Project acronym Ca2Coral
Project Elucidating the molecular and biophysical mechanism of coral calcification in view of the future acidified ocean
Researcher (PI) Tali Mass
Host Institution (HI) UNIVERSITY OF HAIFA
Call Details Starting Grant (StG), LS8, ERC-2017-STG
Summary Although various aspects of biomineralisation in corals have been studied for decades, the basic mechanism of precipitation of the aragonite skeleton remains enigmatic. Two parallel lines of inquiry have emerged: geochemist models of calcification that are directly related to seawater carbonate chemistry at thermodynamic equilibrium. Here, the role of the organisms in the precipitation reaction is largely ignored. The second line is based on biological considerations of the biomineralisation process, which focuses on models of biophysical processes far from thermodynamic equilibrium that concentrate calcium ions, anions and proteins responsible for nucleation in specific compartments. Recently, I identified and cloned a group of highly acidic proteins derived the common stony coral, Stylophora pistillata. All of the cloned proteins precipitate aragonite in seawater at pH 8.2 and 7.6 in-vitro. However, it is not at all clear if the expression of these proteins in-vivo is sufficient for the formation of an aragonite skeleton at seawater pH values below ~7.8. Here using a combination of molecular, biophysical, genomic, and cell biological approaches, we proposed to test the core hypothesis that, unless wounded or otherwise having skeletal material exposed directly to seawater, stony zooxanthellate corals will continue to calcify at pH values projected for the CO2 emissions scenarios for 2100.
Specifically, the objectives of Ca2Coral are to:
1) Use functional genomics to identify the key genes and proteins involved both in the organic matrix and skeleton formation in the adult holobiont and during its larval development.
2) Use a genetics approach to elucidate the roles of specific proteins in the biomineralisation process.
3) Use ultra-high resolution imaging and spectroscopic analysis at different pH levels to elucidate the biomineralisation pathways and mineral precursor in corals in the adult holobiont and during its larval development.
Summary
Although various aspects of biomineralisation in corals have been studied for decades, the basic mechanism of precipitation of the aragonite skeleton remains enigmatic. Two parallel lines of inquiry have emerged: geochemist models of calcification that are directly related to seawater carbonate chemistry at thermodynamic equilibrium. Here, the role of the organisms in the precipitation reaction is largely ignored. The second line is based on biological considerations of the biomineralisation process, which focuses on models of biophysical processes far from thermodynamic equilibrium that concentrate calcium ions, anions and proteins responsible for nucleation in specific compartments. Recently, I identified and cloned a group of highly acidic proteins derived the common stony coral, Stylophora pistillata. All of the cloned proteins precipitate aragonite in seawater at pH 8.2 and 7.6 in-vitro. However, it is not at all clear if the expression of these proteins in-vivo is sufficient for the formation of an aragonite skeleton at seawater pH values below ~7.8. Here using a combination of molecular, biophysical, genomic, and cell biological approaches, we proposed to test the core hypothesis that, unless wounded or otherwise having skeletal material exposed directly to seawater, stony zooxanthellate corals will continue to calcify at pH values projected for the CO2 emissions scenarios for 2100.
Specifically, the objectives of Ca2Coral are to:
1) Use functional genomics to identify the key genes and proteins involved both in the organic matrix and skeleton formation in the adult holobiont and during its larval development.
2) Use a genetics approach to elucidate the roles of specific proteins in the biomineralisation process.
3) Use ultra-high resolution imaging and spectroscopic analysis at different pH levels to elucidate the biomineralisation pathways and mineral precursor in corals in the adult holobiont and during its larval development.
Max ERC Funding
1 499 741 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym CANCER-DC
Project Dissecting Regulatory Networks That Mediate Dendritic Cell Suppression
Researcher (PI) Oren PARNAS
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS6, ERC-2017-STG
Summary Recent advances have shown that therapeutic manipulations of key cell-cell interactions can have dramatic clinical outcomes. Most notable are several early successes in cancer immunotherapy that target the tumor-T cell interface. However, these successes were only partial. This is likely because the few known interactions are just a few pieces of a much larger puzzle, involving additional signaling molecules and cell types. Dendritic cells (DCs), play critical roles in the induction/suppression of T cells. At early cancer stages, DCs capture tumor antigens and present them to T cells. However, in advanced cancers, the tumor microenvironment (TME) disrupts the crosstalk between DCs and T cells.
We will take a multi-step approach to explore how the TME imposes a suppressive effect on DCs and how to reverse this hazardous effect. First, we will use single cell RNA-seq to search for genes in aggressive human and mouse ovarian tumors that are highly expressed in advanced tumors compared to early tumors and that encode molecules that suppress DC activity. Second, we will design a set of CRISPR screens to find genes that are expressed in DCs and regulate the transfer of the suppressive signals. The screens will be performed in the presence of suppressive molecules to mimic the TME and are expected to uncover many key genes in DCs biology. We will develop a new strategy to find synergistic combinations of genes to target (named Perturb-comb), thereby reversing the effect of local tumor immunosuppressive signals. Lastly, we will examine the effect of modified DCs on T cell activation and proliferation in-vivo, and on tumor growth.
We expect to find: (1) Signaling molecules in the TME that affect the immune system. (2) New cytokines and cell surface receptors that are expressed in DCs and signal to T cells. (3) New key regulators in DC biology and their mechanisms. (4) Combinations of genes to target in DCs that reverse the TME’s hazardous effects.
Summary
Recent advances have shown that therapeutic manipulations of key cell-cell interactions can have dramatic clinical outcomes. Most notable are several early successes in cancer immunotherapy that target the tumor-T cell interface. However, these successes were only partial. This is likely because the few known interactions are just a few pieces of a much larger puzzle, involving additional signaling molecules and cell types. Dendritic cells (DCs), play critical roles in the induction/suppression of T cells. At early cancer stages, DCs capture tumor antigens and present them to T cells. However, in advanced cancers, the tumor microenvironment (TME) disrupts the crosstalk between DCs and T cells.
We will take a multi-step approach to explore how the TME imposes a suppressive effect on DCs and how to reverse this hazardous effect. First, we will use single cell RNA-seq to search for genes in aggressive human and mouse ovarian tumors that are highly expressed in advanced tumors compared to early tumors and that encode molecules that suppress DC activity. Second, we will design a set of CRISPR screens to find genes that are expressed in DCs and regulate the transfer of the suppressive signals. The screens will be performed in the presence of suppressive molecules to mimic the TME and are expected to uncover many key genes in DCs biology. We will develop a new strategy to find synergistic combinations of genes to target (named Perturb-comb), thereby reversing the effect of local tumor immunosuppressive signals. Lastly, we will examine the effect of modified DCs on T cell activation and proliferation in-vivo, and on tumor growth.
We expect to find: (1) Signaling molecules in the TME that affect the immune system. (2) New cytokines and cell surface receptors that are expressed in DCs and signal to T cells. (3) New key regulators in DC biology and their mechanisms. (4) Combinations of genes to target in DCs that reverse the TME’s hazardous effects.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym CRISS
Project CRISPR Gene Correction for Severe Combined Immunodeficiency Caused by Mutations in Recombination-activating gene 1 and 2 (RAG1 and RAG2)
Researcher (PI) Ayal Hendel
Host Institution (HI) BAR ILAN UNIVERSITY
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary The severe combined immunodeficiencies (SCIDs) are a set of life threatening genetic diseases in which patients are born with mutations in single genes and are unable to develop functional immune systems. While allogeneic bone marrow transplantation can be curative for these diseases, there remain significant limitations to this approach. Gene therapy using viral vectors containing a corrective transgene is being developed for some of these disorders, most successfully for ADA-SCID. However, for other SCID disorders, such as those caused by genetic mutations in RAG1 and RAG2, the transgene needs to be expressed in a precise, developmental and lineage specific manner to achieve functional gene correction and to avoid the risks of cellular transformation. In contrast to using viral vectors to deliver transgenes in an uncontrolled fashion, we are working towards using genome editing by homologous recombination (HR) to correct the disease causing mutation by precisely modifying the genome. We have shown that by using clustered, regularly interspaced, short palindromic repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9) system we can stimulate genome editing by HR at frequencies that should be therapeutically beneficial (>10%) in hematopoietic stem and progenitor cells (HSPCs). The overall focus of the proposal is to translate our basic science studies to use in RAG-SCID patient-derived HSPCs in methodical, careful and pre-clinically relevant fashion. The fundamental approach is to develop a highly active functional genome editing system using CRISPR-Cas9 for RAG-SCIDs and complete pre-clinical efficacy and safety studies to show the approach has a clear path towards future clinical trials. Our goal with this proposal is to develop the next wave of curative therapies for SCIDs and other hematopoietic disorders using genome editing.
Summary
The severe combined immunodeficiencies (SCIDs) are a set of life threatening genetic diseases in which patients are born with mutations in single genes and are unable to develop functional immune systems. While allogeneic bone marrow transplantation can be curative for these diseases, there remain significant limitations to this approach. Gene therapy using viral vectors containing a corrective transgene is being developed for some of these disorders, most successfully for ADA-SCID. However, for other SCID disorders, such as those caused by genetic mutations in RAG1 and RAG2, the transgene needs to be expressed in a precise, developmental and lineage specific manner to achieve functional gene correction and to avoid the risks of cellular transformation. In contrast to using viral vectors to deliver transgenes in an uncontrolled fashion, we are working towards using genome editing by homologous recombination (HR) to correct the disease causing mutation by precisely modifying the genome. We have shown that by using clustered, regularly interspaced, short palindromic repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9) system we can stimulate genome editing by HR at frequencies that should be therapeutically beneficial (>10%) in hematopoietic stem and progenitor cells (HSPCs). The overall focus of the proposal is to translate our basic science studies to use in RAG-SCID patient-derived HSPCs in methodical, careful and pre-clinically relevant fashion. The fundamental approach is to develop a highly active functional genome editing system using CRISPR-Cas9 for RAG-SCIDs and complete pre-clinical efficacy and safety studies to show the approach has a clear path towards future clinical trials. Our goal with this proposal is to develop the next wave of curative therapies for SCIDs and other hematopoietic disorders using genome editing.
Max ERC Funding
1 372 839 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym CuHypMECH
Project New Nuclear Medicine Imaging Radiotracer 64Cu(II) for diagnosing Hypoxia Conditions Based on the Cellular Copper Cycle
Researcher (PI) Sharon RUTHSTEIN
Host Institution (HI) BAR ILAN UNIVERSITY
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary Imaging of hypoxia is important in many disease states in oncology, cardiology, and neurology. Hypoxia is a common condition encountered within the tumour microenvironment that drives proliferation, angiogenesis, and resistance to therapy. Despite on-going efforts to identify hypoxia, until now there is no clinically approved imaging biomarker, due to both low tumour uptake, and a low signal to background (S/B) ratio that affects the imaging quality. Nuclear Medicine is using labelled radio-isotopes for PET/CT and SPECT imaging. These radio-tracers diagnose the metabolic processes in the body. Among these tracers, 18F-FDG is the most routinely used as a marker of glucose metabolism. However, not all tumours consume glucose, and glucose consumption is not specific only for malignant tumours, which limits its application. Copper is a nutritional metal, recently examined as a radiotracer for hypoxia, owing to its to the oxidising environment. Clinical and in-vivo studies on various 64Cu(II)-PET radiotracers resulted in controversial reports on the specificity of the current tracers for hypoxia imaging due to non-selective bio-distribution & low S/B ratio. This multidisciplinary proposal focuses on the discovery of comprehensive signal pathways of the cellular copper cycle using advanced biophysical methods and a proprietary design of 64Cu(II) radiotracer. This radiotracer will be incorporated in the cellular copper cycle, and will enable to selectively target the oxidising environment in tumours. The design of the new radiotracer is based on systematic structural & functional mapping of the copper binding sites to the various copper proteins and the visualisation of the transfer mechanism. This new copper tracer should increase the selectivity of tumour uptake, stability, and improve bio-distribution. This project assimilates cold and hot chemistry and biology, while emphasising the clinical unmet need in metal based radiotracer that form stable complexes.
Summary
Imaging of hypoxia is important in many disease states in oncology, cardiology, and neurology. Hypoxia is a common condition encountered within the tumour microenvironment that drives proliferation, angiogenesis, and resistance to therapy. Despite on-going efforts to identify hypoxia, until now there is no clinically approved imaging biomarker, due to both low tumour uptake, and a low signal to background (S/B) ratio that affects the imaging quality. Nuclear Medicine is using labelled radio-isotopes for PET/CT and SPECT imaging. These radio-tracers diagnose the metabolic processes in the body. Among these tracers, 18F-FDG is the most routinely used as a marker of glucose metabolism. However, not all tumours consume glucose, and glucose consumption is not specific only for malignant tumours, which limits its application. Copper is a nutritional metal, recently examined as a radiotracer for hypoxia, owing to its to the oxidising environment. Clinical and in-vivo studies on various 64Cu(II)-PET radiotracers resulted in controversial reports on the specificity of the current tracers for hypoxia imaging due to non-selective bio-distribution & low S/B ratio. This multidisciplinary proposal focuses on the discovery of comprehensive signal pathways of the cellular copper cycle using advanced biophysical methods and a proprietary design of 64Cu(II) radiotracer. This radiotracer will be incorporated in the cellular copper cycle, and will enable to selectively target the oxidising environment in tumours. The design of the new radiotracer is based on systematic structural & functional mapping of the copper binding sites to the various copper proteins and the visualisation of the transfer mechanism. This new copper tracer should increase the selectivity of tumour uptake, stability, and improve bio-distribution. This project assimilates cold and hot chemistry and biology, while emphasising the clinical unmet need in metal based radiotracer that form stable complexes.
Max ERC Funding
1 499 345 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym cureCD
Project Function of long non-coding RNA in Crohn Disease Ulcer Pathogenesis
Researcher (PI) Yael HABERMAN ZIV
Host Institution (HI) MEDICAL RESEARCH INFRASTRUCTURE DEVELOPMENT AND HEALTH SERVICES FUND BY THE SHEBA MEDICAL CENTER
Call Details Starting Grant (StG), LS4, ERC-2017-STG
Summary The Inflammatory Bowel Diseases (IBD), Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic/relapsing disorders that affect over six million individuals worldwide. Mucosal ulcers, the hallmark of CD, are the result of a complex interaction between microbiota, immune cells, and gut epithelia. Healing of mucosal ulcers is associated with better outcomes, but is achieved in less than half of cases. Past attempts to suppress central and conserved nodes of the immune system failed due to opposing off-target deleterious effects on epithelial renewal. Therefore, there is a critical need to identify more tissue specific targets that lead to mucosal healing and to improved outcomes.
Using mRNAseq of intestinal biopsies, we identified a widespread dysregulation of long non-coding RNAs (lncRNA) in the ileum of treatment naïve pediatric CD patients. Importently, we identified significant correlations between lncRNA and mucosal ulcers. CD lncRNA, after carful mechanistic exploration, are highly promising targets for potential future intervention as they regulate diverse cellular functions and exhibit a more tissue specific expression in comparison to protein coding genes. The core goal of this proposal is to understand the role of CD lncRNA in ulcer pathogenesis focusing on granulocytes and epithelial functions in the contexts of their interactions with the microbiota.
I plan to utilize state of the art informatics, RNAseq and microbiome profiles together with advanced and novel experimental lab model and co-culture systems, patients-derived prospectively collected tissues, and gut microbiota to explore the role of CD lncRNA function in mediating healing of mucosal ulcers. This work carries the potential to guide new novel therapeutic strategies for mucosal healing with minimal off-targets effects. In a broader prospective, this work will expand our relative limited understanding regarding the role of lncRNA in mediating human diseases.
Summary
The Inflammatory Bowel Diseases (IBD), Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic/relapsing disorders that affect over six million individuals worldwide. Mucosal ulcers, the hallmark of CD, are the result of a complex interaction between microbiota, immune cells, and gut epithelia. Healing of mucosal ulcers is associated with better outcomes, but is achieved in less than half of cases. Past attempts to suppress central and conserved nodes of the immune system failed due to opposing off-target deleterious effects on epithelial renewal. Therefore, there is a critical need to identify more tissue specific targets that lead to mucosal healing and to improved outcomes.
Using mRNAseq of intestinal biopsies, we identified a widespread dysregulation of long non-coding RNAs (lncRNA) in the ileum of treatment naïve pediatric CD patients. Importently, we identified significant correlations between lncRNA and mucosal ulcers. CD lncRNA, after carful mechanistic exploration, are highly promising targets for potential future intervention as they regulate diverse cellular functions and exhibit a more tissue specific expression in comparison to protein coding genes. The core goal of this proposal is to understand the role of CD lncRNA in ulcer pathogenesis focusing on granulocytes and epithelial functions in the contexts of their interactions with the microbiota.
I plan to utilize state of the art informatics, RNAseq and microbiome profiles together with advanced and novel experimental lab model and co-culture systems, patients-derived prospectively collected tissues, and gut microbiota to explore the role of CD lncRNA function in mediating healing of mucosal ulcers. This work carries the potential to guide new novel therapeutic strategies for mucosal healing with minimal off-targets effects. In a broader prospective, this work will expand our relative limited understanding regarding the role of lncRNA in mediating human diseases.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym DecodingInfection
Project Decoding the host-pathogen interspecies crosstalk at a multiparametric single-cell level
Researcher (PI) Roi AVRAHAM
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS6, ERC-2017-STG
Summary Bacterial pathogens remain a significant threat to global health, necessitating a better understanding of host-pathogen biology. While various evidence point to early infection as a key event in the eventual progression to disease, our recent preliminary data show that during this stage, highly adaptable and dynamic host cells and bacteria engage in complex, diverse interactions that contribute to well-documented heterogeneous outcomes of infection. However, current methodologies rely on measurements of bulk populations, thereby overlooking this diversity that can trigger different outcomes. This application focuses on understanding heterogeneity during the first stages of infection in order to reduce the complexity of these interactions into informative readouts of population physiology and predictors of infection outcome. We will apply multiparametric single-cell analysis to obtain an accurate and complete description of infection with the enteric intracellular pathogen Salmonella of macrophages in vitro, and in early stages of mice colonization. We will characterize the molecular details that underlie distinct infection outcomes of individual encounters, to reconstruct the repertoire of host and pathogen strategies that prevail at critical stages of early infection.
We propose the following three objectives: (1) Develop methodologies to simultaneously profile host and pathogen transcriptional changes on a single cell level; 2) Characterizing the molecular details that underlie the formation of subpopulations during macrophage infection; and (3) Determine how host and pathogen encounters in vivo result in emergence of specialized subpopulations, recruitment of immune cells and pathogen dissemination.
We anticipate that this work will fundamentally shift our paradigms of infectious disease pathogenesis and lay the groundwork for the development of a new generation of therapeutic agents targeting the specific host-pathogen interactions ultimately driving disease.
Summary
Bacterial pathogens remain a significant threat to global health, necessitating a better understanding of host-pathogen biology. While various evidence point to early infection as a key event in the eventual progression to disease, our recent preliminary data show that during this stage, highly adaptable and dynamic host cells and bacteria engage in complex, diverse interactions that contribute to well-documented heterogeneous outcomes of infection. However, current methodologies rely on measurements of bulk populations, thereby overlooking this diversity that can trigger different outcomes. This application focuses on understanding heterogeneity during the first stages of infection in order to reduce the complexity of these interactions into informative readouts of population physiology and predictors of infection outcome. We will apply multiparametric single-cell analysis to obtain an accurate and complete description of infection with the enteric intracellular pathogen Salmonella of macrophages in vitro, and in early stages of mice colonization. We will characterize the molecular details that underlie distinct infection outcomes of individual encounters, to reconstruct the repertoire of host and pathogen strategies that prevail at critical stages of early infection.
We propose the following three objectives: (1) Develop methodologies to simultaneously profile host and pathogen transcriptional changes on a single cell level; 2) Characterizing the molecular details that underlie the formation of subpopulations during macrophage infection; and (3) Determine how host and pathogen encounters in vivo result in emergence of specialized subpopulations, recruitment of immune cells and pathogen dissemination.
We anticipate that this work will fundamentally shift our paradigms of infectious disease pathogenesis and lay the groundwork for the development of a new generation of therapeutic agents targeting the specific host-pathogen interactions ultimately driving disease.
Max ERC Funding
1 499 999 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym FORMICA
Project Microclimatic buffering of plant responses to macroclimate warming in temperate forests
Researcher (PI) Pieter DE FRENNE
Host Institution (HI) UNIVERSITEIT GENT
Call Details Starting Grant (StG), LS9, ERC-2017-STG
Summary Recent global warming is acting across ecosystems and threatening biodiversity. Yet, due to slow responses, many biological communities are lagging behind warming of the macroclimate (the climate of a large geographic region). The buffering of microclimates near the ground measured in localized areas, arising from terrain features such as vegetation and topography, can explain why many species are lagging behind macroclimate warming. However, almost all studies ignore the effects of microclimatic buffering and key uncertainties still exist about this mechanism. Microclimates are particularly evident in forests, where understorey habitats are buffered by overstorey trees. In temperate forests, the understorey contains the vast majority of plant diversity and plays an essential role in driving ecosystem processes.
The overall goal of FORMICA (FORest MICroclimate Assessment) is to quantify and understand the role of microclimatic buffering in modulating forest understorey plant responses to macroclimate warming. We will perform the best assessment to date of the effects of microclimates on plants by applying microtemperature loggers, experimental heating, fluorescent tubes and a large-scale transplant experiment in temperate forests across Europe. For the first time, plant data from the individual to ecosystem level will be related to microclimate along wide temperature gradients and forest management regimes. The empirical results will then be integrated in cutting-edge demographic distribution models to forecast plant diversity in temperate forests as macroclimate warms.
FORMICA will provide the first integrative study on microclimatic buffering of macroclimate warming in forests. Interdisciplinary concepts and methods will be applied, including from climatology, forestry and ecology. FORMICA will reshape our current understanding of the impacts of climate change on forests and help land managers and policy makers to develop urgently needed adaptation strategies.
Summary
Recent global warming is acting across ecosystems and threatening biodiversity. Yet, due to slow responses, many biological communities are lagging behind warming of the macroclimate (the climate of a large geographic region). The buffering of microclimates near the ground measured in localized areas, arising from terrain features such as vegetation and topography, can explain why many species are lagging behind macroclimate warming. However, almost all studies ignore the effects of microclimatic buffering and key uncertainties still exist about this mechanism. Microclimates are particularly evident in forests, where understorey habitats are buffered by overstorey trees. In temperate forests, the understorey contains the vast majority of plant diversity and plays an essential role in driving ecosystem processes.
The overall goal of FORMICA (FORest MICroclimate Assessment) is to quantify and understand the role of microclimatic buffering in modulating forest understorey plant responses to macroclimate warming. We will perform the best assessment to date of the effects of microclimates on plants by applying microtemperature loggers, experimental heating, fluorescent tubes and a large-scale transplant experiment in temperate forests across Europe. For the first time, plant data from the individual to ecosystem level will be related to microclimate along wide temperature gradients and forest management regimes. The empirical results will then be integrated in cutting-edge demographic distribution models to forecast plant diversity in temperate forests as macroclimate warms.
FORMICA will provide the first integrative study on microclimatic buffering of macroclimate warming in forests. Interdisciplinary concepts and methods will be applied, including from climatology, forestry and ecology. FORMICA will reshape our current understanding of the impacts of climate change on forests and help land managers and policy makers to develop urgently needed adaptation strategies.
Max ERC Funding
1 498 469 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym HumanTrafficking
Project Human Trafficking: A Labor Perspective
Researcher (PI) Hila Shamir
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Starting Grant (StG), SH2, ERC-2017-STG
Summary This project conducts a theoretical, methodological, and normative paradigm shift in the research and analysis of human trafficking, one of the most pressing moral and political challenges of our times. It moves away from the currently predominant approach to trafficking, which focuses on criminal law, border control, and human rights, towards a labor-based approach that targets the structure of labor markets that are prone to severely exploitative labor practices. This shift represents an essential development both in the research of migratory labor practices and in the process of designing more effective, and more just, anti-trafficking measures, that are context-sensitive as well as cognizant to global legal and economic trends. The project will include four main parts: 1) Theoretical: articulating and justifying the proposed shift on trafficking from individual rights and culpabilities to structural labor market realities. 2) Case-studies: conducting a multidisciplinary study of a series of innovative case studies, in which the labor context emerges as a significant factor in the trafficking nexus – bilateral agreements on migration, national regulations of labor standards and recruiters, unionization, and voluntary corporate codes of conduct. The case studies analysis employs the labor paradigm in elucidating the structural conditions that underlie trafficking, reveal a thus-far mostly unrecognized and under-theorized set of anti-trafficking tools. 3) Clinical Laboratory: collaborating with TAUs Workers' Rights clinic to create a legal laboratory in which the potential and limits of the tools examined in the case studies will be tested. 4) Normative: assessing the success of existing strategies and expanding on them to devise innovative tools for a just, practicable, and effective anti-trafficking policy, that can reach significantly more individuals vulnerable to trafficking, by providing them with legal mechanisms for avoiding and resisting exploitation.
Summary
This project conducts a theoretical, methodological, and normative paradigm shift in the research and analysis of human trafficking, one of the most pressing moral and political challenges of our times. It moves away from the currently predominant approach to trafficking, which focuses on criminal law, border control, and human rights, towards a labor-based approach that targets the structure of labor markets that are prone to severely exploitative labor practices. This shift represents an essential development both in the research of migratory labor practices and in the process of designing more effective, and more just, anti-trafficking measures, that are context-sensitive as well as cognizant to global legal and economic trends. The project will include four main parts: 1) Theoretical: articulating and justifying the proposed shift on trafficking from individual rights and culpabilities to structural labor market realities. 2) Case-studies: conducting a multidisciplinary study of a series of innovative case studies, in which the labor context emerges as a significant factor in the trafficking nexus – bilateral agreements on migration, national regulations of labor standards and recruiters, unionization, and voluntary corporate codes of conduct. The case studies analysis employs the labor paradigm in elucidating the structural conditions that underlie trafficking, reveal a thus-far mostly unrecognized and under-theorized set of anti-trafficking tools. 3) Clinical Laboratory: collaborating with TAUs Workers' Rights clinic to create a legal laboratory in which the potential and limits of the tools examined in the case studies will be tested. 4) Normative: assessing the success of existing strategies and expanding on them to devise innovative tools for a just, practicable, and effective anti-trafficking policy, that can reach significantly more individuals vulnerable to trafficking, by providing them with legal mechanisms for avoiding and resisting exploitation.
Max ERC Funding
1 492 250 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym HybridRetina
Project Hybrid Retinal Prosthesis: High-Resolution Electrode Array Integrated with Neurons for Restoration of Sight
Researcher (PI) Yosef Mandel
Host Institution (HI) BAR ILAN UNIVERSITY
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary Vision restoration in patients with outer retinal degenerative diseases, such as Age-related Macular Degeneration and Retinitis Pigmentosa can be achieved by bypassing the degenerated photoreceptors and the electrical stimulation of the relatively well-preserved inner retina through electrode implants. Although current retinal prostheses have been shown to provide useful vision in blind patients, the obtained visual acuity and quality are still relatively low. Several challenges cannot be addressed with the current retinal prosthetic technologies. First, increasing the electrode density for achieving high visual acuity is limited by the distance between the electrodes and the target neurons. Second, electrical stimulation by the current technologies is not selective for specific retinal circuitry (e.g. ON and OFF pathways). Finally, retinal neurons are stimulated by pulsed rather than in a continuously graded potential fashion, which provides the photoreceptors with an unrivalled dynamic range and sensitivity in natural vision.
Here we propose a paradigm shift toward sight restoration with a hybrid retinal prosthesis aimed at overcoming the aforementioned limitations. The hybrid implant is composed of a very high density electrode array (pixel distance of 15µm) coupled with neurons to create a tight neuron-electrode coupling. Following implantation of the hybrid prosthesis, the neurons integrate and synapse with the host retinal circuits. Upon patterned electrical stimulation of the neurons by the electrodes, the host bipolar cells are activated while preserving the natural vision circuits. The ultimate electrode-neurons proximity allows for the significant increase in pixel density, the low charge neural activation, and the continuous graded potential activation. This research can advance our knowledge in the retinal field and in other neural prosthetics and if successful, it will enable future vision restoration with unprecedented resolution.
Summary
Vision restoration in patients with outer retinal degenerative diseases, such as Age-related Macular Degeneration and Retinitis Pigmentosa can be achieved by bypassing the degenerated photoreceptors and the electrical stimulation of the relatively well-preserved inner retina through electrode implants. Although current retinal prostheses have been shown to provide useful vision in blind patients, the obtained visual acuity and quality are still relatively low. Several challenges cannot be addressed with the current retinal prosthetic technologies. First, increasing the electrode density for achieving high visual acuity is limited by the distance between the electrodes and the target neurons. Second, electrical stimulation by the current technologies is not selective for specific retinal circuitry (e.g. ON and OFF pathways). Finally, retinal neurons are stimulated by pulsed rather than in a continuously graded potential fashion, which provides the photoreceptors with an unrivalled dynamic range and sensitivity in natural vision.
Here we propose a paradigm shift toward sight restoration with a hybrid retinal prosthesis aimed at overcoming the aforementioned limitations. The hybrid implant is composed of a very high density electrode array (pixel distance of 15µm) coupled with neurons to create a tight neuron-electrode coupling. Following implantation of the hybrid prosthesis, the neurons integrate and synapse with the host retinal circuits. Upon patterned electrical stimulation of the neurons by the electrodes, the host bipolar cells are activated while preserving the natural vision circuits. The ultimate electrode-neurons proximity allows for the significant increase in pixel density, the low charge neural activation, and the continuous graded potential activation. This research can advance our knowledge in the retinal field and in other neural prosthetics and if successful, it will enable future vision restoration with unprecedented resolution.
Max ERC Funding
1 499 582 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym MalPar.NET
Project Malaria Parasite Networking: Discovering Modes of Cell-Cell Communication
Researcher (PI) Neta REGEV-RUDZKI
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS6, ERC-2017-STG
Summary Malaria, caused by Plasmodium falciparum, is a devastating parasitic disease effecting hundreds of millions of people worldwide. The parasite’s transmission cycle between humans and mosquitoes involves a remarkable series of morphological transformations. While it is clear that, for such a complex journey, the parasites must develop means to sense their host and coordinate their actions; these modes of communication remain one of the greatest mysteries in malaria biology. In fact, since an individual parasite is enclosed by three membranes inside its human host, the red blood cell (RBC), they were not thought to possess any communication ability. However, we discovered that these parasites, despite the multiple barriers, are able to communicate and exchange episomal genes by releasing exosome-like vesicles, thereby opening the exciting new field of malaria parasite communication. Our initial data demonstrate that these vesicles serve as a secure tool for the delivery of remarkable components.
The overarching goal of this proposal is to take an innovative look at this under-investigated area of parasite sensing and signalling pathways and to decipher the multiple layers of parasite and host signalling networks. Specifically, we will determine the biological roles of Plasmodium exosome cargo components in: parasite-parasite communication - exploring parasite coordination traits in cell-density growth and sexual development (Objective 1); and parasite-host communication - unravelling the mutual communication of the parasite and its hosts, the red blood and immune cells (Objective 2). Simultaneously, we will exploit our experience in cell communication research to investigate the complementary, yet-to-be-explored mode of parasite communication via the secretion of small molecules (Objective 3).
Our project will provide a holistic view of parasite communication networking while potentially providing, in the long term, novel targets for malaria therapeutics.
Summary
Malaria, caused by Plasmodium falciparum, is a devastating parasitic disease effecting hundreds of millions of people worldwide. The parasite’s transmission cycle between humans and mosquitoes involves a remarkable series of morphological transformations. While it is clear that, for such a complex journey, the parasites must develop means to sense their host and coordinate their actions; these modes of communication remain one of the greatest mysteries in malaria biology. In fact, since an individual parasite is enclosed by three membranes inside its human host, the red blood cell (RBC), they were not thought to possess any communication ability. However, we discovered that these parasites, despite the multiple barriers, are able to communicate and exchange episomal genes by releasing exosome-like vesicles, thereby opening the exciting new field of malaria parasite communication. Our initial data demonstrate that these vesicles serve as a secure tool for the delivery of remarkable components.
The overarching goal of this proposal is to take an innovative look at this under-investigated area of parasite sensing and signalling pathways and to decipher the multiple layers of parasite and host signalling networks. Specifically, we will determine the biological roles of Plasmodium exosome cargo components in: parasite-parasite communication - exploring parasite coordination traits in cell-density growth and sexual development (Objective 1); and parasite-host communication - unravelling the mutual communication of the parasite and its hosts, the red blood and immune cells (Objective 2). Simultaneously, we will exploit our experience in cell communication research to investigate the complementary, yet-to-be-explored mode of parasite communication via the secretion of small molecules (Objective 3).
Our project will provide a holistic view of parasite communication networking while potentially providing, in the long term, novel targets for malaria therapeutics.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
