Project acronym CaNANObinoids
Project From Peripheralized to Cell- and Organelle-Targeted Medicine: The 3rd Generation of Cannabinoid-1 Receptor Antagonists for the Treatment of Chronic Kidney Disease
Researcher (PI) Yossef Tam
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary Clinical experience with globally-acting cannabinoid-1 receptor (CB1R) antagonists revealed the benefits of blocking CB1Rs for the treatment of obesity and diabetes. However, their use is hampered by increased CNS-mediated side effects. Recently, I have demonstrated that peripherally-restricted CB1R antagonists have the potential to treat the metabolic syndrome without eliciting these adverse effects. While these results are promising and are currently being developed into the clinic, our ability to rationally design CB1R blockers that would target a diseased organ is limited.
The current proposal aims to develop and test cell- and organelle-specific CB1R antagonists. To establish this paradigm, I will focus our interest on the kidney, since chronic kidney disease (CKD) is the leading cause of increased morbidity and mortality of patients with diabetes. Our first goal will be to characterize the obligatory role of the renal proximal tubular CB1R in the pathogenesis of diabetic renal complications. Next, we will attempt to link renal proximal CB1R with diabetic mitochondrial dysfunction. Finally, we will develop proximal tubular (cell-specific) and mitochondrial (organelle-specific) CB1R blockers and test their effectiveness in treating CKD. To that end, we will encapsulate CB1R blockers into biocompatible polymeric nanoparticles that will serve as targeted drug delivery systems, via their conjugation to targeting ligands.
The implications of this work are far reaching as they will (i) point to renal proximal tubule CB1R as a novel target for CKD; (ii) identify mitochondrial CB1R as a new player in the regulation of proximal tubular cell function, and (iii) eventually become the drug-of-choice in treating diabetic CKD and its comorbidities. Moreover, this work will lead to the development of a novel organ-specific drug delivery system for CB1R blockers, which could be then exploited in other tissues affected by obesity, diabetes and the metabolic syndrome.
Summary
Clinical experience with globally-acting cannabinoid-1 receptor (CB1R) antagonists revealed the benefits of blocking CB1Rs for the treatment of obesity and diabetes. However, their use is hampered by increased CNS-mediated side effects. Recently, I have demonstrated that peripherally-restricted CB1R antagonists have the potential to treat the metabolic syndrome without eliciting these adverse effects. While these results are promising and are currently being developed into the clinic, our ability to rationally design CB1R blockers that would target a diseased organ is limited.
The current proposal aims to develop and test cell- and organelle-specific CB1R antagonists. To establish this paradigm, I will focus our interest on the kidney, since chronic kidney disease (CKD) is the leading cause of increased morbidity and mortality of patients with diabetes. Our first goal will be to characterize the obligatory role of the renal proximal tubular CB1R in the pathogenesis of diabetic renal complications. Next, we will attempt to link renal proximal CB1R with diabetic mitochondrial dysfunction. Finally, we will develop proximal tubular (cell-specific) and mitochondrial (organelle-specific) CB1R blockers and test their effectiveness in treating CKD. To that end, we will encapsulate CB1R blockers into biocompatible polymeric nanoparticles that will serve as targeted drug delivery systems, via their conjugation to targeting ligands.
The implications of this work are far reaching as they will (i) point to renal proximal tubule CB1R as a novel target for CKD; (ii) identify mitochondrial CB1R as a new player in the regulation of proximal tubular cell function, and (iii) eventually become the drug-of-choice in treating diabetic CKD and its comorbidities. Moreover, this work will lead to the development of a novel organ-specific drug delivery system for CB1R blockers, which could be then exploited in other tissues affected by obesity, diabetes and the metabolic syndrome.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym CD40-INN
Project CD40 goes innate: defining and targeting CD40 signaling intermediates in the macrophage to treat atherosclerosis
Researcher (PI) Esther Lutgens Leiner
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Consolidator Grant (CoG), LS4, ERC-2015-CoG
Summary Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVD), is a lipid driven, inflammatory disease of the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of atherosclerosis-induced CVD risk remains unaddressed. Therefore, characterizing mediators of the inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications.
Co-stimulatory molecules are key players in modulating immune interactions. My laboratory has defined the co-stimulatory CD40-CD40L dyad as a major driver of atherosclerosis. Inhibition of CD40, and of its interaction with the adaptor molecule TRAF6 by genetic deficiency, antibody treatment or (nanoparticle based) small molecule inhibitor (SMI) treatment, is one of the most powerful therapies to reduce atherosclerosis in a laboratory setting. Although CD40-CD40L interactions are associated with adaptive immunity, I recently identified the macrophage as a driver of CD40-induced inflammation in atherosclerosis. We will use state-of-the-art in vitro experiments, live cell-, super resolution imaging, proteomics approaches and mutant mouse models to unravel the role of macrophage CD40 in atherosclerosis. Moreover, using structure based virtual ligand screening, I will develop lead SMIs targeting macrophage CD40-signaling, which I will deliver using macrophage-targeting nanoparticles. My goal is to define the role of macrophage CD40 in inflammation and immunity and disentangle how its activation affects atherosclerosis. I will finally test the feasibility of targeting macrophage CD40-signaling as a treatment for CVD.
These studies will define the role of CD40-signaling in the innate immune system in health and (cardiovascular) disease. As components of macrophage CD40-signaling have the potential to be amenable to pharmacological manipulation, we will establish their feasibility as novel targets for (CVD) treatment.
Summary
Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVD), is a lipid driven, inflammatory disease of the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of atherosclerosis-induced CVD risk remains unaddressed. Therefore, characterizing mediators of the inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications.
Co-stimulatory molecules are key players in modulating immune interactions. My laboratory has defined the co-stimulatory CD40-CD40L dyad as a major driver of atherosclerosis. Inhibition of CD40, and of its interaction with the adaptor molecule TRAF6 by genetic deficiency, antibody treatment or (nanoparticle based) small molecule inhibitor (SMI) treatment, is one of the most powerful therapies to reduce atherosclerosis in a laboratory setting. Although CD40-CD40L interactions are associated with adaptive immunity, I recently identified the macrophage as a driver of CD40-induced inflammation in atherosclerosis. We will use state-of-the-art in vitro experiments, live cell-, super resolution imaging, proteomics approaches and mutant mouse models to unravel the role of macrophage CD40 in atherosclerosis. Moreover, using structure based virtual ligand screening, I will develop lead SMIs targeting macrophage CD40-signaling, which I will deliver using macrophage-targeting nanoparticles. My goal is to define the role of macrophage CD40 in inflammation and immunity and disentangle how its activation affects atherosclerosis. I will finally test the feasibility of targeting macrophage CD40-signaling as a treatment for CVD.
These studies will define the role of CD40-signaling in the innate immune system in health and (cardiovascular) disease. As components of macrophage CD40-signaling have the potential to be amenable to pharmacological manipulation, we will establish their feasibility as novel targets for (CVD) treatment.
Max ERC Funding
1 999 420 €
Duration
Start date: 2016-12-01, End date: 2021-11-30
Project acronym GPS-Bat
Project Foraging Decision Making in the Real World – revealed from a bat’s point of view by on-board miniature sensors
Researcher (PI) Yosef Gershon Yovel
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Starting Grant (StG), LS8, ERC-2015-STG
Summary How animals make decisions in the wild is an open key-question in biology. Our lack of knowledge results from a technological gap – the difficulty to track animals over long periods while monitoring their behaviour; and from a conceptual gap – how to identify animals’ decision-points outdoors? We suggest applying our innovative on-board miniature sensors, to study decision making in the wild. We focus on one of the most fundamental contexts of decision making – foraging for food. We will study bats, which constitute over 20% of mammalian species and are extremely diverse, enabling to examine different aspects of decision making. Importantly, echolocating bats emit sound to perceive their environment, allowing us to infer their behavior (attacks on prey and interactions with conspecifics) via sound recording. Our miniature sensors include a GPS and an ultrasonic microphone, which enables us to reveal not only bats’ movements, but also their behavior and accordingly the factors underlying their decisions.
We will study three bat species to elucidate different aspects of foraging decisions: (1) How does animal sociality facilitate decision making? We have developed a system to monitor an entire colony including all conspecific-interactions when bats are in the roost or foraging outside. (2) How do animals weigh current input against previous experience? We will study a bat that must nightly search large areas over sea to find food. (3) How flexible are animal decisions? We will manipulate the natural environment of specific individuals to study how they adjust their foraging.
Our results will have far-reaching implications in many fields, from animal conservation to robotics. The operational and technical difficulty of performing controlled manipulations in the wild drives most disciplines to perform experiments exclusively in artificial laboratory conditions. Our approach opens new opportunities to conduct controlled studies in the natural environment.
Summary
How animals make decisions in the wild is an open key-question in biology. Our lack of knowledge results from a technological gap – the difficulty to track animals over long periods while monitoring their behaviour; and from a conceptual gap – how to identify animals’ decision-points outdoors? We suggest applying our innovative on-board miniature sensors, to study decision making in the wild. We focus on one of the most fundamental contexts of decision making – foraging for food. We will study bats, which constitute over 20% of mammalian species and are extremely diverse, enabling to examine different aspects of decision making. Importantly, echolocating bats emit sound to perceive their environment, allowing us to infer their behavior (attacks on prey and interactions with conspecifics) via sound recording. Our miniature sensors include a GPS and an ultrasonic microphone, which enables us to reveal not only bats’ movements, but also their behavior and accordingly the factors underlying their decisions.
We will study three bat species to elucidate different aspects of foraging decisions: (1) How does animal sociality facilitate decision making? We have developed a system to monitor an entire colony including all conspecific-interactions when bats are in the roost or foraging outside. (2) How do animals weigh current input against previous experience? We will study a bat that must nightly search large areas over sea to find food. (3) How flexible are animal decisions? We will manipulate the natural environment of specific individuals to study how they adjust their foraging.
Our results will have far-reaching implications in many fields, from animal conservation to robotics. The operational and technical difficulty of performing controlled manipulations in the wild drives most disciplines to perform experiments exclusively in artificial laboratory conditions. Our approach opens new opportunities to conduct controlled studies in the natural environment.
Max ERC Funding
1 928 750 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym MULTIATTACK
Project Plant adaptations to unpredictable attack by dynamic insect communities
Researcher (PI) Erik Herman Poelman
Host Institution (HI) WAGENINGEN UNIVERSITY
Call Details Starting Grant (StG), LS8, ERC-2015-STG
Summary Individual plants are exposed to many stresses with insect herbivores being a prominent one. The occurrence of insect herbivores may be unpredictable in terms of when, by which species, and in which order the attack will take place. To deal with unpredictability of attack, plants are phenotypically plastic in their defence. They respond to attackers with the induction of specific defences and saving costs of defence in their absence. However, the induced plant phenotype may attract additional herbivores, alter the entire community composition of attackers and limit physiological capabilities of plant responses to subsequent attackers. An optimal response to one attacker should thus anticipate these consequences of induced responses. To understand the adaptive nature of plant plasticity to herbivore attack, it is essential to assess fitness consequences of an induced response when plants are exposed to multi-herbivory by their entire insect community. This requires a novel approach of comparing plant species adaptations in defence plasticity to the level of predictability in the dynamics of their insect community, such as order of herbivore arrival. To do so, this research proposal has three objectives: 1) Identifying the predictability of dynamic attacker communities of Brassicaceae species, 2) Understanding physiological adaptations to (un)predictable multi-herbivore attack, and 3) Identifying consistency in responses of insect herbivores to induced phenotypes of different Brassicaceae. By integrating community ecology with network inference modelling of insect communities, the nature of predictability of insect communities of nine annual Brassicaceae plant species will be identified and linked to species-specific physiological adaptations to multi-herbivory. This multidisciplinary community approach will provide novel insights into the evolution of plant phenotypic plasticity in defence, which is a central paradigm in the field of plant-insect interactions.
Summary
Individual plants are exposed to many stresses with insect herbivores being a prominent one. The occurrence of insect herbivores may be unpredictable in terms of when, by which species, and in which order the attack will take place. To deal with unpredictability of attack, plants are phenotypically plastic in their defence. They respond to attackers with the induction of specific defences and saving costs of defence in their absence. However, the induced plant phenotype may attract additional herbivores, alter the entire community composition of attackers and limit physiological capabilities of plant responses to subsequent attackers. An optimal response to one attacker should thus anticipate these consequences of induced responses. To understand the adaptive nature of plant plasticity to herbivore attack, it is essential to assess fitness consequences of an induced response when plants are exposed to multi-herbivory by their entire insect community. This requires a novel approach of comparing plant species adaptations in defence plasticity to the level of predictability in the dynamics of their insect community, such as order of herbivore arrival. To do so, this research proposal has three objectives: 1) Identifying the predictability of dynamic attacker communities of Brassicaceae species, 2) Understanding physiological adaptations to (un)predictable multi-herbivore attack, and 3) Identifying consistency in responses of insect herbivores to induced phenotypes of different Brassicaceae. By integrating community ecology with network inference modelling of insect communities, the nature of predictability of insect communities of nine annual Brassicaceae plant species will be identified and linked to species-specific physiological adaptations to multi-herbivory. This multidisciplinary community approach will provide novel insights into the evolution of plant phenotypic plasticity in defence, which is a central paradigm in the field of plant-insect interactions.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-02-01, End date: 2021-01-31
Project acronym TENSION
Project Targeting replication stress recovery pathways in oncology
Researcher (PI) Marcel van vugt
Host Institution (HI) ACADEMISCH ZIEKENHUIS GRONINGEN
Call Details Consolidator Grant (CoG), LS4, ERC-2015-CoG
Summary Genomic instability characterizes tumors, which have no clear ‘oncogenic-driver’ mutation, including triple-negative breast cancers (TNBCs). These patients do not benefit from molecularly targeted treatment and urgently need better treatment options. Increasing evidence points to replication stress as the driver of genomic instability. Since replication stress compromises cell viability, cells have evolved mechanisms to mitigate this threat.
Recently, I discovered a novel cellular mechanism—mitotic Replication Stress Recovery (RSR)—that acts as an ‘emergency brake’ during mitosis, allowing recovery from high levels of replication stress. This machinery is critical for tumor cell survival, and therefore constitutes a promising target for anti-cancer drug development. However, it is unclear how this mitotic RSR is organized molecularly and how it can be targeted therapeutically.
In this project, I aim to molecularly define and therapeutically target the Mitotic Replication Stress Recovery (RSR) machinery in triple-negative breast cancer cells.
To this end, I will implement a series of complementary innovative strategies. First, I will use mass-spec-based proteomics to molecularly characterize components and wiring of the mitotic RSR machinery. Second, to identify the genetic profiles of cancer subgroups that are sensitive to inactivation of the mitotic RSR, functional genetic screens will be combined with visualization and quantification of replication stress in genomically-defined human cancer samples. Finally, my findings will be translated to the pre-clinical situation by exploring the feasibility of therapeutic inactivation of the RSR machinery in vitro and in vivo in a panel of triple-negative breast cancer models.
In summary, TENSION will provide advanced insight into the composition and wiring of the mitotic RSR machinery and will reveal the potency of targeting this pathway therapeutically for TNBCs and other hard-to-treat, genomically instable cancers.
Summary
Genomic instability characterizes tumors, which have no clear ‘oncogenic-driver’ mutation, including triple-negative breast cancers (TNBCs). These patients do not benefit from molecularly targeted treatment and urgently need better treatment options. Increasing evidence points to replication stress as the driver of genomic instability. Since replication stress compromises cell viability, cells have evolved mechanisms to mitigate this threat.
Recently, I discovered a novel cellular mechanism—mitotic Replication Stress Recovery (RSR)—that acts as an ‘emergency brake’ during mitosis, allowing recovery from high levels of replication stress. This machinery is critical for tumor cell survival, and therefore constitutes a promising target for anti-cancer drug development. However, it is unclear how this mitotic RSR is organized molecularly and how it can be targeted therapeutically.
In this project, I aim to molecularly define and therapeutically target the Mitotic Replication Stress Recovery (RSR) machinery in triple-negative breast cancer cells.
To this end, I will implement a series of complementary innovative strategies. First, I will use mass-spec-based proteomics to molecularly characterize components and wiring of the mitotic RSR machinery. Second, to identify the genetic profiles of cancer subgroups that are sensitive to inactivation of the mitotic RSR, functional genetic screens will be combined with visualization and quantification of replication stress in genomically-defined human cancer samples. Finally, my findings will be translated to the pre-clinical situation by exploring the feasibility of therapeutic inactivation of the RSR machinery in vitro and in vivo in a panel of triple-negative breast cancer models.
In summary, TENSION will provide advanced insight into the composition and wiring of the mitotic RSR machinery and will reveal the potency of targeting this pathway therapeutically for TNBCs and other hard-to-treat, genomically instable cancers.
Max ERC Funding
1 972 500 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym Tolerome
Project Evolution of antibiotic tolerance in the 'wild': A quantitative approach
Researcher (PI) Nathalie Balaban
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Consolidator Grant (CoG), LS8, ERC-2015-CoG
Summary Bacterial ability to evolve strategies for evading antibiotic treatment is a fascinating example of an evolutionary process, as well as a major health threat. Despite efforts to understand treatment failure, we lack the means to prevent evolution of resistance when a new drug is released to the market. Most efforts are directed towards understanding the mechanisms of antibiotic resistance. Whereas ‘resistance’ is due to mutations that enable microorganisms to grow even at high concentrations of the drug, ‘tolerance’ is the ability to sustain a transient treatment, for example by entering a mode of transient dormancy. The importance of tolerance in the clinic has not been investigated as thoroughly as resistance. The presence of tolerant bacteria is not detected in the clinic because of the inherent difficulty of tracking dormant bacteria that often constitute only a minute fraction of the bacterial population. I hypothesize that bacterial dormancy may evolve quickly in the host under antibiotic treatment. This hypothesis is strengthened by our recent results demonstrating the rapid evolution of dormancy leading to tolerance in vitro, and by the increasing number of cases of treatment failure in the clinic not explained by resistance. My goal is to develop a multidisciplinary approach to detect, quantify and characterize tolerant bacteria in the clinic. Using my background in quantitative single-cell analyses, I will develop microfluidic devices for the rapid detection of tolerant bacteria in the clinic, systems biology tools to isolate and analyze dormant sub-populations directly from clinical isolates. I will search for the genetic mutations leading to tolerance, namely build what I term here the ‘tolerome’. The results will be analyzed in a mathematical framework of tolerance evolution. This approach should reveal the role of tolerance in the clinic and may lead to a paradigm shift in the way bacterial infections are characterized and treated.
Summary
Bacterial ability to evolve strategies for evading antibiotic treatment is a fascinating example of an evolutionary process, as well as a major health threat. Despite efforts to understand treatment failure, we lack the means to prevent evolution of resistance when a new drug is released to the market. Most efforts are directed towards understanding the mechanisms of antibiotic resistance. Whereas ‘resistance’ is due to mutations that enable microorganisms to grow even at high concentrations of the drug, ‘tolerance’ is the ability to sustain a transient treatment, for example by entering a mode of transient dormancy. The importance of tolerance in the clinic has not been investigated as thoroughly as resistance. The presence of tolerant bacteria is not detected in the clinic because of the inherent difficulty of tracking dormant bacteria that often constitute only a minute fraction of the bacterial population. I hypothesize that bacterial dormancy may evolve quickly in the host under antibiotic treatment. This hypothesis is strengthened by our recent results demonstrating the rapid evolution of dormancy leading to tolerance in vitro, and by the increasing number of cases of treatment failure in the clinic not explained by resistance. My goal is to develop a multidisciplinary approach to detect, quantify and characterize tolerant bacteria in the clinic. Using my background in quantitative single-cell analyses, I will develop microfluidic devices for the rapid detection of tolerant bacteria in the clinic, systems biology tools to isolate and analyze dormant sub-populations directly from clinical isolates. I will search for the genetic mutations leading to tolerance, namely build what I term here the ‘tolerome’. The results will be analyzed in a mathematical framework of tolerance evolution. This approach should reveal the role of tolerance in the clinic and may lead to a paradigm shift in the way bacterial infections are characterized and treated.
Max ERC Funding
1 978 750 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym TSGPs-of-CFSs
Project Role of Tumour Suppressor Gene Products of Common Fragile Sites in Human Diseases
Researcher (PI) Rami Aqeilan
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Consolidator Grant (CoG), LS4, ERC-2015-CoG
Summary Common fragile sites (CFSs) are large chromosomal regions identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs stems from their key role in DNA damage, resulting in chromosomal rearrangements. The instability of CFSs was correlated with genome instability in precancerous lesions and during tumour progression. Two opposing views dominate the discussion regarding the role of CFSs. One school of thought suggested that genomic instability during cancer progression causes collateral damage to genes residing within CFSs, such as WWOX and FHIT. These genes are proposed to be unselected ‘‘passenger’’ mutations. The counter argument is that deletions and other genomic alterations in CFSs occur early in cancer development. Cancer cells with deletions in genes that span CFSs are then selectively expanded due to loss of tumour suppressor functions such as protection of genome stability, coordination of cell cycle or apoptosis.
Recent observations from my lab clearly suggest that gene products from CFSs play driver roles in cancer transformation. Moreover, we have evidence for the involvement of DNA damage and Wwox in pancreatic β-cells in the context of diabetes. Here, I propose to investigate the role of tumour suppressor gene products (TSGPs) of CFSs in human diseases. Three approaches will be taken to tackle this question. First, molecular functions of TSGPs of CFSs will be determined using state-of-the-art genetic tools in vitro. Second, novel transgenic mouse tools will be used to study CFSs and their associated TSGs in preneoplastic lesions and tumours in vivo, with confirmatory studies in human material. Third, we will examine the potential involvement of CFSs and their TSGPs in type-2 diabetes (T2D).
The expected outcome is a detailed molecular understanding of CFSs and their associated TSGPs in genomic instability as well as their roles in cancer and metabolic diseases.
Summary
Common fragile sites (CFSs) are large chromosomal regions identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs stems from their key role in DNA damage, resulting in chromosomal rearrangements. The instability of CFSs was correlated with genome instability in precancerous lesions and during tumour progression. Two opposing views dominate the discussion regarding the role of CFSs. One school of thought suggested that genomic instability during cancer progression causes collateral damage to genes residing within CFSs, such as WWOX and FHIT. These genes are proposed to be unselected ‘‘passenger’’ mutations. The counter argument is that deletions and other genomic alterations in CFSs occur early in cancer development. Cancer cells with deletions in genes that span CFSs are then selectively expanded due to loss of tumour suppressor functions such as protection of genome stability, coordination of cell cycle or apoptosis.
Recent observations from my lab clearly suggest that gene products from CFSs play driver roles in cancer transformation. Moreover, we have evidence for the involvement of DNA damage and Wwox in pancreatic β-cells in the context of diabetes. Here, I propose to investigate the role of tumour suppressor gene products (TSGPs) of CFSs in human diseases. Three approaches will be taken to tackle this question. First, molecular functions of TSGPs of CFSs will be determined using state-of-the-art genetic tools in vitro. Second, novel transgenic mouse tools will be used to study CFSs and their associated TSGs in preneoplastic lesions and tumours in vivo, with confirmatory studies in human material. Third, we will examine the potential involvement of CFSs and their TSGPs in type-2 diabetes (T2D).
The expected outcome is a detailed molecular understanding of CFSs and their associated TSGPs in genomic instability as well as their roles in cancer and metabolic diseases.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym Virocellsphere
Project Host-virus chemical arms race during algal bloom in the ocean at a single cell resolution
Researcher (PI) Asaf Vardi
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Consolidator Grant (CoG), LS8, ERC-2015-CoG
Summary Phytoplankton blooms are ephemeral events of exceptionally high primary productivity that regulate the flux of carbon across marine food webs. The cosmopolitan coccolithophore Emiliania huxleyi (Haptophyta) is a unicellular eukaryotic alga responsible for the largest oceanic algal blooms covering thousands of square kilometers. These annual blooms are frequently terminated by a specific large dsDNA E. huxleyi virus (EhV).
Despite the huge ecological importance of host-virus interactions, the ability to assess their ecological impact is limited to current approaches, which focus mainly on quantification of viral abundance and diversity. On the molecular basis, a major challenge in the current understanding of host-virus interactions in the marine environment is the ability to decode the wealth of “omics” data and translate it into cellular mechanisms that mediate host susceptibility and resistance to viral infection.
In the current proposal we intend to provide novel functional insights into molecular mechanisms that regulate host-virus interactions at the single-cell level by unravelling phenotypic heterogeneity within infected populations. By using physiological markers and single-cell transcriptomics, we propose to discern between host subpopulations and define their different “metabolic states”, in order to map them into different modes of susceptibility and resistance. By using advanced metabolomic approaches, we also aim to define the infochemical microenvironment generated during viral infection and examine how it can shape host phenotypic plasticity. Mapping the transcriptomic and metabolic footprints of viral infection will provide a meaningful tool to assess the dynamics of active viral infection during natural E. huxleyi blooms. Our novel approaches will pave the way for unprecedented quantification of the “viral shunt” that drives nutrient fluxes in marine food webs, from a single-cell level to a population and eventually ecosystem levels.
Summary
Phytoplankton blooms are ephemeral events of exceptionally high primary productivity that regulate the flux of carbon across marine food webs. The cosmopolitan coccolithophore Emiliania huxleyi (Haptophyta) is a unicellular eukaryotic alga responsible for the largest oceanic algal blooms covering thousands of square kilometers. These annual blooms are frequently terminated by a specific large dsDNA E. huxleyi virus (EhV).
Despite the huge ecological importance of host-virus interactions, the ability to assess their ecological impact is limited to current approaches, which focus mainly on quantification of viral abundance and diversity. On the molecular basis, a major challenge in the current understanding of host-virus interactions in the marine environment is the ability to decode the wealth of “omics” data and translate it into cellular mechanisms that mediate host susceptibility and resistance to viral infection.
In the current proposal we intend to provide novel functional insights into molecular mechanisms that regulate host-virus interactions at the single-cell level by unravelling phenotypic heterogeneity within infected populations. By using physiological markers and single-cell transcriptomics, we propose to discern between host subpopulations and define their different “metabolic states”, in order to map them into different modes of susceptibility and resistance. By using advanced metabolomic approaches, we also aim to define the infochemical microenvironment generated during viral infection and examine how it can shape host phenotypic plasticity. Mapping the transcriptomic and metabolic footprints of viral infection will provide a meaningful tool to assess the dynamics of active viral infection during natural E. huxleyi blooms. Our novel approaches will pave the way for unprecedented quantification of the “viral shunt” that drives nutrient fluxes in marine food webs, from a single-cell level to a population and eventually ecosystem levels.
Max ERC Funding
2 749 901 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
