinary fundamental and scaling potentials of nanoscience and nanotechnology. A solution to concentrate optical fields into sub-diffracting volumes is the excitation of surface polaritons –coupled excitations of photons and mobile/bound charges in metals/polar materials (plasmons/phonons)-. However, their initial promises have been hindered by either strong optical losses or lack of electrical control in metals, and difficulties to fabricate high optical quality nanostructures in polar materials.
With the advent of two-dimensional (2D) materials and their extraordinary optical properties, during the last 2-3 years the visualization of both low-loss and electrically tunable (active) plasmons in graphene and high optical quality phonons in monolayer and multilayer h-BN nanostructures have been demonstrated in the mid-infrared spectral range, thus introducing a very encouraging arena for scientifically ground-breaking discoveries in nano-optics. Inspired by these extraordinary prospects, this ERC project aims to make use of our knowledge and unique expertise in 2D nanoplasmonics, and the recent advances in nanophononics, to establish a technological platform that, including coherent sources, waveguides, routers, and efficient detectors, permits an unprecedented active control and manipulation (at room temperature) of light and light-matter interactions on the nanoscale, thus laying experimentally the foundations of a 2D nano-optics field.
Summary
Ubiquitous in nature, light-matter interactions are of fundamental importance in science and all optical technologies. Understanding and controlling them has been a long-pursued objective in modern physics. However, so far, related experiments have relied on traditional optical schemes where, owing to the classical diffraction limit, control of optical fields to length scales below the wavelength of light is prevented. Importantly, this limitation impedes to exploit the extraordinary fundamental and scaling potentials of nanoscience and nanotechnology. A solution to concentrate optical fields into sub-diffracting volumes is the excitation of surface polaritons –coupled excitations of photons and mobile/bound charges in metals/polar materials (plasmons/phonons)-. However, their initial promises have been hindered by either strong optical losses or lack of electrical control in metals, and difficulties to fabricate high optical quality nanostructures in polar materials.
With the advent of two-dimensional (2D) materials and their extraordinary optical properties, during the last 2-3 years the visualization of both low-loss and electrically tunable (active) plasmons in graphene and high optical quality phonons in monolayer and multilayer h-BN nanostructures have been demonstrated in the mid-infrared spectral range, thus introducing a very encouraging arena for scientifically ground-breaking discoveries in nano-optics. Inspired by these extraordinary prospects, this ERC project aims to make use of our knowledge and unique expertise in 2D nanoplasmonics, and the recent advances in nanophononics, to establish a technological platform that, including coherent sources, waveguides, routers, and efficient detectors, permits an unprecedented active control and manipulation (at room temperature) of light and light-matter interactions on the nanoscale, thus laying experimentally the foundations of a 2D nano-optics field.
Max ERC Funding
1 459 219 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym 2DQP
Project Two-dimensional quantum photonics
Researcher (PI) Brian David GERARDOT
Host Institution (HI) HERIOT-WATT UNIVERSITY
Call Details Consolidator Grant (CoG), PE3, ERC-2016-COG
Summary Quantum optics, the study of how discrete packets of light (photons) and matter interact, has led to the development of remarkable new technologies which exploit the bizarre properties of quantum mechanics. These quantum technologies are primed to revolutionize the fields of communication, information processing, and metrology in the coming years. Similar to contemporary technologies, the future quantum machinery will likely consist of a semiconductor platform to create and process the quantum information. However, to date the demanding requirements on a quantum photonic platform have yet to be satisfied with conventional bulk (three-dimensional) semiconductors.
To surmount these well-known obstacles, a new paradigm in quantum photonics is required. Initiated by the recent discovery of single photon emitters in atomically flat (two-dimensional) semiconducting materials, 2DQP aims to be at the nucleus of a new approach by realizing quantum optics with ultra-stable (coherent) quantum states integrated into devices with electronic and photonic functionality. We will characterize, identify, engineer, and coherently manipulate localized quantum states in this two-dimensional quantum photonic platform. A vital component of 2DQP’s vision is to go beyond the fundamental science and achieve the ideal solid-state single photon device yielding perfect extraction - 100% efficiency - of on-demand indistinguishable single photons. Finally, we will exploit this ideal device to implement the critical building block for a photonic quantum computer.
Summary
Quantum optics, the study of how discrete packets of light (photons) and matter interact, has led to the development of remarkable new technologies which exploit the bizarre properties of quantum mechanics. These quantum technologies are primed to revolutionize the fields of communication, information processing, and metrology in the coming years. Similar to contemporary technologies, the future quantum machinery will likely consist of a semiconductor platform to create and process the quantum information. However, to date the demanding requirements on a quantum photonic platform have yet to be satisfied with conventional bulk (three-dimensional) semiconductors.
To surmount these well-known obstacles, a new paradigm in quantum photonics is required. Initiated by the recent discovery of single photon emitters in atomically flat (two-dimensional) semiconducting materials, 2DQP aims to be at the nucleus of a new approach by realizing quantum optics with ultra-stable (coherent) quantum states integrated into devices with electronic and photonic functionality. We will characterize, identify, engineer, and coherently manipulate localized quantum states in this two-dimensional quantum photonic platform. A vital component of 2DQP’s vision is to go beyond the fundamental science and achieve the ideal solid-state single photon device yielding perfect extraction - 100% efficiency - of on-demand indistinguishable single photons. Finally, we will exploit this ideal device to implement the critical building block for a photonic quantum computer.
Max ERC Funding
1 999 135 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym 2DTHERMS
Project Design of new thermoelectric devices based on layered and field modulated nanostructures of strongly correlated electron systems
Researcher (PI) Jose Francisco Rivadulla Fernandez
Host Institution (HI) UNIVERSIDAD DE SANTIAGO DE COMPOSTELA
Call Details Starting Grant (StG), PE3, ERC-2010-StG_20091028
Summary Design of new thermoelectric devices based on layered and field modulated nanostructures of strongly correlated electron systems
Summary
Design of new thermoelectric devices based on layered and field modulated nanostructures of strongly correlated electron systems
Max ERC Funding
1 427 190 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym 2SEXES_1GENOME
Project Sex-specific genetic effects on fitness and human disease
Researcher (PI) Edward Hugh Morrow
Host Institution (HI) THE UNIVERSITY OF SUSSEX
Call Details Starting Grant (StG), LS8, ERC-2011-StG_20101109
Summary Darwin’s theory of natural selection rests on the principle that fitness variation in natural populations has a heritable component, on which selection acts, thereby leading to evolutionary change. A fundamental and so far unresolved question for the field of evolutionary biology is to identify the genetic loci responsible for this fitness variation, thereby coming closer to an understanding of how variation is maintained in the face of continual selection. One important complicating factor in the search for fitness related genes however is the existence of separate sexes – theoretical expectations and empirical data both suggest that sexually antagonistic genes are common. The phrase “two sexes, one genome” nicely sums up the problem; selection may favour alleles in one sex, even if they have detrimental effects on the fitness of the opposite sex, since it is their net effect across both sexes that determine the likelihood that alleles persist in a population. This theoretical framework raises an interesting, and so far entirely unexplored issue: that in one sex the functional performance of some alleles is predicted to be compromised and this effect may account for some common human diseases and conditions which show genotype-sex interactions. I propose to explore the genetic basis of sex-specific fitness in a model organism in both laboratory and natural conditions and to test whether those genes identified as having sexually antagonistic effects can help explain the incidence of human diseases that display sexual dimorphism in prevalence, age of onset or severity. This multidisciplinary project directly addresses some fundamental unresolved questions in evolutionary biology: the genetic basis and maintenance of fitness variation; the evolution of sexual dimorphism; and aims to provide novel insights into the genetic basis of some common human diseases.
Summary
Darwin’s theory of natural selection rests on the principle that fitness variation in natural populations has a heritable component, on which selection acts, thereby leading to evolutionary change. A fundamental and so far unresolved question for the field of evolutionary biology is to identify the genetic loci responsible for this fitness variation, thereby coming closer to an understanding of how variation is maintained in the face of continual selection. One important complicating factor in the search for fitness related genes however is the existence of separate sexes – theoretical expectations and empirical data both suggest that sexually antagonistic genes are common. The phrase “two sexes, one genome” nicely sums up the problem; selection may favour alleles in one sex, even if they have detrimental effects on the fitness of the opposite sex, since it is their net effect across both sexes that determine the likelihood that alleles persist in a population. This theoretical framework raises an interesting, and so far entirely unexplored issue: that in one sex the functional performance of some alleles is predicted to be compromised and this effect may account for some common human diseases and conditions which show genotype-sex interactions. I propose to explore the genetic basis of sex-specific fitness in a model organism in both laboratory and natural conditions and to test whether those genes identified as having sexually antagonistic effects can help explain the incidence of human diseases that display sexual dimorphism in prevalence, age of onset or severity. This multidisciplinary project directly addresses some fundamental unresolved questions in evolutionary biology: the genetic basis and maintenance of fitness variation; the evolution of sexual dimorphism; and aims to provide novel insights into the genetic basis of some common human diseases.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym 2STEPPARKIN
Project A novel two-step model for neurodegeneration in Parkinson’s disease
Researcher (PI) Emi Nagoshi
Host Institution (HI) UNIVERSITE DE GENEVE
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary Parkinson’s disease (PD) is the second most common neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). Despite the advances in gene discovery associated with PD, the knowledge of the PD pathogenesis is largely limited to the involvement of these genes in the generic cell death pathways, and why degeneration is specific to DA neurons and why the degeneration is progressive remain enigmatic. Broad goal of our work is therefore to elucidate the mechanisms underlying specific and progressive DA neuron degeneration in PD. Our new Drosophila model of PD ⎯Fer2 gene loss-of-function mutation⎯ is unusually well suited to address these questions. Fer2 mutants exhibit specific and progressive death of brain DA neurons as well as severe locomotor defects and short life span. Strikingly, the death of DA neuron is initiated in a small cluster of Fer2-expressing DA neurons and subsequently propagates to Fer2-negative DA neurons. We therefore propose a novel two-step model of the neurodegeneration in PD: primary cell death occurs in a specific subset of dopamindegic neurons that are genetically defined, and subsequently the failure of the neuronal connectivity triggers and propagates secondary cell death to remaining DA neurons. In this research, we will test this hypothesis and investigate the underlying molecular mechanisms. This will be the first study to examine circuit-dependency in DA neuron degeneration. Our approach will use a combination of non-biased genomic techniques and candidate-based screening, in addition to the powerful Drosophila genetic toolbox. Furthermore, to test this hypothesis beyond the Drosophila model, we will establish new mouse models of PD that exhibit progressive DA neuron degeneration. Outcome of this research will likely revolutionize the understanding of PD pathogenesis and open an avenue toward the discovery of effective therapy strategies against PD.
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). Despite the advances in gene discovery associated with PD, the knowledge of the PD pathogenesis is largely limited to the involvement of these genes in the generic cell death pathways, and why degeneration is specific to DA neurons and why the degeneration is progressive remain enigmatic. Broad goal of our work is therefore to elucidate the mechanisms underlying specific and progressive DA neuron degeneration in PD. Our new Drosophila model of PD ⎯Fer2 gene loss-of-function mutation⎯ is unusually well suited to address these questions. Fer2 mutants exhibit specific and progressive death of brain DA neurons as well as severe locomotor defects and short life span. Strikingly, the death of DA neuron is initiated in a small cluster of Fer2-expressing DA neurons and subsequently propagates to Fer2-negative DA neurons. We therefore propose a novel two-step model of the neurodegeneration in PD: primary cell death occurs in a specific subset of dopamindegic neurons that are genetically defined, and subsequently the failure of the neuronal connectivity triggers and propagates secondary cell death to remaining DA neurons. In this research, we will test this hypothesis and investigate the underlying molecular mechanisms. This will be the first study to examine circuit-dependency in DA neuron degeneration. Our approach will use a combination of non-biased genomic techniques and candidate-based screening, in addition to the powerful Drosophila genetic toolbox. Furthermore, to test this hypothesis beyond the Drosophila model, we will establish new mouse models of PD that exhibit progressive DA neuron degeneration. Outcome of this research will likely revolutionize the understanding of PD pathogenesis and open an avenue toward the discovery of effective therapy strategies against PD.
Max ERC Funding
1 518 960 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
Project acronym 3DMOSHBOND
Project Three-Dimensional Mapping Of a Single Hydrogen Bond
Researcher (PI) Adam Marc SWEETMAN
Host Institution (HI) UNIVERSITY OF LEEDS
Call Details Starting Grant (StG), PE3, ERC-2017-STG
Summary All properties of matter are ultimately governed by the forces between single atoms, but our knowledge of interatomic, and intermolecular, potentials is often derived indirectly.
In 3DMOSHBOND, I outline a program of work designed to create a paradigm shift in the direct measurement of complex interatomic potentials via a fundamental reimagining of how atomic resolution imaging, and force measurement, techniques are applied.
To provide a clear proof of principle demonstration of the power of this concept, I propose to map the strength, shape and extent of single hydrogen bonding (H-bonding) interactions in 3D with sub-Angstrom precision. H-bonding is a key component governing intermolecular interactions, particularly for biologically important molecules. Despite its critical importance, H-bonding is relatively poorly understood, and the IUPAC definition of the H-bond was changed as recently as 2011- highlighting the relevance of a new means to engage with these fundamental interactions.
Hitherto unprecedented resolution and accuracy will be achieved via a creation of a novel layer of vertically oriented H-bonding molecules, functionalisation of the tip of a scanning probe microscope with a single complementary H-bonding molecule, and by complete characterisation of the position of all atoms in the junction. This will place two H-bonding groups “end on” and map the extent, and magnitude, of the H-bond with sub-Angstrom precision for a variety of systems. This investigation of the H-bond will present us with an unparalleled level of information regarding its properties.
Experimental results will be compared with ab initio density functional theory (DFT) simulations, to investigate the extent to which state-of-the-art simulations are able to reproduce the behaviour of the H-bonding interaction. The project will create a new generalised probe for the study of single atomic and molecular interactions.
Summary
All properties of matter are ultimately governed by the forces between single atoms, but our knowledge of interatomic, and intermolecular, potentials is often derived indirectly.
In 3DMOSHBOND, I outline a program of work designed to create a paradigm shift in the direct measurement of complex interatomic potentials via a fundamental reimagining of how atomic resolution imaging, and force measurement, techniques are applied.
To provide a clear proof of principle demonstration of the power of this concept, I propose to map the strength, shape and extent of single hydrogen bonding (H-bonding) interactions in 3D with sub-Angstrom precision. H-bonding is a key component governing intermolecular interactions, particularly for biologically important molecules. Despite its critical importance, H-bonding is relatively poorly understood, and the IUPAC definition of the H-bond was changed as recently as 2011- highlighting the relevance of a new means to engage with these fundamental interactions.
Hitherto unprecedented resolution and accuracy will be achieved via a creation of a novel layer of vertically oriented H-bonding molecules, functionalisation of the tip of a scanning probe microscope with a single complementary H-bonding molecule, and by complete characterisation of the position of all atoms in the junction. This will place two H-bonding groups “end on” and map the extent, and magnitude, of the H-bond with sub-Angstrom precision for a variety of systems. This investigation of the H-bond will present us with an unparalleled level of information regarding its properties.
Experimental results will be compared with ab initio density functional theory (DFT) simulations, to investigate the extent to which state-of-the-art simulations are able to reproduce the behaviour of the H-bonding interaction. The project will create a new generalised probe for the study of single atomic and molecular interactions.
Max ERC Funding
1 971 468 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym 3SPIN
Project Three Dimensional Spintronics
Researcher (PI) Russell Paul Cowburn
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), PE3, ERC-2009-AdG
Summary Spintronics, in which both the spin and the charge of the electron are used, is one of the most exciting new disciplines to emerge from nanoscience. The 3SPIN project seeks to open a new research front within spintronics: namely 3-dimensional spintronics, in which magnetic nanostructures are formed into a 3-dimensional interacting network of unrivalled density and hence technological benefit. 3SPIN will explore early-stage science that could underpin 3-dimensional metallic spintronics. The thesis of the project is: that by careful control of the constituent nanostructure properties, a 3-dimensional medium can be created in which a large number of topological solitons can exist. Although hardly studied at all to date, these solitons should be stable at room temperature, extremely compact and easy to manipulate and propagate. This makes them potentially ideal candidates to form the basis of a new spintronics in which the soliton is the basic transport vector instead of electrical current. ¬3.5M of funding is requested to form a new team of 5 researchers who, over a period of 60 months, will perform computer simulations and experimental studies of solitons in 3-dimensional networks of magnetic nanostructures and develop a laboratory demonstrator 3-dimensional memory device using solitons to represent and store data. A high performance electron beam lithography system (cost 1M¬) will be purchased to allow state-of-the-art magnetic nanostructures to be fabricated with perfect control over their magnetic properties, thus allowing the ideal conditions for solitons to be created and controllably manipulated. Outputs from the project will be a complete understanding of the properties of these new objects and a road map charting the next steps for research in the field.
Summary
Spintronics, in which both the spin and the charge of the electron are used, is one of the most exciting new disciplines to emerge from nanoscience. The 3SPIN project seeks to open a new research front within spintronics: namely 3-dimensional spintronics, in which magnetic nanostructures are formed into a 3-dimensional interacting network of unrivalled density and hence technological benefit. 3SPIN will explore early-stage science that could underpin 3-dimensional metallic spintronics. The thesis of the project is: that by careful control of the constituent nanostructure properties, a 3-dimensional medium can be created in which a large number of topological solitons can exist. Although hardly studied at all to date, these solitons should be stable at room temperature, extremely compact and easy to manipulate and propagate. This makes them potentially ideal candidates to form the basis of a new spintronics in which the soliton is the basic transport vector instead of electrical current. ¬3.5M of funding is requested to form a new team of 5 researchers who, over a period of 60 months, will perform computer simulations and experimental studies of solitons in 3-dimensional networks of magnetic nanostructures and develop a laboratory demonstrator 3-dimensional memory device using solitons to represent and store data. A high performance electron beam lithography system (cost 1M¬) will be purchased to allow state-of-the-art magnetic nanostructures to be fabricated with perfect control over their magnetic properties, thus allowing the ideal conditions for solitons to be created and controllably manipulated. Outputs from the project will be a complete understanding of the properties of these new objects and a road map charting the next steps for research in the field.
Max ERC Funding
2 799 996 €
Duration
Start date: 2010-03-01, End date: 2016-02-29
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 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