Project acronym 3D-VIEW
Project Seeing the invisible: Light-based 3D imaging of opaque nanostructures
Researcher (PI) Stefan WITTE
Host Institution (HI) STICHTING NEDERLANDSE WETENSCHAPPELIJK ONDERZOEK INSTITUTEN
Country Netherlands
Call Details Consolidator Grant (CoG), PE7, ERC-2019-COG
Summary Nanostructures drive the world around us. Every modern electronic device contains integrated circuits and nano-electronics to provide its functionality. Advances in nanotechnology directly impact society by enabling smartphones, autonomous devices, the internet of things, data storage, and essentially all forms of advanced technology. Fabricating such nanostructures crucially depends on having the tools to make them visible without destroying them. Modern nanodevices often have complex three-dimensional architectures with small features in all dimensions. While imaging methods that achieve nanometer-scale resolution exist, there are currently no compact tools that can look inside 3D nanostructures made out of metals and semiconductors without damaging their delicate internal structure. I will address this challenge by developing compact tools to image 3D nanostructures in a non-invasive way. Even though most nanostructures are completely opaque to visible light, I will develop light-based methods, combined with computational imaging techniques developed in my previous ERC project, to look inside them with unprecedented resolution and contrast. Light-based imaging is unparalleled in speed and versatility, and allows contact-free detection. My proposal is to: 1) Use compact laser-produced soft-X-ray sources to image nanostructures with high 3D resolution and element-sensitive contrast; 2) Use laser-induced ultrasound pulses to image complex 3D nanostructures, even through strongly absorbing materials; 3) Employ computational imaging methods to reconstruct high-resolution 3D object images from the resulting complex diffraction signals. I will forge a coordinated research program to bring these concepts to reality. This program provides exciting prospects for fundamental science and industrial metrology. I will go beyond the state-of-the-art in nano-imaging, to extend our vision into the complex interior of the smallest structures found in science and technology.
Summary
Nanostructures drive the world around us. Every modern electronic device contains integrated circuits and nano-electronics to provide its functionality. Advances in nanotechnology directly impact society by enabling smartphones, autonomous devices, the internet of things, data storage, and essentially all forms of advanced technology. Fabricating such nanostructures crucially depends on having the tools to make them visible without destroying them. Modern nanodevices often have complex three-dimensional architectures with small features in all dimensions. While imaging methods that achieve nanometer-scale resolution exist, there are currently no compact tools that can look inside 3D nanostructures made out of metals and semiconductors without damaging their delicate internal structure. I will address this challenge by developing compact tools to image 3D nanostructures in a non-invasive way. Even though most nanostructures are completely opaque to visible light, I will develop light-based methods, combined with computational imaging techniques developed in my previous ERC project, to look inside them with unprecedented resolution and contrast. Light-based imaging is unparalleled in speed and versatility, and allows contact-free detection. My proposal is to: 1) Use compact laser-produced soft-X-ray sources to image nanostructures with high 3D resolution and element-sensitive contrast; 2) Use laser-induced ultrasound pulses to image complex 3D nanostructures, even through strongly absorbing materials; 3) Employ computational imaging methods to reconstruct high-resolution 3D object images from the resulting complex diffraction signals. I will forge a coordinated research program to bring these concepts to reality. This program provides exciting prospects for fundamental science and industrial metrology. I will go beyond the state-of-the-art in nano-imaging, to extend our vision into the complex interior of the smallest structures found in science and technology.
Max ERC Funding
2 000 000 €
Duration
Start date: 2020-10-01, End date: 2025-09-30
Project acronym 4D-EEG
Project 4D-EEG: A new tool to investigate the spatial and temporal activity patterns in the brain
Researcher (PI) Franciscus C.T. Van Der Helm
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Country Netherlands
Call Details Advanced Grant (AdG), PE7, ERC-2011-ADG_20110209
Summary Our first goal is to develop a new tool to determine brain activity with a high temporal (< 1 msec) and spatial (about 2 mm) resolution with the focus on motor control. High density EEG (up to 256 electrodes) will be used for EEG source localization. Advanced force-controlled robot manipulators will be used to impose continuous force perturbations to the joints. Advanced closed-loop system identification algorithms will identify the dynamic EEG response of multiple brain areas to the perturbation, leading to a functional interpretation of EEG. The propagation of the signal in time and 3D space through the cortex can be monitored: 4D-EEG. Preliminary experiments with EEG localization have shown that the continuous force perturbations resulted in a better signal-to-noise ratio and coherence than the current method using transient perturbations..
4D-EEG will be a direct measure of the neural activity in the brain with an excellent temporal response and easy to use in combination with motor control tasks. The new 4D-EEG method is expected to provide a breakthrough in comparison to functional MRI (fMRI) when elucidating the meaning of cortical map plasticity in motor learning.
Our second goal is to generate and validate new hypotheses about the longitudinal relationship between motor learning and cortical map plasticity by clinically using 4D-EEG in an intensive, repeated measurement design in patients suffering from a stroke. The application of 4D-EEG combined with haptic robots will allow us to discover how dynamics in cortical map plasticity are related with upper limb recovery after stroke in terms of neural repair and using behavioral compensation strategies while performing a meaningful motor tasks.. The non-invasive 4D-EEG technique combined with haptic robots will open the window about what and how patients (re)learn when showing motor recovery after stroke in order to allow us to develop more effective patient-tailored therapies in neuro-rehabilitation.
Summary
Our first goal is to develop a new tool to determine brain activity with a high temporal (< 1 msec) and spatial (about 2 mm) resolution with the focus on motor control. High density EEG (up to 256 electrodes) will be used for EEG source localization. Advanced force-controlled robot manipulators will be used to impose continuous force perturbations to the joints. Advanced closed-loop system identification algorithms will identify the dynamic EEG response of multiple brain areas to the perturbation, leading to a functional interpretation of EEG. The propagation of the signal in time and 3D space through the cortex can be monitored: 4D-EEG. Preliminary experiments with EEG localization have shown that the continuous force perturbations resulted in a better signal-to-noise ratio and coherence than the current method using transient perturbations..
4D-EEG will be a direct measure of the neural activity in the brain with an excellent temporal response and easy to use in combination with motor control tasks. The new 4D-EEG method is expected to provide a breakthrough in comparison to functional MRI (fMRI) when elucidating the meaning of cortical map plasticity in motor learning.
Our second goal is to generate and validate new hypotheses about the longitudinal relationship between motor learning and cortical map plasticity by clinically using 4D-EEG in an intensive, repeated measurement design in patients suffering from a stroke. The application of 4D-EEG combined with haptic robots will allow us to discover how dynamics in cortical map plasticity are related with upper limb recovery after stroke in terms of neural repair and using behavioral compensation strategies while performing a meaningful motor tasks.. The non-invasive 4D-EEG technique combined with haptic robots will open the window about what and how patients (re)learn when showing motor recovery after stroke in order to allow us to develop more effective patient-tailored therapies in neuro-rehabilitation.
Max ERC Funding
3 477 202 €
Duration
Start date: 2012-06-01, End date: 2017-05-31
Project acronym AARTFAAC
Project Amsterdam-ASTRON Radio Transient Facility And Analysis Centre: Probing the Extremes of Astrophysics
Researcher (PI) Ralph Antoine Marie Joseph Wijers
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Country Netherlands
Call Details Advanced Grant (AdG), PE9, ERC-2009-AdG
Summary Some of the most extreme tests of physical law come from its manifestations in the behaviour of black holes and neutron stars, and as such these objects should be used as fundamental physics labs. Due to advances in both theoretical work and observational techniques, I have a major opportunity now to significantly push this agenda forward and get better answers to questions like: How are black holes born? How can energy be extracted from black holes? What is the origin of magnetic fields and cosmic rays in jets and shocks? Is their primary energy stream hadronic or magnetic? I propose to do this by exploiting the advent of wide-field radio astronomy: extreme objects are very rare and usually transient, so not only must one survey large areas of sky, but also must one do this often. I propose to form and shape a group that will use the LOFAR wide-field radio telescope to hunt for these extreme transients and systematically collect enough well-documented examples of the behaviour of each type of transient. Furthermore, I propose to expand LOFAR with a true 24/7 all-sky monitor to catch and study even the rarest of events. Next, I will use my experience in gamma-ray burst followup to conduct a vigorous multi-wavelength programme of study of these objects, to constrain their physics from as many angles as possible. This will eventually include results from multi-messenger astrophysics, in which we use neutrinos, gravity waves, and other non-electromagnetic messengers as extra diagnostics of the physics of these sources. Finally, I will build on my experience in modelling accretion phenomena and relativistic explosions to develop a theoretical framework for these phenomena and constrain the resulting models with the rich data sets we obtain.
Summary
Some of the most extreme tests of physical law come from its manifestations in the behaviour of black holes and neutron stars, and as such these objects should be used as fundamental physics labs. Due to advances in both theoretical work and observational techniques, I have a major opportunity now to significantly push this agenda forward and get better answers to questions like: How are black holes born? How can energy be extracted from black holes? What is the origin of magnetic fields and cosmic rays in jets and shocks? Is their primary energy stream hadronic or magnetic? I propose to do this by exploiting the advent of wide-field radio astronomy: extreme objects are very rare and usually transient, so not only must one survey large areas of sky, but also must one do this often. I propose to form and shape a group that will use the LOFAR wide-field radio telescope to hunt for these extreme transients and systematically collect enough well-documented examples of the behaviour of each type of transient. Furthermore, I propose to expand LOFAR with a true 24/7 all-sky monitor to catch and study even the rarest of events. Next, I will use my experience in gamma-ray burst followup to conduct a vigorous multi-wavelength programme of study of these objects, to constrain their physics from as many angles as possible. This will eventually include results from multi-messenger astrophysics, in which we use neutrinos, gravity waves, and other non-electromagnetic messengers as extra diagnostics of the physics of these sources. Finally, I will build on my experience in modelling accretion phenomena and relativistic explosions to develop a theoretical framework for these phenomena and constrain the resulting models with the rich data sets we obtain.
Max ERC Funding
3 499 128 €
Duration
Start date: 2010-10-01, End date: 2016-09-30
Project acronym ABCvolume
Project The ABC of Cell Volume Regulation
Researcher (PI) Berend Poolman
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Country Netherlands
Call Details Advanced Grant (AdG), LS1, ERC-2014-ADG
Summary Cell volume regulation is crucial for any living cell because changes in volume determine the metabolic activity through e.g. changes in ionic strength, pH, macromolecular crowding and membrane tension. These physical chemical parameters influence interaction rates and affinities of biomolecules, folding rates, and fold stabilities in vivo. Understanding of the underlying volume regulatory mechanisms has immediate application in biotechnology and health, yet these factors are generally ignored in systems analyses of cellular functions.
My team has uncovered a number of mechanisms and insights of cell volume regulation. The next step forward is to elucidate how the components of a cell volume regulatory circuit work together and control the physicochemical conditions of the cell.
I propose construction of a synthetic cell in which an osmoregulatory transporter and mechanosensitive channel form a minimal volume regulatory network. My group has developed the technology to reconstitute membrane proteins into lipid vesicles (synthetic cells). One of the challenges is to incorporate into the vesicles an efficient pathway for ATP production and maintain energy homeostasis while the load on the system varies. We aim to control the transmembrane flux of osmolytes, which requires elucidation of the molecular mechanism of gating of the osmoregulatory transporter. We will focus on the glycine betaine ABC importer, which is one of the most complex transporters known to date with ten distinct protein domains, transiently interacting with each other.
The proposed synthetic metabolic circuit constitutes a fascinating out-of-equilibrium system, allowing us to understand cell volume regulatory mechanisms in a context and at a level of complexity minimally needed for life. Analysis of this circuit will address many outstanding questions and eventually allow us to design more sophisticated vesicular systems with applications, for example as compartmentalized reaction networks.
Summary
Cell volume regulation is crucial for any living cell because changes in volume determine the metabolic activity through e.g. changes in ionic strength, pH, macromolecular crowding and membrane tension. These physical chemical parameters influence interaction rates and affinities of biomolecules, folding rates, and fold stabilities in vivo. Understanding of the underlying volume regulatory mechanisms has immediate application in biotechnology and health, yet these factors are generally ignored in systems analyses of cellular functions.
My team has uncovered a number of mechanisms and insights of cell volume regulation. The next step forward is to elucidate how the components of a cell volume regulatory circuit work together and control the physicochemical conditions of the cell.
I propose construction of a synthetic cell in which an osmoregulatory transporter and mechanosensitive channel form a minimal volume regulatory network. My group has developed the technology to reconstitute membrane proteins into lipid vesicles (synthetic cells). One of the challenges is to incorporate into the vesicles an efficient pathway for ATP production and maintain energy homeostasis while the load on the system varies. We aim to control the transmembrane flux of osmolytes, which requires elucidation of the molecular mechanism of gating of the osmoregulatory transporter. We will focus on the glycine betaine ABC importer, which is one of the most complex transporters known to date with ten distinct protein domains, transiently interacting with each other.
The proposed synthetic metabolic circuit constitutes a fascinating out-of-equilibrium system, allowing us to understand cell volume regulatory mechanisms in a context and at a level of complexity minimally needed for life. Analysis of this circuit will address many outstanding questions and eventually allow us to design more sophisticated vesicular systems with applications, for example as compartmentalized reaction networks.
Max ERC Funding
2 247 231 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
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 ACCENT
Project How antibodies and complement orchestrate protective immune responses against bacteria
Researcher (PI) suzan ROOIJAKKERS
Host Institution (HI) UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Country Netherlands
Call Details Consolidator Grant (CoG), LS6, ERC-2020-COG
Summary Due to antibiotic resistance, there is now great interest in the development of antibody-based therapies against bacterial infections, for instance via antibodies that boost the host immune system. In order to kill bacteria, antibodies should trigger activation of the complement cascade, which forms bactericidal Membrane Attack Complex (MAC) pores and strongly enhances phagocytosis. Although the power of complement could be exploited for antibody therapies, such developments are hampered by our limited insights into the mechanisms underlying antibody-dependent complement activation on bacteria. My team has developed unique assays to study complement activation on bacteria. In this proposal, we will combine our function-driven approaches with novel B cell sequencing methods to identify anti-bacterial antibodies with strong complement-activating potential. We will develop novel approaches to identify the variable (VH:VL) sequences of human antibodies that recognize whole bacterial cells. After FACS sorting of memory B cells or yeast Fab display, we will use multi-well functional assays to select monoclonal antibodies driving potent complement activation and subsequent killing of E. coli (via neutrophils or MAC). Thanks to our unique tools and unprecedented insights, we are in an unique position to decipher basic mechanisms by which antibodies induce bacterial killing via neutrophils or MAC. We will combine live-cell imaging and structural approaches to determine how bactericidal antibodies assemble lethal MAC pores in the bacterial cell envelope. Finally, we will explore the design of potent antibody combinations and study the mechanisms by which antibodies steer different effector functions, both in the context of clinical and non-pathogenic E. coli strains. Altogether, this grant will lead to fundamental knowledge about the functioning of the immune system and provide a biological basis for the development of antibody-based therapies against bacteria.
Summary
Due to antibiotic resistance, there is now great interest in the development of antibody-based therapies against bacterial infections, for instance via antibodies that boost the host immune system. In order to kill bacteria, antibodies should trigger activation of the complement cascade, which forms bactericidal Membrane Attack Complex (MAC) pores and strongly enhances phagocytosis. Although the power of complement could be exploited for antibody therapies, such developments are hampered by our limited insights into the mechanisms underlying antibody-dependent complement activation on bacteria. My team has developed unique assays to study complement activation on bacteria. In this proposal, we will combine our function-driven approaches with novel B cell sequencing methods to identify anti-bacterial antibodies with strong complement-activating potential. We will develop novel approaches to identify the variable (VH:VL) sequences of human antibodies that recognize whole bacterial cells. After FACS sorting of memory B cells or yeast Fab display, we will use multi-well functional assays to select monoclonal antibodies driving potent complement activation and subsequent killing of E. coli (via neutrophils or MAC). Thanks to our unique tools and unprecedented insights, we are in an unique position to decipher basic mechanisms by which antibodies induce bacterial killing via neutrophils or MAC. We will combine live-cell imaging and structural approaches to determine how bactericidal antibodies assemble lethal MAC pores in the bacterial cell envelope. Finally, we will explore the design of potent antibody combinations and study the mechanisms by which antibodies steer different effector functions, both in the context of clinical and non-pathogenic E. coli strains. Altogether, this grant will lead to fundamental knowledge about the functioning of the immune system and provide a biological basis for the development of antibody-based therapies against bacteria.
Max ERC Funding
2 000 000 €
Duration
Start date: 2021-06-01, End date: 2026-05-31
Project acronym ACTIVATION OF XCI
Project Molecular mechanisms controlling X chromosome inactivation
Researcher (PI) Joost Henk Gribnau
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Country Netherlands
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.
Summary
In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym ActiveBioFluids
Project Origins of Collective Motion in Active Biofluids
Researcher (PI) Daniel TAM
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Country Netherlands
Call Details Starting Grant (StG), PE3, ERC-2016-STG
Summary The emergence of coherent behaviour is ubiquitous in the natural world and has long captivated biologists and physicists alike. One area of growing interest is the collective motion and synchronization arising within and between simple motile organisms. My goal is to develop and use a novel experimental approach to unravel the origins of spontaneous coherent motion in three model systems of biofluids: (1) the synchronization of the two flagella of green algae Chlamydomonas Rheinhardtii, (2) the metachronal wave in the cilia of protist Paramecium and (3) the collective motion of swimming microorganisms in active suspensions. Understanding the mechanisms leading to collective motion is of tremendous importance because it is crucial to many biological processes such as mechanical signal transduction, embryonic development and biofilm formation.
Up till now, most of the work has been theoretical and has led to the dominant view that hydrodynamic interactions are the main driving force for synchronization and collective motion. Recent experiments have challenged this view and highlighted the importance of direct mechanical contact. New experimental studies are now crucially needed. The state-of-the-art of experimental approaches consists of observations of unperturbed cells. The key innovation in our approach is to dynamically interact with microorganisms in real-time, at the relevant time and length scales. I will investigate the origins of coherent motion by reproducing synthetically the mechanical signatures of physiological flows and direct mechanical interactions and track precisely the response of the organism to the perturbations. Our new approach will incorporate optical tweezers to interact with motile cells, and a unique μ-Tomographic PIV setup to track their 3D micron-scale motion.
This proposal tackles a timely question in biophysics and will yield new insight into the fundamental principles underlying collective motion in active biological matter.
Summary
The emergence of coherent behaviour is ubiquitous in the natural world and has long captivated biologists and physicists alike. One area of growing interest is the collective motion and synchronization arising within and between simple motile organisms. My goal is to develop and use a novel experimental approach to unravel the origins of spontaneous coherent motion in three model systems of biofluids: (1) the synchronization of the two flagella of green algae Chlamydomonas Rheinhardtii, (2) the metachronal wave in the cilia of protist Paramecium and (3) the collective motion of swimming microorganisms in active suspensions. Understanding the mechanisms leading to collective motion is of tremendous importance because it is crucial to many biological processes such as mechanical signal transduction, embryonic development and biofilm formation.
Up till now, most of the work has been theoretical and has led to the dominant view that hydrodynamic interactions are the main driving force for synchronization and collective motion. Recent experiments have challenged this view and highlighted the importance of direct mechanical contact. New experimental studies are now crucially needed. The state-of-the-art of experimental approaches consists of observations of unperturbed cells. The key innovation in our approach is to dynamically interact with microorganisms in real-time, at the relevant time and length scales. I will investigate the origins of coherent motion by reproducing synthetically the mechanical signatures of physiological flows and direct mechanical interactions and track precisely the response of the organism to the perturbations. Our new approach will incorporate optical tweezers to interact with motile cells, and a unique μ-Tomographic PIV setup to track their 3D micron-scale motion.
This proposal tackles a timely question in biophysics and will yield new insight into the fundamental principles underlying collective motion in active biological matter.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
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 AEONS
Project Advancing the Equation of state of Neutron Stars
Researcher (PI) Anna WATTS
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Country Netherlands
Call Details Consolidator Grant (CoG), PE9, ERC-2019-COG
Summary Densities in neutron star (NS) cores can reach up to ten times the density of a normal atomic nucleus, and the stabilising effect of gravitational confinement permits long-timescale weak interactions. This generates nucleonic matter that is extremely neutron-rich, and the exciting possibility of stable states of strange matter (hyperons or deconfined quarks). Our uncertainty about the nature of cold ultradense matter is encoded in the Equation of State (EOS), which can be mapped via the stellar structure equations to quantities like mass M and radius R that determine the exterior space-time.
One very promising technique for measuring the EOS exploits hotspots that form on the NS surface due to the pulsar mechanism, accretion streams, or during thermonuclear explosions in the stellar ocean. As the NS rotates, the hotspot gives rise to a pulsation and relativistic effects encode information about the EOS into the pulse profile. Pulse Profile Modelling (PPM), which employs relativistic ray-tracing and Bayesian inference codes to measure M-R and the EOS, is being pioneered by NASA’s NICER telescope, which is poised to deliver its first results in 2019.
Complexities, that have only become apparent with exposure to real data, mean that there is work to be done if we are to have confidence in the nominal 5-10% accuracy of NICER’s M-R results. AEONS will deliver this. The project will also look ahead to the next generation of large-area X-ray timing telescopes, since it is only then that PPM will place tight constraints on dense matter models. The sources these missions target, accreting neutron stars, pose challenges for PPM such as variability, surface pattern uncertainty, and polarimetric signatures. AEONS will develop a robust pipeline for accreting NS PPM and embed it in a multi-messenger EOS inference framework with radio and gravitational wave constraints. This will ensure that PPM delivers major advances in our understanding of the nature of matter.
Summary
Densities in neutron star (NS) cores can reach up to ten times the density of a normal atomic nucleus, and the stabilising effect of gravitational confinement permits long-timescale weak interactions. This generates nucleonic matter that is extremely neutron-rich, and the exciting possibility of stable states of strange matter (hyperons or deconfined quarks). Our uncertainty about the nature of cold ultradense matter is encoded in the Equation of State (EOS), which can be mapped via the stellar structure equations to quantities like mass M and radius R that determine the exterior space-time.
One very promising technique for measuring the EOS exploits hotspots that form on the NS surface due to the pulsar mechanism, accretion streams, or during thermonuclear explosions in the stellar ocean. As the NS rotates, the hotspot gives rise to a pulsation and relativistic effects encode information about the EOS into the pulse profile. Pulse Profile Modelling (PPM), which employs relativistic ray-tracing and Bayesian inference codes to measure M-R and the EOS, is being pioneered by NASA’s NICER telescope, which is poised to deliver its first results in 2019.
Complexities, that have only become apparent with exposure to real data, mean that there is work to be done if we are to have confidence in the nominal 5-10% accuracy of NICER’s M-R results. AEONS will deliver this. The project will also look ahead to the next generation of large-area X-ray timing telescopes, since it is only then that PPM will place tight constraints on dense matter models. The sources these missions target, accreting neutron stars, pose challenges for PPM such as variability, surface pattern uncertainty, and polarimetric signatures. AEONS will develop a robust pipeline for accreting NS PPM and embed it in a multi-messenger EOS inference framework with radio and gravitational wave constraints. This will ensure that PPM delivers major advances in our understanding of the nature of matter.
Max ERC Funding
2 425 000 €
Duration
Start date: 2020-06-01, End date: 2025-05-31
