Project acronym AMAIZE
Project Atlas of leaf growth regulatory networks in MAIZE
Researcher (PI) Dirk, Gustaaf Inzé
Host Institution (HI) VIB
Call Details Advanced Grant (AdG), LS9, ERC-2013-ADG
Summary "Understanding how organisms regulate size is one of the most fascinating open questions in biology. The aim of the AMAIZE project is to unravel how growth of maize leaves is controlled. Maize leaf development offers great opportunities to study the dynamics of growth regulatory networks, essentially because leaf development is a linear system with cell division at the leaf basis followed by cell expansion and maturation. Furthermore, the growth zone is relatively large allowing easy access of tissues at different positions. Four different perturbations of maize leaf size will be analyzed with cellular resolution: wild-type and plants having larger leaves (as a consequence of GA20OX1 overexpression), both grown under either well-watered or mild drought conditions. Firstly, a 3D cellular map of the growth zone of the fourth leaf will be made. RNA-SEQ of three different tissues (adaxial- and abaxial epidermis; mesophyll) obtained by laser dissection with an interval of 2.5 mm along the growth zone will allow for the analysis of the transcriptome with high resolution. Additionally, the composition of fifty selected growth regulatory protein complexes and DNA targets of transcription factors will be determined with an interval of 5 mm along the growth zone. Computational methods will be used to construct comprehensive integrative maps of the cellular and molecular processes occurring along the growth zone. Finally, selected regulatory nodes of the growth regulatory networks will be further functionally analyzed using a transactivation system in maize.
AMAIZE opens up new perspectives for the identification of optimal growth regulatory networks that can be selected for by advanced breeding or for which more robust variants (e.g. reduced susceptibility to drought) can be obtained through genetic engineering. The ability to improve the growth of maize and in analogy other cereals could have a high impact in providing food security"
Summary
"Understanding how organisms regulate size is one of the most fascinating open questions in biology. The aim of the AMAIZE project is to unravel how growth of maize leaves is controlled. Maize leaf development offers great opportunities to study the dynamics of growth regulatory networks, essentially because leaf development is a linear system with cell division at the leaf basis followed by cell expansion and maturation. Furthermore, the growth zone is relatively large allowing easy access of tissues at different positions. Four different perturbations of maize leaf size will be analyzed with cellular resolution: wild-type and plants having larger leaves (as a consequence of GA20OX1 overexpression), both grown under either well-watered or mild drought conditions. Firstly, a 3D cellular map of the growth zone of the fourth leaf will be made. RNA-SEQ of three different tissues (adaxial- and abaxial epidermis; mesophyll) obtained by laser dissection with an interval of 2.5 mm along the growth zone will allow for the analysis of the transcriptome with high resolution. Additionally, the composition of fifty selected growth regulatory protein complexes and DNA targets of transcription factors will be determined with an interval of 5 mm along the growth zone. Computational methods will be used to construct comprehensive integrative maps of the cellular and molecular processes occurring along the growth zone. Finally, selected regulatory nodes of the growth regulatory networks will be further functionally analyzed using a transactivation system in maize.
AMAIZE opens up new perspectives for the identification of optimal growth regulatory networks that can be selected for by advanced breeding or for which more robust variants (e.g. reduced susceptibility to drought) can be obtained through genetic engineering. The ability to improve the growth of maize and in analogy other cereals could have a high impact in providing food security"
Max ERC Funding
2 418 429 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym APOLs
Project Role of Apolipoproteins L in immunity and disease
Researcher (PI) Etienne Pays
Host Institution (HI) UNIVERSITE LIBRE DE BRUXELLES
Call Details Advanced Grant (AdG), LS6, ERC-2014-ADG
Summary Work conducted in my laboratory on the trypanosome killing factor of human serum led to the identification
of the primate-specific Apolipoprotein L1 (APOL1) as a novel pore-forming protein with striking similarities
with proteins of the apoptotic BCL2 family. APOL1 belongs to a family of proteins induced under
inflammatory conditions in myeloid and endothelial cells. APOL1 is efficiently neutralized by the SRA
protein of Trypanosoma rhodesiense, accounting for the ability of this trypanosome subspecies to infect
humans and cause sleeping sickness. We found that natural APOL1 variants escaping SRA neutralization and
therefore conferring human resistance to T. rhodesiense are associated with chronic kidney disease.
Moreover, transgenic mice expressing these APOL1 variants exhibit an obese phenotype. Our unpublished
results also indicate that APOLs control the lifespan of dendritic cells and podocytes activated by viral
stimuli. Therefore, we propose that the pathology of APOL variants is due to their deregulated activity on the
control of the cellular lifespan in myeloid/endothelial cells activated by pathogen detection.
This project aims at characterizing (i) the molecular mechanism by which APOLs control the lifespan of
activated dendritic cells and podocytes, which has direct impact on innate immunity and inflammation, and
(ii) the mechanism by which APOL1 variants cause pathology. In addition, we plan to detail the
physiological function of APOLs by studying the phenotype of transgenic mice either expressing human
APOL1 (wild-type and variants) or devoid of APOL genes, which we have recently generated. Finally, we
propose to exploit the extraordinary potential of trypanosomes for antigenic variation in order to produce
SRA variants able to neutralize the pathogenic APOL1 variants. Preliminary experiments suggest that in
podocytes SRA antagonizes APOL1 induction by viral stimulus and subsequent cell death, opening new
perspectives to treat kidney disease.
Summary
Work conducted in my laboratory on the trypanosome killing factor of human serum led to the identification
of the primate-specific Apolipoprotein L1 (APOL1) as a novel pore-forming protein with striking similarities
with proteins of the apoptotic BCL2 family. APOL1 belongs to a family of proteins induced under
inflammatory conditions in myeloid and endothelial cells. APOL1 is efficiently neutralized by the SRA
protein of Trypanosoma rhodesiense, accounting for the ability of this trypanosome subspecies to infect
humans and cause sleeping sickness. We found that natural APOL1 variants escaping SRA neutralization and
therefore conferring human resistance to T. rhodesiense are associated with chronic kidney disease.
Moreover, transgenic mice expressing these APOL1 variants exhibit an obese phenotype. Our unpublished
results also indicate that APOLs control the lifespan of dendritic cells and podocytes activated by viral
stimuli. Therefore, we propose that the pathology of APOL variants is due to their deregulated activity on the
control of the cellular lifespan in myeloid/endothelial cells activated by pathogen detection.
This project aims at characterizing (i) the molecular mechanism by which APOLs control the lifespan of
activated dendritic cells and podocytes, which has direct impact on innate immunity and inflammation, and
(ii) the mechanism by which APOL1 variants cause pathology. In addition, we plan to detail the
physiological function of APOLs by studying the phenotype of transgenic mice either expressing human
APOL1 (wild-type and variants) or devoid of APOL genes, which we have recently generated. Finally, we
propose to exploit the extraordinary potential of trypanosomes for antigenic variation in order to produce
SRA variants able to neutralize the pathogenic APOL1 variants. Preliminary experiments suggest that in
podocytes SRA antagonizes APOL1 induction by viral stimulus and subsequent cell death, opening new
perspectives to treat kidney disease.
Max ERC Funding
2 250 000 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym ASTHMACRYSTALCLEAR
Project Role of protein crystallization in type 2 immunity and asthma
Researcher (PI) Bart LAMBRECHT
Host Institution (HI) VIB
Call Details Advanced Grant (AdG), LS6, ERC-2017-ADG
Summary Spontaneous protein crystallization is a rare event in biology. Eosinophilic inflammation such as seen in the airways in asthma, chronic rhinosinusitis and helminth infection is however accompanied by accumulation of large amounts of extracellular Charcot-Leyden crystals. These are made of Galectin-10, a protein of unknown function produced by eosinophils, hallmark cells of type 2 immunity. In mice, eosinophilic inflammation is also accompanied by protein crystal build up, composed of the chitinase-like proteins Ym1 and Ym2, produced by alternatively activated macrophages. Here we challenge the current view that these crystals are just markers of eosinophil demise or macrophages activation. We hypothesize that protein crystallization serves an active role in immunoregulation of type 2 immunity. On the one hand, crystallization might turn a harmless protein into a danger signal. On the other hand, crystallization might sequester and eliminate the physiological function of soluble Galectin-10 and Ym1, or prolong it via slow release elution. For full understanding, we therefore need to understand the function of the proteins in a soluble and crystalline state. Our program at the frontline of immunology, molecular structural biology and clinical science combines innovative tool creation and integrative research to investigate the structure, function, and physiology of galectin-10 and related protein crystals. We chose to study asthma as the crystallizing proteins are abundantly present in human and murine disease. There is still a large medical need for novel therapies that could benefit patients with chronic steroid-resistant disease, and are alternatives to eosinophil-depleting antibodies whose long term effects are unknown.
Summary
Spontaneous protein crystallization is a rare event in biology. Eosinophilic inflammation such as seen in the airways in asthma, chronic rhinosinusitis and helminth infection is however accompanied by accumulation of large amounts of extracellular Charcot-Leyden crystals. These are made of Galectin-10, a protein of unknown function produced by eosinophils, hallmark cells of type 2 immunity. In mice, eosinophilic inflammation is also accompanied by protein crystal build up, composed of the chitinase-like proteins Ym1 and Ym2, produced by alternatively activated macrophages. Here we challenge the current view that these crystals are just markers of eosinophil demise or macrophages activation. We hypothesize that protein crystallization serves an active role in immunoregulation of type 2 immunity. On the one hand, crystallization might turn a harmless protein into a danger signal. On the other hand, crystallization might sequester and eliminate the physiological function of soluble Galectin-10 and Ym1, or prolong it via slow release elution. For full understanding, we therefore need to understand the function of the proteins in a soluble and crystalline state. Our program at the frontline of immunology, molecular structural biology and clinical science combines innovative tool creation and integrative research to investigate the structure, function, and physiology of galectin-10 and related protein crystals. We chose to study asthma as the crystallizing proteins are abundantly present in human and murine disease. There is still a large medical need for novel therapies that could benefit patients with chronic steroid-resistant disease, and are alternatives to eosinophil-depleting antibodies whose long term effects are unknown.
Max ERC Funding
2 499 846 €
Duration
Start date: 2018-08-01, End date: 2023-07-31
Project acronym BEAL
Project Bioenergetics in microalgae : regulation modes of mitochondrial respiration, photosynthesis, and fermentative pathways, and their interactions in secondary algae
Researcher (PI) Pierre Antoine Georges Cardol
Host Institution (HI) UNIVERSITE DE LIEGE
Call Details Consolidator Grant (CoG), LS8, ERC-2015-CoG
Summary During the course of eukaryote evolution, photosynthesis was propagated from primary eukaryotic algae to non-photosynthetic organisms through multiple secondary endosymbiotic events. Collectively referred to as “secondary algae”, these photosynthetic organisms account for only 1-2% of the total global biomass, but produce a far larger part of the global annual fixation of carbon on Earth.
ATP is the universal chemical energy carrier in living cells. In photosynthetic eukaryotes, it is produced by two major cellular processes: photosynthesis and respiration taking place in chloroplasts and mitochondria, respectively. Both processes support the production of biomass and govern gas (O2 and CO2) exchanges. On the other hand, anaerobic fermentative enzymes have also been identified in several primary and secondary algae. The regulation modes and interactions of respiration, photosynthesis and fermentation are fairly well understood in primary green algae. Conversely, the complex evolutionary history of secondary algae implies a great variety of original regulatory mechanisms that have been barely investigated to date.
Over the last years my laboratory has developed and optimized a range of multidisciplinary approaches that now allow us, within the frame of the BEAL (BioEnergetics in microALgae) project, to (i) characterize and compare the photosynthetic regulation modes by biophysical approaches, (ii) use genetic and biochemical approaches to gain fundamental knowledge on aerobic respiration and anaerobic fermentative pathways, and (iii) investigate and compare interconnections between respiration, photosynthesis, and fermentation in organisms resulting from distinct evolutionary scenarios. On a long term, these developments will be instrumental to unravel bioenergetics constraints on growth in microalgae, a required knowledge to exploit the microalgal diversity in a biotechnological perspective, and to understand the complexity of the marine phytoplankton.
Summary
During the course of eukaryote evolution, photosynthesis was propagated from primary eukaryotic algae to non-photosynthetic organisms through multiple secondary endosymbiotic events. Collectively referred to as “secondary algae”, these photosynthetic organisms account for only 1-2% of the total global biomass, but produce a far larger part of the global annual fixation of carbon on Earth.
ATP is the universal chemical energy carrier in living cells. In photosynthetic eukaryotes, it is produced by two major cellular processes: photosynthesis and respiration taking place in chloroplasts and mitochondria, respectively. Both processes support the production of biomass and govern gas (O2 and CO2) exchanges. On the other hand, anaerobic fermentative enzymes have also been identified in several primary and secondary algae. The regulation modes and interactions of respiration, photosynthesis and fermentation are fairly well understood in primary green algae. Conversely, the complex evolutionary history of secondary algae implies a great variety of original regulatory mechanisms that have been barely investigated to date.
Over the last years my laboratory has developed and optimized a range of multidisciplinary approaches that now allow us, within the frame of the BEAL (BioEnergetics in microALgae) project, to (i) characterize and compare the photosynthetic regulation modes by biophysical approaches, (ii) use genetic and biochemical approaches to gain fundamental knowledge on aerobic respiration and anaerobic fermentative pathways, and (iii) investigate and compare interconnections between respiration, photosynthesis, and fermentation in organisms resulting from distinct evolutionary scenarios. On a long term, these developments will be instrumental to unravel bioenergetics constraints on growth in microalgae, a required knowledge to exploit the microalgal diversity in a biotechnological perspective, and to understand the complexity of the marine phytoplankton.
Max ERC Funding
1 837 625 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym BIONICbacteria
Project Integrating a novel layer of synthetic biology tools in Pseudomonas, inspired by bacterial viruses
Researcher (PI) Rob LAVIGNE
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Consolidator Grant (CoG), LS9, ERC-2018-COG
Summary As nature’s first bioengineers, bacteriophages have evolved to modify, adapt and control their bacterial hosts through billions of years of interactions. Indeed, like modern synthetic biologists aspire to do, bacteriophages already evade bacterial silencing of their xenogeneic DNA, subvert host gene expression, and co-opt both the central and peripheral metabolisms of their hosts. Studying these key insights from a molecular systems biology perspective, inspired us to develop these evolutionary fully-adapted phage mechanisms as a next-level layer of synthetic biology tools. Thus, BIONICbacteria will provide conceptual novel synthetic biology tools that allow direct manipulation of specific protein activity, post-translational modifications, RNA stability, and metabolite concentrations.
The goal of BIONICbacteria is to pioneer an unconventional way to perform synthetic biology, tapping an unlimited source of novel phage tools genetic circuits and phage modulators. To achieve these goals, we will apply and develop state-of-the-art technologies in molecular microbiology and focus on three principal aims:
(1) To exploit new phage-encoded genetic circuits as synthetic biology parts and as intricate biotechnological chassis.
(2) To build synthetic phage modulators (SPMs) as novel payloads to directly impact the bacterial metabolism in a targeted manner.
(3) To create designer bacteria by integrating SPMs-containing circuits into bacterial strains as proof-of-concepts for applications in industrial fermentations and vaccine design.
This proposed “plug-in” approach of evolutionary-adapted synthetic modules, will allow us to domesticate Pseudomonas strains in radically new ways. By building proofs-of-concept for applications in industrial fermentations and vaccine development, we address key problem in these areas with potentially high-gain solutions for society and industry.
Summary
As nature’s first bioengineers, bacteriophages have evolved to modify, adapt and control their bacterial hosts through billions of years of interactions. Indeed, like modern synthetic biologists aspire to do, bacteriophages already evade bacterial silencing of their xenogeneic DNA, subvert host gene expression, and co-opt both the central and peripheral metabolisms of their hosts. Studying these key insights from a molecular systems biology perspective, inspired us to develop these evolutionary fully-adapted phage mechanisms as a next-level layer of synthetic biology tools. Thus, BIONICbacteria will provide conceptual novel synthetic biology tools that allow direct manipulation of specific protein activity, post-translational modifications, RNA stability, and metabolite concentrations.
The goal of BIONICbacteria is to pioneer an unconventional way to perform synthetic biology, tapping an unlimited source of novel phage tools genetic circuits and phage modulators. To achieve these goals, we will apply and develop state-of-the-art technologies in molecular microbiology and focus on three principal aims:
(1) To exploit new phage-encoded genetic circuits as synthetic biology parts and as intricate biotechnological chassis.
(2) To build synthetic phage modulators (SPMs) as novel payloads to directly impact the bacterial metabolism in a targeted manner.
(3) To create designer bacteria by integrating SPMs-containing circuits into bacterial strains as proof-of-concepts for applications in industrial fermentations and vaccine design.
This proposed “plug-in” approach of evolutionary-adapted synthetic modules, will allow us to domesticate Pseudomonas strains in radically new ways. By building proofs-of-concept for applications in industrial fermentations and vaccine development, we address key problem in these areas with potentially high-gain solutions for society and industry.
Max ERC Funding
1 998 750 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym BREEDIT
Project A NOVEL BREEDING STRATEGY USING MULTIPLEX GENOME EDITING IN MAIZE
Researcher (PI) Dirk INZE
Host Institution (HI) VIB
Call Details Advanced Grant (AdG), LS9, ERC-2018-ADG
Summary Feeding the growing world population under changing climate conditions poses an unprecedented challenge on global agriculture and our current pace to breed new high yielding crop varieties is too low to face the imminent threats on food security. This ERC project proposes a novel crossing scheme that allows for an expeditious evaluation of combinations of potential yield contributing alleles by unifying ‘classical’ breeding with gene-centric molecular biology. The acronym BREEDIT, a word fusion of breeding and editing, reflects the basic concept of combining breeding with multiplex genome editing of yield related genes. By introducing plants with distinct combinations of genome edited mutations in more than 80 known yield related genes into a crossing scheme, the combinatorial effect of these mutations on plant growth and yield will be evaluated. Subsequent rounds of crossings will increase the number of stacked gene-edits per plant, thus increasing the combinatorial complexity. Phenotypic evaluations throughout plant development will be done on our in-house automated image-analysis based phenotyping platform. The nature and frequency of Cas9-mediated mutations in the entire plant collection will be characterised by multiplex amplicon sequencing to follow the efficiency of CRISPR-cas9 genome editing and to identify the underlying combinations of genes that cause beneficial phenotypes (genetic gain). The obtained knowledge on yield regulatory networks can be directly implemented into current molecular breeding programs and the project will provide the basis to develop targeted breeding schemes implementing the optimal combinations of beneficial alleles into elite material.
BREEDIT will be a major step forward in integrating basic knowledge on genes with plant breeding and has the potential to provoke a paradigm shift in improving crop yield.
Summary
Feeding the growing world population under changing climate conditions poses an unprecedented challenge on global agriculture and our current pace to breed new high yielding crop varieties is too low to face the imminent threats on food security. This ERC project proposes a novel crossing scheme that allows for an expeditious evaluation of combinations of potential yield contributing alleles by unifying ‘classical’ breeding with gene-centric molecular biology. The acronym BREEDIT, a word fusion of breeding and editing, reflects the basic concept of combining breeding with multiplex genome editing of yield related genes. By introducing plants with distinct combinations of genome edited mutations in more than 80 known yield related genes into a crossing scheme, the combinatorial effect of these mutations on plant growth and yield will be evaluated. Subsequent rounds of crossings will increase the number of stacked gene-edits per plant, thus increasing the combinatorial complexity. Phenotypic evaluations throughout plant development will be done on our in-house automated image-analysis based phenotyping platform. The nature and frequency of Cas9-mediated mutations in the entire plant collection will be characterised by multiplex amplicon sequencing to follow the efficiency of CRISPR-cas9 genome editing and to identify the underlying combinations of genes that cause beneficial phenotypes (genetic gain). The obtained knowledge on yield regulatory networks can be directly implemented into current molecular breeding programs and the project will provide the basis to develop targeted breeding schemes implementing the optimal combinations of beneficial alleles into elite material.
BREEDIT will be a major step forward in integrating basic knowledge on genes with plant breeding and has the potential to provoke a paradigm shift in improving crop yield.
Max ERC Funding
2 474 790 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym CAPCAN
Project Molecular and Genetic Study of the human infections by Capnocytophaga canimorsus
Researcher (PI) Guy Richard Cornelis
Host Institution (HI) UNIVERSITE DE NAMUR ASBL
Call Details Advanced Grant (AdG), LS6, ERC-2011-ADG_20110310
Summary "Capnocytophaga canimorsus are Gram-negative bacteria from the normal oral flora of dogs, which cause rare but severe infections in humans that have been bitten or simply licked. The most common syndrome is fulminant septicemia with peripheral gangrene. Mortality reaches 40 % in spite of antibiotherapy and amputations. My laboratory pioneered recently the study of this new pathogen. We engineered genetic tools, sequenced and annotated the genome and determined the surface proteome of a strain isolated from a fatal infection. This showed that C. canimorsus have abundant surface-exposed lipoproteins forming a new kind of feeding complexes, some of them specialized in deglycosylating glycoproteins from the host. This property allows C. canimorsus to feed by grazing oligosaccharides at the surface of human cells. The present research program aims at characterizing these deglycosylating complexes, unravelling their role in neutralizing the innate immunity and promoting growth within the host and finally characterizing their assembly at the bacterial surface. Genomic comparisons will help defining which of these many complexes play a critical role in human pathogenesis. Besides this, the lipopolysaccharide structure will be determined and genetically manipulated to understand its low endotoxicity and small anti-inflammatory effectors present in the culture supernatant of C. canimorsus will be identified. Growth in human blood of wild type and mutant strains will be monitored by isothermal microcalorimetry in the hope of developing a surrogate of animal model. Such a ""virulence"" model would allow to address the question whether all dog's strains are equally dangerous for humans. It would also open an avenue for testing differences in individual human susceptibility. All this knowledge will give new insights in this emerging pathogen and might lead to prevention of the disease caused by C. canimorsus"
Summary
"Capnocytophaga canimorsus are Gram-negative bacteria from the normal oral flora of dogs, which cause rare but severe infections in humans that have been bitten or simply licked. The most common syndrome is fulminant septicemia with peripheral gangrene. Mortality reaches 40 % in spite of antibiotherapy and amputations. My laboratory pioneered recently the study of this new pathogen. We engineered genetic tools, sequenced and annotated the genome and determined the surface proteome of a strain isolated from a fatal infection. This showed that C. canimorsus have abundant surface-exposed lipoproteins forming a new kind of feeding complexes, some of them specialized in deglycosylating glycoproteins from the host. This property allows C. canimorsus to feed by grazing oligosaccharides at the surface of human cells. The present research program aims at characterizing these deglycosylating complexes, unravelling their role in neutralizing the innate immunity and promoting growth within the host and finally characterizing their assembly at the bacterial surface. Genomic comparisons will help defining which of these many complexes play a critical role in human pathogenesis. Besides this, the lipopolysaccharide structure will be determined and genetically manipulated to understand its low endotoxicity and small anti-inflammatory effectors present in the culture supernatant of C. canimorsus will be identified. Growth in human blood of wild type and mutant strains will be monitored by isothermal microcalorimetry in the hope of developing a surrogate of animal model. Such a ""virulence"" model would allow to address the question whether all dog's strains are equally dangerous for humans. It would also open an avenue for testing differences in individual human susceptibility. All this knowledge will give new insights in this emerging pathogen and might lead to prevention of the disease caused by C. canimorsus"
Max ERC Funding
1 473 338 €
Duration
Start date: 2012-07-01, End date: 2016-06-30
Project acronym Cholstim
Project Cholinergic modulation of immune homeostasis: new opportunities for treatment
Researcher (PI) Guy Eduard Elisabeth Boeckxstaens
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Advanced Grant (AdG), LS7, ERC-2013-ADG
Summary In the gastrointestinal tract, the balance between activation of the mucosal immune system and tolerance should be tightly regulated to maintain immune homeostasis to prevent chronic inflammation and tissue damage. Recently, the new concept was introduced that the vagus nerve plays an important role in modulating immune homeostasis as part of a so-called inflammatory reflex. We provided evidence for this concept in the gastrointestinal tract and showed that vagus nerve stimulation (VNS) reduced inflammation of the intestinal muscle layer. Moreover, we showed that this effect was mediated by activation of enteric cholinergic neurons (cholinergic tone) interacting with intestinal macrophages in the muscle layer. Of interest, we have collected exciting data that the vagus nerve (and thus the cholinergic tone) also significantly contributes to mucosal immune homeostasis. Mice that underwent vagotomy lost their ability to develop tolerance to oral feeding of an antigen, whereas VNS reduced mucosal inflammation in a model of food allergy. Based on these data, we hypothesize that the cholinergic tone is a major determinant of the tolerogenic microenvironment of the mucosal immune system, and want to further explore the immune-modulatory effect of the vagal innervation and enteric neurons on the macrophages residing in the lamina propria. In addition, we will further explore the therapeutic potential and the mechanisms involved of chronic VNS in colitis and food allergy. Finally, we will translate our preclinical findings to the human situation. The anti-inflammatory effect of VNS (applied during surgery) will be studied in human intestinal tissue whereas the therapeutic potential of chronic VNS in Crohn’s disease will be studied in a pilot trial.
The outcome of this project will be ground-breaking and will have an immense impact on clinical management as it will provide new therapeutic opportunities for the treatment of immune-mediated gastrointestinal disorders.
Summary
In the gastrointestinal tract, the balance between activation of the mucosal immune system and tolerance should be tightly regulated to maintain immune homeostasis to prevent chronic inflammation and tissue damage. Recently, the new concept was introduced that the vagus nerve plays an important role in modulating immune homeostasis as part of a so-called inflammatory reflex. We provided evidence for this concept in the gastrointestinal tract and showed that vagus nerve stimulation (VNS) reduced inflammation of the intestinal muscle layer. Moreover, we showed that this effect was mediated by activation of enteric cholinergic neurons (cholinergic tone) interacting with intestinal macrophages in the muscle layer. Of interest, we have collected exciting data that the vagus nerve (and thus the cholinergic tone) also significantly contributes to mucosal immune homeostasis. Mice that underwent vagotomy lost their ability to develop tolerance to oral feeding of an antigen, whereas VNS reduced mucosal inflammation in a model of food allergy. Based on these data, we hypothesize that the cholinergic tone is a major determinant of the tolerogenic microenvironment of the mucosal immune system, and want to further explore the immune-modulatory effect of the vagal innervation and enteric neurons on the macrophages residing in the lamina propria. In addition, we will further explore the therapeutic potential and the mechanisms involved of chronic VNS in colitis and food allergy. Finally, we will translate our preclinical findings to the human situation. The anti-inflammatory effect of VNS (applied during surgery) will be studied in human intestinal tissue whereas the therapeutic potential of chronic VNS in Crohn’s disease will be studied in a pilot trial.
The outcome of this project will be ground-breaking and will have an immense impact on clinical management as it will provide new therapeutic opportunities for the treatment of immune-mediated gastrointestinal disorders.
Max ERC Funding
2 495 200 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym CONNECT
Project Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver disease
Researcher (PI) Mathieu Frederick Alexander Vinken
Host Institution (HI) VRIJE UNIVERSITEIT BRUSSEL
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary The CONNECT project intends to contribute to the substantiation of the controversial scientific concept stating that hemichannels consisting of connexin32 and connexin43 as well as pannexin1 channels act as pathological pores. This hypothesis will be verified in the specific context of cell death and inflammation, both which are key features of acute liver failure and liver fibrosis. As such, the project is organised in 3 workpackages. In the first workpackage, connexin32, connexin43 and pannexin1 expression and activity will be studied in human and animal diseased liver tissue. The second workpackage is targeted towards the in vitro characterisation of recently generated inhibitors of hemichannels consisting of connexin32 and connexin43 as well as pannexin1 channels, namely Gap24, Gap19 and 10Panx1, respectively. Particular attention will be paid to their target selectivity and potential to reduce cell death and inflammation in liver-based in vitro models. The goal of the third workpackage is to test the in vivo extrapolation of the established in vitro findings. To this end, Gap24, Gap19 and 10Panx1 will be administered to animal models of acute liver failure or liver fibrosis, followed by evaluation of their outcome on cell death, inflammation and clinically relevant read-outs. The CONNECT project is anticipated to significantly impact the connexin and pannexin research area, as it foresees the development and optimisation of new tools and technology to study connexin hemichannels and pannexin channels. The clinical utility of this high risk/high gain project is dual, as it aspires the establishment of novel drug targets and tissue biomarkers for, respectively, the treatment and diagnosis of liver disease. However, given the generic nature of the driving concept, the outcome of the CONNECT project is equally of clinical relevance for a plethora of other pathologies.
Summary
The CONNECT project intends to contribute to the substantiation of the controversial scientific concept stating that hemichannels consisting of connexin32 and connexin43 as well as pannexin1 channels act as pathological pores. This hypothesis will be verified in the specific context of cell death and inflammation, both which are key features of acute liver failure and liver fibrosis. As such, the project is organised in 3 workpackages. In the first workpackage, connexin32, connexin43 and pannexin1 expression and activity will be studied in human and animal diseased liver tissue. The second workpackage is targeted towards the in vitro characterisation of recently generated inhibitors of hemichannels consisting of connexin32 and connexin43 as well as pannexin1 channels, namely Gap24, Gap19 and 10Panx1, respectively. Particular attention will be paid to their target selectivity and potential to reduce cell death and inflammation in liver-based in vitro models. The goal of the third workpackage is to test the in vivo extrapolation of the established in vitro findings. To this end, Gap24, Gap19 and 10Panx1 will be administered to animal models of acute liver failure or liver fibrosis, followed by evaluation of their outcome on cell death, inflammation and clinically relevant read-outs. The CONNECT project is anticipated to significantly impact the connexin and pannexin research area, as it foresees the development and optimisation of new tools and technology to study connexin hemichannels and pannexin channels. The clinical utility of this high risk/high gain project is dual, as it aspires the establishment of novel drug targets and tissue biomarkers for, respectively, the treatment and diagnosis of liver disease. However, given the generic nature of the driving concept, the outcome of the CONNECT project is equally of clinical relevance for a plethora of other pathologies.
Max ERC Funding
1 473 929 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
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
