Project acronym CRADLE
Project Cancer treatment during pregnancy: from fetal safety to maternal efficacy
Researcher (PI) Frederic Amant
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary The evolution in drug regulation of the last 50 years has left pregnant women and their fetuses orphaned. This is particularly problematic for cancer during pregnancy, which raises a difficult and conflicting medical ethical decision process and which has recently become increasingly frequent. In 2012 we published the first prospective study indicating that antenatal exposure to cancer treatment can overall be considered safe. Building on this proof of concept, the current proposal wants to take a groundbreaking step towards developing a standard of care for cancer during pregnancy by addressing –in an integrated fashion- the challenges at the level of the fetus, the mother and the fetomaternal barrier. At the core of this proposal lies an international registry of pregnant women with cancer, along with a registry of their children, and biobanks of maternal, placental, cord blood and tumoral tissues. Research track ‘child’ aims to deliver robust evidence of fetal safety. Research track ‘mother’ aims to address the emerging concerns in the oncological management of the mother, and specifically, the possible distinct biology of pregnancy-associated breast cancer, the most frequent cancer type in pregnancy. The research approach includes large-scale clinical follow-up studies along with laboratory studies on patient biomaterials, including pharmacological investigations and RNA-sequencing studies. Complementary to these studies is research track ‘placenta’ in which cutting-edge models of human placental research are used to address the poorly understood physiological basis of the placental barrier function in this specific situation. This ambitious program will rely on a multidisciplinary team of experts. Not only may the scientific deliverables of this proposal constitute a major step forward to the well-being of both mother and fetus in a pregnancy complicated by cancer, the methodological approach may also provide critical impetus to further research in this field.
Summary
The evolution in drug regulation of the last 50 years has left pregnant women and their fetuses orphaned. This is particularly problematic for cancer during pregnancy, which raises a difficult and conflicting medical ethical decision process and which has recently become increasingly frequent. In 2012 we published the first prospective study indicating that antenatal exposure to cancer treatment can overall be considered safe. Building on this proof of concept, the current proposal wants to take a groundbreaking step towards developing a standard of care for cancer during pregnancy by addressing –in an integrated fashion- the challenges at the level of the fetus, the mother and the fetomaternal barrier. At the core of this proposal lies an international registry of pregnant women with cancer, along with a registry of their children, and biobanks of maternal, placental, cord blood and tumoral tissues. Research track ‘child’ aims to deliver robust evidence of fetal safety. Research track ‘mother’ aims to address the emerging concerns in the oncological management of the mother, and specifically, the possible distinct biology of pregnancy-associated breast cancer, the most frequent cancer type in pregnancy. The research approach includes large-scale clinical follow-up studies along with laboratory studies on patient biomaterials, including pharmacological investigations and RNA-sequencing studies. Complementary to these studies is research track ‘placenta’ in which cutting-edge models of human placental research are used to address the poorly understood physiological basis of the placental barrier function in this specific situation. This ambitious program will rely on a multidisciplinary team of experts. Not only may the scientific deliverables of this proposal constitute a major step forward to the well-being of both mother and fetus in a pregnancy complicated by cancer, the methodological approach may also provide critical impetus to further research in this field.
Max ERC Funding
2 000 000 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym ISIFit
Project Individualised and self-adapting sound processing for cochlear implants
Researcher (PI) Tom Mark H. Francart
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Starting Grant (StG), LS7, ERC-2014-STG
Summary Cochlear implants (CIs) are successful auditory prostheses that enable people with deafness to hear through electrical stimulation of the auditory nerve. In a CI sound processor, a sound signal is converted into a sequence of electrical pulses. This conversion entails many parameters that should ideally be fine-tuned (fitted) for every individual patient, to account for various anatomical and physiological differences. In current clinical practice, devices are fitted during the initial rehabilitation and yearly thereafter. As fitting is very time consuming, only the bare minimum number of parameters is fitted individually. However, for many other parameters, for which currently the same default values are used for all patients, better speech understanding can be achieved with individual fitting. Apart from the fitting, CIs do not take into account the neural or perceptual effects of stimulation.
The objective of this project is to provide better fitting to individual patients by developing a closed-loop CI that automatically adjusts its fitting and sound processing based on the neural response to speech. To achieve this, we will (1) objectively measure speech understanding, by recording the electroencephalogram (EEG) in response to ecological speech signals, (2) automatically fit a wide array of sound processing parameters accordingly using a genetic algorithm, and (3) develop a wearable closed-loop CI that continuously records the EEG and adjusts the fitting in real-life situations.
This will lead to a better understanding of speech perception of people with a hearing impairment, an objective measure of speech intelligibility with many applications in diagnostics, a method to automatically fit CIs, and a novel closed-loop CI. For the patient this means improved speech intelligibility in noise and therefore better communication and quality of life. For the clinic this means improved efficiency and the ability to better fit devices.
Summary
Cochlear implants (CIs) are successful auditory prostheses that enable people with deafness to hear through electrical stimulation of the auditory nerve. In a CI sound processor, a sound signal is converted into a sequence of electrical pulses. This conversion entails many parameters that should ideally be fine-tuned (fitted) for every individual patient, to account for various anatomical and physiological differences. In current clinical practice, devices are fitted during the initial rehabilitation and yearly thereafter. As fitting is very time consuming, only the bare minimum number of parameters is fitted individually. However, for many other parameters, for which currently the same default values are used for all patients, better speech understanding can be achieved with individual fitting. Apart from the fitting, CIs do not take into account the neural or perceptual effects of stimulation.
The objective of this project is to provide better fitting to individual patients by developing a closed-loop CI that automatically adjusts its fitting and sound processing based on the neural response to speech. To achieve this, we will (1) objectively measure speech understanding, by recording the electroencephalogram (EEG) in response to ecological speech signals, (2) automatically fit a wide array of sound processing parameters accordingly using a genetic algorithm, and (3) develop a wearable closed-loop CI that continuously records the EEG and adjusts the fitting in real-life situations.
This will lead to a better understanding of speech perception of people with a hearing impairment, an objective measure of speech intelligibility with many applications in diagnostics, a method to automatically fit CIs, and a novel closed-loop CI. For the patient this means improved speech intelligibility in noise and therefore better communication and quality of life. For the clinic this means improved efficiency and the ability to better fit devices.
Max ERC Funding
1 734 360 €
Duration
Start date: 2015-11-01, End date: 2020-10-31
Project acronym MANGO
Project The determinants of cross-seeding of protein aggregation: a Multiple TANGO
Researcher (PI) Joost Schymkowitz
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS2, ERC-2014-CoG
Summary Amyloid-like protein aggregation is a process of protein assembly via the formation of intermolecular β-structures by short aggregation prone sequence regions. This occurs as an unwanted side-reaction of impaired protein folding in disease, but also for the construction of natural nanomaterials. Aggregates appear to be strongly enriched in particular proteins, suggesting that the assembly process itself is specific, but the cross-seeding of the aggregation of one protein by aggregates of another protein has also been reported.
The key question that I aim to address in this proposal is how the beta-interactions of the amino acids in the aggregate spine determine the trade-off between the specificity of aggregation versus cross-seeding. To this end, I will determine the energy difference between homotypic versus heterotypic interactions and how differences in sequence translate into energy gaps. Moreover, I will analyse the sequence variations of aggregation prone stretches in natural proteomes to understand the danger of widespread co-aggregation.
To achieve these outcomes, I will study the interactions and cross-seeding of aggregating proteins and model peptides in vitro and in cells. I will extract the sequence and structural determinants of co-aggregation, and employ these to construct novel bioinformatics algorithm that can accurately predict co-aggregation and cross-seeding. I will use these to analyse co-aggregation cascades in natural proteomes looking for mechanisms that protect them from wide-spread cross-seeding.
This work will have a significant impact on the understanding of the downstream effects of protein aggregates and may reveal co-aggregation networks in human diseases such as the major neurodegenerative diseases or cancer, potentially opening up new research lines on the mechanisms underlying these pathologies and thus identify targets for novel therapies.
Summary
Amyloid-like protein aggregation is a process of protein assembly via the formation of intermolecular β-structures by short aggregation prone sequence regions. This occurs as an unwanted side-reaction of impaired protein folding in disease, but also for the construction of natural nanomaterials. Aggregates appear to be strongly enriched in particular proteins, suggesting that the assembly process itself is specific, but the cross-seeding of the aggregation of one protein by aggregates of another protein has also been reported.
The key question that I aim to address in this proposal is how the beta-interactions of the amino acids in the aggregate spine determine the trade-off between the specificity of aggregation versus cross-seeding. To this end, I will determine the energy difference between homotypic versus heterotypic interactions and how differences in sequence translate into energy gaps. Moreover, I will analyse the sequence variations of aggregation prone stretches in natural proteomes to understand the danger of widespread co-aggregation.
To achieve these outcomes, I will study the interactions and cross-seeding of aggregating proteins and model peptides in vitro and in cells. I will extract the sequence and structural determinants of co-aggregation, and employ these to construct novel bioinformatics algorithm that can accurately predict co-aggregation and cross-seeding. I will use these to analyse co-aggregation cascades in natural proteomes looking for mechanisms that protect them from wide-spread cross-seeding.
This work will have a significant impact on the understanding of the downstream effects of protein aggregates and may reveal co-aggregation networks in human diseases such as the major neurodegenerative diseases or cancer, potentially opening up new research lines on the mechanisms underlying these pathologies and thus identify targets for novel therapies.
Max ERC Funding
1 995 523 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
Project acronym NANOBUBBLE
Project Laser-induced vapour nanobubbles for intracellular delivery of nanomaterials and treatment of biofilm infections
Researcher (PI) Kevin Braeckmans
Host Institution (HI) UNIVERSITEIT GENT
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary Lasers have found widespread application in medicine, such as for photothermal therapy. Gold nanoparticles (AuNPs), are often used as enhancers of the photothermal effect since they can efficiently absorb laser light and convert it into thermal energy. When absorbing intense nano- or picosecond laser pulses, AuNPs can become extremely hot and water vapor nanobubbles (VNBs) can emerge around these particles in tissue. A VNB will expand up to several hundred nm until the thermal energy from the AuNP is consumed, after which the bubble violently collapses, causing mechanical damage to neighbouring structures. In this project the aim is to make use of the disruptive mechanical force of VNBs to enable highly controlled and efficient delivery of macromolecules and nanoparticles in cells and biofilms. First, optical set-ups and microfluidics devices will be developed for high-throughput treatment of cells and biofilms. Second, VNBs will be used to achieve efficient cytosolic delivery of functional macromolecules in mammalian cells by cell membrane perforation or by inducing endosomal escape of endocytosed nanomedicine formulations that are functionalized with AuNPs. These concepts will be applied to tumorigenesis research, generation of induced pluripotent stem cells and modulation of effector T-cells for adoptive T-cell anti-cancer therapy. Third, contrast nanoparticles for cell imaging will be delivered into the cytosol of mammalian cells through VNB induced cell membrane perforation. This will enable more reliable in vivo imaging of labelled cells, labelling of subcellular structures for time-lapse microscopy and intracellular biosensing. Finally, [... confidential...] laser-induced VNBs will be used [... confidential...] for improved eradication of biofilms. This concept will be applied to biofilm infections in dental root canals and chronic wounds.
Summary
Lasers have found widespread application in medicine, such as for photothermal therapy. Gold nanoparticles (AuNPs), are often used as enhancers of the photothermal effect since they can efficiently absorb laser light and convert it into thermal energy. When absorbing intense nano- or picosecond laser pulses, AuNPs can become extremely hot and water vapor nanobubbles (VNBs) can emerge around these particles in tissue. A VNB will expand up to several hundred nm until the thermal energy from the AuNP is consumed, after which the bubble violently collapses, causing mechanical damage to neighbouring structures. In this project the aim is to make use of the disruptive mechanical force of VNBs to enable highly controlled and efficient delivery of macromolecules and nanoparticles in cells and biofilms. First, optical set-ups and microfluidics devices will be developed for high-throughput treatment of cells and biofilms. Second, VNBs will be used to achieve efficient cytosolic delivery of functional macromolecules in mammalian cells by cell membrane perforation or by inducing endosomal escape of endocytosed nanomedicine formulations that are functionalized with AuNPs. These concepts will be applied to tumorigenesis research, generation of induced pluripotent stem cells and modulation of effector T-cells for adoptive T-cell anti-cancer therapy. Third, contrast nanoparticles for cell imaging will be delivered into the cytosol of mammalian cells through VNB induced cell membrane perforation. This will enable more reliable in vivo imaging of labelled cells, labelling of subcellular structures for time-lapse microscopy and intracellular biosensing. Finally, [... confidential...] laser-induced VNBs will be used [... confidential...] for improved eradication of biofilms. This concept will be applied to biofilm infections in dental root canals and chronic wounds.
Max ERC Funding
2 236 250 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym NSETHIO
Project Nodding Syndrome: a trans-disciplinary approach to identify the cause and decrease the incidence of river epilepsy
Researcher (PI) Robert Colebunders
Host Institution (HI) UNIVERSITEIT ANTWERPEN
Call Details Advanced Grant (AdG), LS7, ERC-2014-ADG
Summary Nodding syndrome (NS) is a neurological, incurable syndrome, currently affecting mainly children between 5 and 15 years of age in South Sudan, Uganda and Tanzania. Since 1950, when NS was first described, its cause has remained a mystery. NS is characterized by head-nodding (an atonic form of epilepsy), often followed by clonic - tonic seizures, developmental retardation and faltering growth. In the affected regions, NS is a major public health problem associated with severe socio-economic consequences. After exploratory missions to South Sudan, Uganda and the Democratic Republic of the Congo (DRC), we gathered epidemiological evidence that supports the hypothesis that NS is a disease caused by a pathogen transmitted by blackflies, the vectors that transmit the parasitic worm that causes onchocerciasis. This pathogen could be an unknown neurotropic virus or another pathogen that is transmitted either independently or as a symbiont of the worm. We postulate that this pathogen is able to cause typical NS, but also other forms of epidemic epilepsy. We hypothesise that the same disease is also endemic in other onchocerciasis hyper-endemic regions e.g. in the Mbam valley, Cameroon and the Orientale Province, DRC (where it is referred to as “river epilepsy”). In this project we aim to investigate our hypotheses in South Sudan, Uganda, Tanzania, Cameroon and the DRC with a trans-disciplinary approach including clinical-epidemiological, post-mortem, eco-entomological, and metagenomic studies. We will study the effect of vector control methods and ivermectin distribution on the incidence of river epilepsy. So far a multi-country study on NS was never done and nearly all previous studies were cross-sectional, carried out during short country visits. With this long term research plan we hope to finally discover the cause of NS and detect effective control strategies to decrease the incidence of epilepsy in onchocerciasis endemic areas.
Summary
Nodding syndrome (NS) is a neurological, incurable syndrome, currently affecting mainly children between 5 and 15 years of age in South Sudan, Uganda and Tanzania. Since 1950, when NS was first described, its cause has remained a mystery. NS is characterized by head-nodding (an atonic form of epilepsy), often followed by clonic - tonic seizures, developmental retardation and faltering growth. In the affected regions, NS is a major public health problem associated with severe socio-economic consequences. After exploratory missions to South Sudan, Uganda and the Democratic Republic of the Congo (DRC), we gathered epidemiological evidence that supports the hypothesis that NS is a disease caused by a pathogen transmitted by blackflies, the vectors that transmit the parasitic worm that causes onchocerciasis. This pathogen could be an unknown neurotropic virus or another pathogen that is transmitted either independently or as a symbiont of the worm. We postulate that this pathogen is able to cause typical NS, but also other forms of epidemic epilepsy. We hypothesise that the same disease is also endemic in other onchocerciasis hyper-endemic regions e.g. in the Mbam valley, Cameroon and the Orientale Province, DRC (where it is referred to as “river epilepsy”). In this project we aim to investigate our hypotheses in South Sudan, Uganda, Tanzania, Cameroon and the DRC with a trans-disciplinary approach including clinical-epidemiological, post-mortem, eco-entomological, and metagenomic studies. We will study the effect of vector control methods and ivermectin distribution on the incidence of river epilepsy. So far a multi-country study on NS was never done and nearly all previous studies were cross-sectional, carried out during short country visits. With this long term research plan we hope to finally discover the cause of NS and detect effective control strategies to decrease the incidence of epilepsy in onchocerciasis endemic areas.
Max ERC Funding
2 417 000 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym PROCELLDEATH
Project Unraveling the regulatory network of developmental programmed cell death in plants
Researcher (PI) Moritz Karl Nowack
Host Institution (HI) VIB
Call Details Starting Grant (StG), LS3, ERC-2014-STG
Summary Programmed cell death (PCD) is a fundamental biological process that actively terminates a cell’s vital functions by a well-ordered sequence of events. In both animals and plants, various types of PCD are crucial for development, health, and the responses to various stresses. Despite their importance, only little is known about PCD processes and their molecular control in plants. Still, an intricate regulatory network must exist that renders specific plant cell types competent to initiate and execute PCD at precisely determined developmental stages. I recently established a powerful developmental PCD model system in Arabidopsis thaliana, based on a PCD process occurring during root cap development. This root cap model has the potential to revolutionize existing concepts of plant PCD, as it combines a precisely predictable PCD process in easily accessible cells on the root periphery with the abundance of resources available for Arabidopsis research. Exploiting the root cap system will enable me to tackle unresolved fundamental questions about the regulation of developmental PCD in plants: How do cells acquire PCD competency during differentiation? Which signals trigger PCD execution at just the right moment? What are the actual mechanisms that disrupt the vital functions of a plant cell? I will obtain answers to these questions through a comprehensive strategy combining complementary approaches, taking advantage of cell-type specific transcriptomics, forward and reverse genetics, advanced live-cell imaging, biochemistry, and computational modeling. Our unpublished data point to the existence of a common core mechanism controlling PCD not only in the root cap, but also in other vital organs including the vasculature, anthers, or developing seeds. Thus, this project will not only be significant to advance our knowledge on PCD as a general developmental mechanism in plants, but also to generate new leads to tap the so far underexploited potential of PCD in agriculture.
Summary
Programmed cell death (PCD) is a fundamental biological process that actively terminates a cell’s vital functions by a well-ordered sequence of events. In both animals and plants, various types of PCD are crucial for development, health, and the responses to various stresses. Despite their importance, only little is known about PCD processes and their molecular control in plants. Still, an intricate regulatory network must exist that renders specific plant cell types competent to initiate and execute PCD at precisely determined developmental stages. I recently established a powerful developmental PCD model system in Arabidopsis thaliana, based on a PCD process occurring during root cap development. This root cap model has the potential to revolutionize existing concepts of plant PCD, as it combines a precisely predictable PCD process in easily accessible cells on the root periphery with the abundance of resources available for Arabidopsis research. Exploiting the root cap system will enable me to tackle unresolved fundamental questions about the regulation of developmental PCD in plants: How do cells acquire PCD competency during differentiation? Which signals trigger PCD execution at just the right moment? What are the actual mechanisms that disrupt the vital functions of a plant cell? I will obtain answers to these questions through a comprehensive strategy combining complementary approaches, taking advantage of cell-type specific transcriptomics, forward and reverse genetics, advanced live-cell imaging, biochemistry, and computational modeling. Our unpublished data point to the existence of a common core mechanism controlling PCD not only in the root cap, but also in other vital organs including the vasculature, anthers, or developing seeds. Thus, this project will not only be significant to advance our knowledge on PCD as a general developmental mechanism in plants, but also to generate new leads to tap the so far underexploited potential of PCD in agriculture.
Max ERC Funding
1 499 746 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym PV-COAT
Project PROSTHETIC VALVE BIOACTIVE SURFACE COATING TO REDUCE THE PREVALENCE OF THROMBOSIS
Researcher (PI) Patrizio Lancellotti
Host Institution (HI) UNIVERSITE DE LIEGE
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary Heart valve prostheses are currently among the most widely used cardiovascular devices. To maintain enduring optimal biomechanical properties, the mechanical prostheses, based on carbon, metallic and polymeric components, require permanent anticoagulation, which often leads to adverse reactions, i.e. higher risks of thromboembolism, hemorrhage, and hemolysis.
Continuing advances in heart valve prosthesis design and in techniques for implantation have improved the survival length and quality of life of patients who receive these devices. In an ongoing effort to develop a more durable and biocompatible heart valve prosthesis, researchers have used a variety of techniques to determine the suitability of given valve materials for a given implant application. In recent years, advances in polymer science have given rise to new ways of improving artificial cardiovascular devices biostability and hemocompatibility.
To date, no polymer coated mechanical prosthetic heart valve exists.
The present research project aims to improve the hemocompatibility and long-term in vivo performance of mechanical prosthetic heart valves by reducing contact-induced thrombosis through bioactive polymer prosthetic valve surface coating.
These new coated prosthetic heart valves will be designed for hemodynamic performance and durability similar to uncoated materials, combined with a greater thromboresistance, both in vitro and in animal studies.
With these promising advances, bioactive surface coated prosthetic heart valves could replace previous generation of prosthetic valves in the near future. The utmost perspective of the current project paves the way for the development of new bioactive coating for other implantable cardiovascular devices or materials.
Summary
Heart valve prostheses are currently among the most widely used cardiovascular devices. To maintain enduring optimal biomechanical properties, the mechanical prostheses, based on carbon, metallic and polymeric components, require permanent anticoagulation, which often leads to adverse reactions, i.e. higher risks of thromboembolism, hemorrhage, and hemolysis.
Continuing advances in heart valve prosthesis design and in techniques for implantation have improved the survival length and quality of life of patients who receive these devices. In an ongoing effort to develop a more durable and biocompatible heart valve prosthesis, researchers have used a variety of techniques to determine the suitability of given valve materials for a given implant application. In recent years, advances in polymer science have given rise to new ways of improving artificial cardiovascular devices biostability and hemocompatibility.
To date, no polymer coated mechanical prosthetic heart valve exists.
The present research project aims to improve the hemocompatibility and long-term in vivo performance of mechanical prosthetic heart valves by reducing contact-induced thrombosis through bioactive polymer prosthetic valve surface coating.
These new coated prosthetic heart valves will be designed for hemodynamic performance and durability similar to uncoated materials, combined with a greater thromboresistance, both in vitro and in animal studies.
With these promising advances, bioactive surface coated prosthetic heart valves could replace previous generation of prosthetic valves in the near future. The utmost perspective of the current project paves the way for the development of new bioactive coating for other implantable cardiovascular devices or materials.
Max ERC Funding
2 367 055 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym RobustSynapses
Project Maintaining synaptic function for a healthy brain: Membrane trafficking and autophagy in neurodegeneration
Researcher (PI) Patrik Verstreken
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary Neurodegeneration is characterized by misfolded proteins and dysfunctional synapses. Synapses are often located very far away from their cell bodies and they must therefore largely independently cope with the unfolded, dysfunctional proteins that form as a result of synaptic activity and stress. My hypothesis is that synaptic terminals have adopted specific mechanisms to maintain robustness over their long lives and that these may become disrupted in neurodegenerative diseases. Recent evidence indicates an intriguing relationship between several Parkinson disease genes, synaptic vesicle trafficking and autophagy, providing an excellent entry point to study key molecular mechanisms and interactions in synaptic membrane trafficking and synaptic autophagy. We will use novel genome editing methodologies enabling fast in vivo structure-function studies in fruit flies and we will use differentiated human neurons to assess the conservation of mechanisms across evolution. In a complementary approach I also propose to capitalize on innovative in vitro liposome-based proteome-wide screening methods as well as in vivo genetic screens in fruit flies to find novel membrane-associated machines that mediate synaptic autophagy with the ultimate aim to reveal how these mechanisms regulate the maintenance of synaptic health. Our work not only has the capacity to uncover novel aspects in the regulation of presynaptic autophagy and function, but it will also reveal mechanisms of synaptic dysfunction in models of neuronal demise and open new research lines on mechanisms of synaptic plasticity.
Summary
Neurodegeneration is characterized by misfolded proteins and dysfunctional synapses. Synapses are often located very far away from their cell bodies and they must therefore largely independently cope with the unfolded, dysfunctional proteins that form as a result of synaptic activity and stress. My hypothesis is that synaptic terminals have adopted specific mechanisms to maintain robustness over their long lives and that these may become disrupted in neurodegenerative diseases. Recent evidence indicates an intriguing relationship between several Parkinson disease genes, synaptic vesicle trafficking and autophagy, providing an excellent entry point to study key molecular mechanisms and interactions in synaptic membrane trafficking and synaptic autophagy. We will use novel genome editing methodologies enabling fast in vivo structure-function studies in fruit flies and we will use differentiated human neurons to assess the conservation of mechanisms across evolution. In a complementary approach I also propose to capitalize on innovative in vitro liposome-based proteome-wide screening methods as well as in vivo genetic screens in fruit flies to find novel membrane-associated machines that mediate synaptic autophagy with the ultimate aim to reveal how these mechanisms regulate the maintenance of synaptic health. Our work not only has the capacity to uncover novel aspects in the regulation of presynaptic autophagy and function, but it will also reveal mechanisms of synaptic dysfunction in models of neuronal demise and open new research lines on mechanisms of synaptic plasticity.
Max ERC Funding
1 999 025 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym TREECLIMBERS
Project Modelling lianas as key drivers of tropical forest responses to climate change
Researcher (PI) Hans Joris Verbeeck
Host Institution (HI) UNIVERSITEIT GENT
Call Details Starting Grant (StG), LS8, ERC-2014-STG
Summary Tropical forests are essential components of the earth system. Yet, much uncertainty exists about the exact role of this biome in the global carbon cycle. Our limited understanding of tropical forest functioning is reflected in uncertain global vegetation model projections. A large source of uncertainty in these models is their representation of ecosystem demographic processes. Interestingly, fieldwork has revealed lianas as important components of tropical forests, which are apparently increasing in abundance. Liana proliferation might be a key adaptation mechanism of tropical forests to climate change, which has potentially large impacts on the long term tropical forest biome carbon balance. Nevertheless, no single terrestrial ecosystem model currently includes lianas. TREECLIMBERS will generate important insights into the mechanisms by which lianas influence the carbon balance of tropical forests, by building the first vegetation model that includes lianas. We will make the first integrative study of (1) the contribution of lianas to instantaneous carbon and water fluxes, (2) liana contribution and influence on canopy structure, (3) their role for long term demographic processes, and (4) of their role in forest responses to drought events. TREECLIMBERS will develop the first liana plant functional type (PFT) by combining a unique global meta-analysis of existing data with innovative terrestrial LiDAR 3D measurements of the canopy to study the contribution of lianas to the canopy structure. New and available data will be integrated in the Ecosystem Demography (ED) model, a forerunner of the next generation of vegetation models. By using model-data fusion we will, for the first time, integrate the large amount of available and emerging liana data, leading to an integrated insight into the role of lianas in tropical forest functioning. This project aims to show that shifts in floristic composition due to global change may have important impacts in tropical forests.
Summary
Tropical forests are essential components of the earth system. Yet, much uncertainty exists about the exact role of this biome in the global carbon cycle. Our limited understanding of tropical forest functioning is reflected in uncertain global vegetation model projections. A large source of uncertainty in these models is their representation of ecosystem demographic processes. Interestingly, fieldwork has revealed lianas as important components of tropical forests, which are apparently increasing in abundance. Liana proliferation might be a key adaptation mechanism of tropical forests to climate change, which has potentially large impacts on the long term tropical forest biome carbon balance. Nevertheless, no single terrestrial ecosystem model currently includes lianas. TREECLIMBERS will generate important insights into the mechanisms by which lianas influence the carbon balance of tropical forests, by building the first vegetation model that includes lianas. We will make the first integrative study of (1) the contribution of lianas to instantaneous carbon and water fluxes, (2) liana contribution and influence on canopy structure, (3) their role for long term demographic processes, and (4) of their role in forest responses to drought events. TREECLIMBERS will develop the first liana plant functional type (PFT) by combining a unique global meta-analysis of existing data with innovative terrestrial LiDAR 3D measurements of the canopy to study the contribution of lianas to the canopy structure. New and available data will be integrated in the Ecosystem Demography (ED) model, a forerunner of the next generation of vegetation models. By using model-data fusion we will, for the first time, integrate the large amount of available and emerging liana data, leading to an integrated insight into the role of lianas in tropical forest functioning. This project aims to show that shifts in floristic composition due to global change may have important impacts in tropical forests.
Max ERC Funding
1 499 375 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
