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
Country Switzerland
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 A-HERO
Project Anthelmintic Research and Optimization
Researcher (PI) Jennifer Irene Keiser
Host Institution (HI) SCHWEIZERISCHES TROPEN- UND PUBLIC HEALTH-INSTITUT
Country Switzerland
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
Project acronym ABC
Project Targeting Multidrug Resistant Cancer
Researcher (PI) Gergely Szakacs
Host Institution (HI) TERMESZETTUDOMANYI KUTATOKOZPONT
Country Hungary
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Summary
Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Max ERC Funding
1 499 640 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym ACCENT
Project Unravelling the architecture and the cartography of the human centriole
Researcher (PI) Paul, Philippe, Desire GUICHARD
Host Institution (HI) UNIVERSITE DE GENEVE
Country Switzerland
Call Details Starting Grant (StG), LS1, ERC-2016-STG
Summary The centriole is the largest evolutionary conserved macromolecular structure responsible for building centrosomes and cilia or flagella in many eukaryotes. Centrioles are critical for the proper execution of important biological processes ranging from cell division to cell signaling. Moreover, centriolar defects have been associated to several human pathologies including ciliopathies and cancer. This state of facts emphasizes the importance of understanding centriole biogenesis. The study of centriole formation is a deep-rooted question, however our current knowledge on its molecular organization at high resolution remains fragmented and limited. In particular, exquisite details of the overall molecular architecture of the human centriole and in particular of its central core region are lacking to understand the basis of centriole organization and function. Resolving this important question represents a challenge that needs to be undertaken and will undoubtedly lead to groundbreaking advances. Another important question to tackle next is to develop innovative methods to enable the nanometric molecular mapping of centriolar proteins within distinct architectural elements of the centriole. This missing information will be key to unravel the molecular mechanisms behind centriolar organization.
This research proposal aims at building a cartography of the human centriole by elucidating its molecular composition and architecture. To this end, we will combine the use of innovative and multidisciplinary techniques encompassing spatial proteomics, cryo-electron tomography, state-of-the-art microscopy and in vitro assays and to achieve a comprehensive molecular and structural view of the human centriole. All together, we expect that these advances will help understand basic principles underlying centriole and cilia formation as well as might have further relevance for human health.
Summary
The centriole is the largest evolutionary conserved macromolecular structure responsible for building centrosomes and cilia or flagella in many eukaryotes. Centrioles are critical for the proper execution of important biological processes ranging from cell division to cell signaling. Moreover, centriolar defects have been associated to several human pathologies including ciliopathies and cancer. This state of facts emphasizes the importance of understanding centriole biogenesis. The study of centriole formation is a deep-rooted question, however our current knowledge on its molecular organization at high resolution remains fragmented and limited. In particular, exquisite details of the overall molecular architecture of the human centriole and in particular of its central core region are lacking to understand the basis of centriole organization and function. Resolving this important question represents a challenge that needs to be undertaken and will undoubtedly lead to groundbreaking advances. Another important question to tackle next is to develop innovative methods to enable the nanometric molecular mapping of centriolar proteins within distinct architectural elements of the centriole. This missing information will be key to unravel the molecular mechanisms behind centriolar organization.
This research proposal aims at building a cartography of the human centriole by elucidating its molecular composition and architecture. To this end, we will combine the use of innovative and multidisciplinary techniques encompassing spatial proteomics, cryo-electron tomography, state-of-the-art microscopy and in vitro assays and to achieve a comprehensive molecular and structural view of the human centriole. All together, we expect that these advances will help understand basic principles underlying centriole and cilia formation as well as might have further relevance for human health.
Max ERC Funding
1 498 965 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym ADIPODIF
Project Adipocyte Differentiation and Metabolic Functions in Obesity and Type 2 Diabetes
Researcher (PI) Christian Wolfrum
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Starting Grant (StG), LS6, ERC-2007-StG
Summary Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.
Summary
Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.
Max ERC Funding
1 607 105 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym AGILEFLIGHT
Project Low-latency Perception and Action for Agile Vision-based Flight
Researcher (PI) Davide SCARAMUZZA
Host Institution (HI) UNIVERSITAT ZURICH
Country Switzerland
Call Details Consolidator Grant (CoG), PE7, ERC-2019-COG
Summary Drones are disrupting industries, such as agriculture, package delivery, inspection, and search and rescue. However, they are still either controlled by a human pilot or heavily rely on GPS for navigating autonomously. The alternative to GPS are onboard sensors, such as cameras: from the raw data, a local 3D map of the environment is built, which is then used to plan a safe trajectory to the goal. While the underlying algorithms are well understood, we are still far from having autonomous drones that can navigate through complex environments as good as human pilots. State-of-the-art perception and control algorithms are mature but not robust: coping with unreliable state estimation, low-latency perception, real-time planning in dynamic environments, and tight coupling of perception and action under severe resource constraints are all still unsolved research problems. Another issue is that, because battery energy density is increasing at a very slow rate, drones need to navigate faster in order to accomplish more within their limited flight time. To obtain more agile robots, we need faster sensors and low-latency processing.
The goal of this project is to develop novel scientific methods that would allow me to demonstrate autonomous, vision-based, agile quadrotor navigation in unknown, GPS-denied, and cluttered environments with possibly moving obstacles, which can be as effective in terms of maneuverability and agility as those of professional drone pilots. The outcome would not only be beneficial for disaster response scenarios, but also for other scenarios, such as aerial delivery or inspection. To achieve this ambitious goal, I will first develop robust, low-latency, multimodal perception algorithms that combine the advantages of standard cameras with event cameras. Then, I will develop novel methods that unify perception and state estimation together with planning and control to enable agile maneuvers through cluttered, unknown, and dynamic environments.
Summary
Drones are disrupting industries, such as agriculture, package delivery, inspection, and search and rescue. However, they are still either controlled by a human pilot or heavily rely on GPS for navigating autonomously. The alternative to GPS are onboard sensors, such as cameras: from the raw data, a local 3D map of the environment is built, which is then used to plan a safe trajectory to the goal. While the underlying algorithms are well understood, we are still far from having autonomous drones that can navigate through complex environments as good as human pilots. State-of-the-art perception and control algorithms are mature but not robust: coping with unreliable state estimation, low-latency perception, real-time planning in dynamic environments, and tight coupling of perception and action under severe resource constraints are all still unsolved research problems. Another issue is that, because battery energy density is increasing at a very slow rate, drones need to navigate faster in order to accomplish more within their limited flight time. To obtain more agile robots, we need faster sensors and low-latency processing.
The goal of this project is to develop novel scientific methods that would allow me to demonstrate autonomous, vision-based, agile quadrotor navigation in unknown, GPS-denied, and cluttered environments with possibly moving obstacles, which can be as effective in terms of maneuverability and agility as those of professional drone pilots. The outcome would not only be beneficial for disaster response scenarios, but also for other scenarios, such as aerial delivery or inspection. To achieve this ambitious goal, I will first develop robust, low-latency, multimodal perception algorithms that combine the advantages of standard cameras with event cameras. Then, I will develop novel methods that unify perception and state estimation together with planning and control to enable agile maneuvers through cluttered, unknown, and dynamic environments.
Max ERC Funding
2 000 000 €
Duration
Start date: 2020-09-01, End date: 2025-08-31
Project acronym AGRISCENTS
Project Scents and sensibility in agriculture: exploiting specificity in herbivore- and pathogen-induced plant volatiles for real-time crop monitoring
Researcher (PI) Theodoor Turlings
Host Institution (HI) UNIVERSITE DE NEUCHATEL
Country Switzerland
Call Details Advanced Grant (AdG), LS9, ERC-2017-ADG
Summary Plants typically release large quantities of volatiles in response to attack by herbivores or pathogens. I may claim to have contributed to various breakthroughs in this research field, including the discovery that the volatile blends induced by different attackers are astonishingly specific, resulting in characteristic, readily distinguishable odour blends. Using maize as our model plant, I wish to take several leaps forward in our understanding of this signal specificity and use this knowledge to develop sensors for the real-time detection of crop pests and diseases. For this, three interconnected work-packages will aim to:
• Develop chemical analytical techniques and statistical models to decipher the odorous vocabulary of plants, and to create a complete inventory of “odour-prints” for a wide range of herbivore-plant and pathogen-plant combinations, including simultaneous infestations.
• Develop and optimize nano-mechanical sensors for the detection of specific plant volatile mixtures. For this, we will initially adapt a prototype sensor that has been successfully developed for the detection of cancer-related volatiles in human breath.
• Genetically manipulate maize plants to release a unique blend of root-produced volatiles upon herbivory. For this, we will engineer gene cassettes that combine recently identified P450 (CYP) genes from poplar with inducible, root-specific promoters from maize. This will result in maize plants that, in response to pest attack, release easy-to-detect aldoximes and nitriles from their roots.
In short, by investigating and manipulating the specificity of inducible odour blends we will generate the necessary knowhow to develop a novel odour-detection device. The envisioned sensor technology will permit real-time monitoring of the pests and enable farmers to apply crop protection treatments at the right time and in the right place.
Summary
Plants typically release large quantities of volatiles in response to attack by herbivores or pathogens. I may claim to have contributed to various breakthroughs in this research field, including the discovery that the volatile blends induced by different attackers are astonishingly specific, resulting in characteristic, readily distinguishable odour blends. Using maize as our model plant, I wish to take several leaps forward in our understanding of this signal specificity and use this knowledge to develop sensors for the real-time detection of crop pests and diseases. For this, three interconnected work-packages will aim to:
• Develop chemical analytical techniques and statistical models to decipher the odorous vocabulary of plants, and to create a complete inventory of “odour-prints” for a wide range of herbivore-plant and pathogen-plant combinations, including simultaneous infestations.
• Develop and optimize nano-mechanical sensors for the detection of specific plant volatile mixtures. For this, we will initially adapt a prototype sensor that has been successfully developed for the detection of cancer-related volatiles in human breath.
• Genetically manipulate maize plants to release a unique blend of root-produced volatiles upon herbivory. For this, we will engineer gene cassettes that combine recently identified P450 (CYP) genes from poplar with inducible, root-specific promoters from maize. This will result in maize plants that, in response to pest attack, release easy-to-detect aldoximes and nitriles from their roots.
In short, by investigating and manipulating the specificity of inducible odour blends we will generate the necessary knowhow to develop a novel odour-detection device. The envisioned sensor technology will permit real-time monitoring of the pests and enable farmers to apply crop protection treatments at the right time and in the right place.
Max ERC Funding
2 498 086 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym AimingT6SS
Project Mechanisms of dynamic localization of the bacterial Type 6 secretion system assembly
Researcher (PI) Marek BASLER
Host Institution (HI) UNIVERSITAT BASEL
Country Switzerland
Call Details Consolidator Grant (CoG), LS6, ERC-2019-COG
Summary The Type 6 secretion system (T6SS) allows Gram-negative bacteria to deliver toxins into both eukaryotic and bacterial target cells and thus cause disease or kill competitors. T6SS is composed of four main parts: a membrane complex, a baseplate and a long spring-like sheath wrapped around an inner tube. Sheath contraction generates a large amount of energy to push the tube with associated toxins through the baseplate and membrane complex out of the cell. However, the reach of the T6SS tube is limited and thus a direct contact with the target membrane and precise positioning of T6SS assembly is required for protein translocation. In this proposal, we will unravel principles of spatial and temporal coordination of T6SS assembly that we have recently observed in several bacterial species. We will study how cells sense attacks from neighboring bacteria to dynamically localize its T6SS. We will describe how bacteria initiate and position T6SS assembly in response to physical cell-cell interactions. We will identify the principles and the role of T6SS localization in intracellular pathogens. Using genetic and biochemical approaches, we will identify and characterize proteins interacting with the core components of T6SS and test their role in initiation and positioning of T6SS assembly. We will search for peptidoglycan remodeling enzymes required for T6SS assembly. We will use advanced microscopy techniques to describe dynamic localization of proteins upon T6SS activation to establish the order of their assembly. We will quantify how much T6SS aiming increases efficiency of protein delivery and T6SS function during bacterial competition and pathogenesis. Overall, we will unravel novel principles of spatial and temporal control of localization of protein complexes and show how this allows bacteria to quickly respond to external cues and interact with their environment.
Summary
The Type 6 secretion system (T6SS) allows Gram-negative bacteria to deliver toxins into both eukaryotic and bacterial target cells and thus cause disease or kill competitors. T6SS is composed of four main parts: a membrane complex, a baseplate and a long spring-like sheath wrapped around an inner tube. Sheath contraction generates a large amount of energy to push the tube with associated toxins through the baseplate and membrane complex out of the cell. However, the reach of the T6SS tube is limited and thus a direct contact with the target membrane and precise positioning of T6SS assembly is required for protein translocation. In this proposal, we will unravel principles of spatial and temporal coordination of T6SS assembly that we have recently observed in several bacterial species. We will study how cells sense attacks from neighboring bacteria to dynamically localize its T6SS. We will describe how bacteria initiate and position T6SS assembly in response to physical cell-cell interactions. We will identify the principles and the role of T6SS localization in intracellular pathogens. Using genetic and biochemical approaches, we will identify and characterize proteins interacting with the core components of T6SS and test their role in initiation and positioning of T6SS assembly. We will search for peptidoglycan remodeling enzymes required for T6SS assembly. We will use advanced microscopy techniques to describe dynamic localization of proteins upon T6SS activation to establish the order of their assembly. We will quantify how much T6SS aiming increases efficiency of protein delivery and T6SS function during bacterial competition and pathogenesis. Overall, we will unravel novel principles of spatial and temporal control of localization of protein complexes and show how this allows bacteria to quickly respond to external cues and interact with their environment.
Max ERC Funding
2 493 650 €
Duration
Start date: 2021-01-01, End date: 2025-12-31
Project acronym AMADEUS
Project Advancing CO2 Capture Materials by Atomic Scale Design: the Quest for Understanding
Researcher (PI) Christoph Ruediger MueLLER
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Consolidator Grant (CoG), PE8, ERC-2018-COG
Summary Carbon dioxide capture and storage is a technology to mitigate climate change by removing CO2 from flue gas streams or the atmosphere and storing it in geological formations. While CO2 removal from natural gas by amine scrubbing is implemented on the large scale, the cost of such process is currently prohibitively expensive. Inexpensive alkali earth metal oxides (MgO and CaO) feature high theoretical CO2 uptakes, but suffer from poor cyclic stability and slow kinetics. Yet, the key objective of recent research on alkali earth metal oxide based CO2 sorbents has been the processing of inexpensive, naturally occurring CO2 sorbents, notably limestone and dolomite, to stabilize their modest CO2 uptake and to establish re-activation methods through engineering approaches. While this research demonstrated a landmark Megawatt (MW) scale viability of the process, our fundamental understanding of the underlying CO2 capture, regeneration and deactivation pathways did not improve. The latter knowledge is, however, vital for the rational design of improved, yet practical CaO and MgO sorbents. Hence this proposal is concerned with obtaining an understanding of the underlying mechanisms that control the ability of an alkali metal oxide to capture a large quantity of CO2 with a high rate, to regenerate and to operate with high cyclic stability. Achieving these aims relies on the ability to fabricate model structures and to characterize in great detail their surface chemistry, morphology, chemical composition and changes therein under reactive conditions. This makes the development of operando and in situ characterization tools an essential prerequisite. Advances in these areas shall allow achieving the overall goal of this project, viz. to formulate a roadmap to fabricate improved CO2 sorbents through their precisely engineered structure, composition and morphology.
Summary
Carbon dioxide capture and storage is a technology to mitigate climate change by removing CO2 from flue gas streams or the atmosphere and storing it in geological formations. While CO2 removal from natural gas by amine scrubbing is implemented on the large scale, the cost of such process is currently prohibitively expensive. Inexpensive alkali earth metal oxides (MgO and CaO) feature high theoretical CO2 uptakes, but suffer from poor cyclic stability and slow kinetics. Yet, the key objective of recent research on alkali earth metal oxide based CO2 sorbents has been the processing of inexpensive, naturally occurring CO2 sorbents, notably limestone and dolomite, to stabilize their modest CO2 uptake and to establish re-activation methods through engineering approaches. While this research demonstrated a landmark Megawatt (MW) scale viability of the process, our fundamental understanding of the underlying CO2 capture, regeneration and deactivation pathways did not improve. The latter knowledge is, however, vital for the rational design of improved, yet practical CaO and MgO sorbents. Hence this proposal is concerned with obtaining an understanding of the underlying mechanisms that control the ability of an alkali metal oxide to capture a large quantity of CO2 with a high rate, to regenerate and to operate with high cyclic stability. Achieving these aims relies on the ability to fabricate model structures and to characterize in great detail their surface chemistry, morphology, chemical composition and changes therein under reactive conditions. This makes the development of operando and in situ characterization tools an essential prerequisite. Advances in these areas shall allow achieving the overall goal of this project, viz. to formulate a roadmap to fabricate improved CO2 sorbents through their precisely engineered structure, composition and morphology.
Max ERC Funding
1 994 900 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym Amygdala Circuits
Project Amygdala Circuits for Appetitive Conditioning
Researcher (PI) Andreas Luthi
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Country Switzerland
Call Details Advanced Grant (AdG), LS5, ERC-2014-ADG
Summary The project outlined here addresses the fundamental question how the brain encodes and controls behavior. While we have a reasonable understanding of the role of entire brain areas in such processes, and of mechanisms at the molecular and synaptic levels, there is a big gap in our knowledge of how behavior is controlled at the level of defined neuronal circuits.
In natural environments, chances for survival depend on learning about possible aversive and appetitive outcomes and on the appropriate behavioral responses. Most studies addressing the underlying mechanisms at the level of neuronal circuits have focused on aversive learning, such as in Pavlovian fear conditioning. Understanding how activity in defined neuronal circuits mediates appetitive learning, as well as how these circuitries are shared and interact with aversive learning circuits, is a central question in the neuroscience of learning and memory and the focus of this grant application.
Using a multidisciplinary approach in mice, combining behavioral, in vivo and in vitro electrophysiological, imaging, optogenetic and state-of-the-art viral circuit tracing techniques, we aim at dissecting the neuronal circuitry of appetitive Pavlovian conditioning with a focus on the amygdala, a key brain region important for both aversive and appetitive learning. Ultimately, elucidating these mechanisms at the level of defined neurons and circuits is fundamental not only for an understanding of memory processes in the brain in general, but also to inform a mechanistic approach to psychiatric conditions associated with amygdala dysfunction and dysregulated emotional responses including anxiety and mood disorders.
Summary
The project outlined here addresses the fundamental question how the brain encodes and controls behavior. While we have a reasonable understanding of the role of entire brain areas in such processes, and of mechanisms at the molecular and synaptic levels, there is a big gap in our knowledge of how behavior is controlled at the level of defined neuronal circuits.
In natural environments, chances for survival depend on learning about possible aversive and appetitive outcomes and on the appropriate behavioral responses. Most studies addressing the underlying mechanisms at the level of neuronal circuits have focused on aversive learning, such as in Pavlovian fear conditioning. Understanding how activity in defined neuronal circuits mediates appetitive learning, as well as how these circuitries are shared and interact with aversive learning circuits, is a central question in the neuroscience of learning and memory and the focus of this grant application.
Using a multidisciplinary approach in mice, combining behavioral, in vivo and in vitro electrophysiological, imaging, optogenetic and state-of-the-art viral circuit tracing techniques, we aim at dissecting the neuronal circuitry of appetitive Pavlovian conditioning with a focus on the amygdala, a key brain region important for both aversive and appetitive learning. Ultimately, elucidating these mechanisms at the level of defined neurons and circuits is fundamental not only for an understanding of memory processes in the brain in general, but also to inform a mechanistic approach to psychiatric conditions associated with amygdala dysfunction and dysregulated emotional responses including anxiety and mood disorders.
Max ERC Funding
2 497 200 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
