Project acronym Amitochondriates
Project Life without mitochondrion
Researcher (PI) Vladimir HAMPL
Host Institution (HI) UNIVERZITA KARLOVA
Call Details Consolidator Grant (CoG), LS8, ERC-2017-COG
Summary Mitochondria are often referred to as the “power houses” of eukaryotic cells. All eukaryotes were thought to have mitochondria of some form until 2016, when the first eukaryote thriving without mitochondria was discovered by our laboratory – a flagellate Monocercomonoides. Understanding cellular functions of these cells, which represent a new functional type of eukaryotes, and understanding the circumstances of the unique event of mitochondrial loss are motivations for this proposal. The first objective focuses on the cell physiology. We will perform a metabolomic study revealing major metabolic pathways and concentrate further on elucidating its unique system of iron-sulphur cluster assembly. In the second objective, we will investigate in details the unique case of mitochondrial loss. We will examine two additional potentially amitochondriate lineages by means of genomics and transcriptomics, conduct experiments simulating the moments of mitochondrial loss and try to induce the mitochondrial loss in vitro by knocking out or down genes for mitochondrial biogenesis. We have chosen Giardia intestinalis and Entamoeba histolytica as models for the latter experiments, because their mitochondria are already reduced to minimalistic “mitosomes” and because some genetic tools are already available for them. Successful mitochondrial knock-outs would enable us to study mitochondrial loss in ‘real time’ and in vivo. In the third objective, we will focus on transforming Monocercomonoides into a tractable laboratory model by developing methods of axenic cultivation and genetic manipulation. This will open new possibilities in the studies of this organism and create a cell culture representing an amitochondriate model for cell biological studies enabling the dissection of mitochondrial effects from those of other compartments. The team is composed of the laboratory of PI and eight invited experts and we hope it has the ability to address these challenging questions.
Summary
Mitochondria are often referred to as the “power houses” of eukaryotic cells. All eukaryotes were thought to have mitochondria of some form until 2016, when the first eukaryote thriving without mitochondria was discovered by our laboratory – a flagellate Monocercomonoides. Understanding cellular functions of these cells, which represent a new functional type of eukaryotes, and understanding the circumstances of the unique event of mitochondrial loss are motivations for this proposal. The first objective focuses on the cell physiology. We will perform a metabolomic study revealing major metabolic pathways and concentrate further on elucidating its unique system of iron-sulphur cluster assembly. In the second objective, we will investigate in details the unique case of mitochondrial loss. We will examine two additional potentially amitochondriate lineages by means of genomics and transcriptomics, conduct experiments simulating the moments of mitochondrial loss and try to induce the mitochondrial loss in vitro by knocking out or down genes for mitochondrial biogenesis. We have chosen Giardia intestinalis and Entamoeba histolytica as models for the latter experiments, because their mitochondria are already reduced to minimalistic “mitosomes” and because some genetic tools are already available for them. Successful mitochondrial knock-outs would enable us to study mitochondrial loss in ‘real time’ and in vivo. In the third objective, we will focus on transforming Monocercomonoides into a tractable laboratory model by developing methods of axenic cultivation and genetic manipulation. This will open new possibilities in the studies of this organism and create a cell culture representing an amitochondriate model for cell biological studies enabling the dissection of mitochondrial effects from those of other compartments. The team is composed of the laboratory of PI and eight invited experts and we hope it has the ability to address these challenging questions.
Max ERC Funding
1 935 500 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym CIRCUIT
Project Neural circuits for space representation in the mammalian cortex
Researcher (PI) Edvard Ingjald Moser
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Neuroscience is one of the fastest-developing areas of science, but it is fair to say that we are still far from understanding how the brain produces subjective experience. For example, simple questions about the origin of thought, imagination, social interaction, or feelings lack even rudimentary answers. We have learnt much about the workings of individual cells and synapses, but psychological phenomena cannot be understood only at this level. These phenomena all emerge from interactions between large numbers of diverse cells in intermingled neural circuits. A major obstacle has been the absence of concepts and tools for investigating neural computation at the circuit level. The aim of this proposal is to combine new transgenic methods for cell type-specific intervention with large-scale multisite single-cell recording to determine how a basic cognitive function self-localization is generated in a functionally well-described mammalian neural circuit. We shall use our recent discovery of entorhinal grid cells as an access ramp. Grid cells fire only when the animal moves through certain locations. For each cell, these locations define a periodic triangular array spanning the whole environment. Grid cells co-exist with other entorhinal cell types encoding head direction, geometric borders, or conjunctions of features. This network is thought to form an essential part of the brain s coordinate system for metric navigation but the detailed wiring, the mechanism of grid formation, and the function of each morphological and functional cell type all remain to be determined. We shall address these open questions by measuring how dynamic spatial representation is affected by transgene-induced activation or inactivation of the individual components of the circuit. The endeavour will pioneer the functional analysis of neural circuits and may, perhaps for the first time, provide us with mechanistic insight into a non-sensory cognitive function in the mammalian cortex.
Summary
Neuroscience is one of the fastest-developing areas of science, but it is fair to say that we are still far from understanding how the brain produces subjective experience. For example, simple questions about the origin of thought, imagination, social interaction, or feelings lack even rudimentary answers. We have learnt much about the workings of individual cells and synapses, but psychological phenomena cannot be understood only at this level. These phenomena all emerge from interactions between large numbers of diverse cells in intermingled neural circuits. A major obstacle has been the absence of concepts and tools for investigating neural computation at the circuit level. The aim of this proposal is to combine new transgenic methods for cell type-specific intervention with large-scale multisite single-cell recording to determine how a basic cognitive function self-localization is generated in a functionally well-described mammalian neural circuit. We shall use our recent discovery of entorhinal grid cells as an access ramp. Grid cells fire only when the animal moves through certain locations. For each cell, these locations define a periodic triangular array spanning the whole environment. Grid cells co-exist with other entorhinal cell types encoding head direction, geometric borders, or conjunctions of features. This network is thought to form an essential part of the brain s coordinate system for metric navigation but the detailed wiring, the mechanism of grid formation, and the function of each morphological and functional cell type all remain to be determined. We shall address these open questions by measuring how dynamic spatial representation is affected by transgene-induced activation or inactivation of the individual components of the circuit. The endeavour will pioneer the functional analysis of neural circuits and may, perhaps for the first time, provide us with mechanistic insight into a non-sensory cognitive function in the mammalian cortex.
Max ERC Funding
2 499 112 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym CODE
Project Coincidence detection of proteins and lipids in regulation of cellular membrane dynamics
Researcher (PI) Harald STENMARK
Host Institution (HI) UNIVERSITETET I OSLO
Call Details Advanced Grant (AdG), LS3, ERC-2017-ADG
Summary Specific recruitment of different proteins to distinct intracellular membranes is fundamental in the biology of eukaryotic cells, but the molecular basis for specificity is incompletely understood. This proposal investigates the hypothesis that coincidence detection of proteins and lipids constitutes a major mechanism for specific recruitment of proteins to intracellular membranes in order to control cellular membrane dynamics. CODE will establish and validate mathematical models for coincidence detection, identify and functionally characterise novel coincidence detectors, and engineer artificial coincidence detectors as novel tools in cell biology and biotechnology.
Summary
Specific recruitment of different proteins to distinct intracellular membranes is fundamental in the biology of eukaryotic cells, but the molecular basis for specificity is incompletely understood. This proposal investigates the hypothesis that coincidence detection of proteins and lipids constitutes a major mechanism for specific recruitment of proteins to intracellular membranes in order to control cellular membrane dynamics. CODE will establish and validate mathematical models for coincidence detection, identify and functionally characterise novel coincidence detectors, and engineer artificial coincidence detectors as novel tools in cell biology and biotechnology.
Max ERC Funding
2 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym EPIFISH
Project INNOVATIVE EPIGENETIC MARKERS FOR FISH DOMESTICATION
Researcher (PI) Jorge Manuel De Oliveira Fernandes
Host Institution (HI) NORD UNIVERSITET
Call Details Consolidator Grant (CoG), LS9, ERC-2015-CoG
Summary Aquaculture is the fastest growing food production sector in the world, since there is an increasing demand for fish protein to feed a growing global population, which cannot be met by fisheries. In order to ensure the sustainability of this sector it is critical to domesticate and selectively improve the major commercial fish species. To date, the genetic markers used in selective breeding of fish account only for a fraction of the observed phenotypic variation. EPIFISH is a scientifically innovative and timely project that will address fish domestication and selection from a new perspective using a multidisciplinary approach. The rapid pace of substantial phenotypic changes during adaptation to new environmental conditions in fish undergoing domestication raises the original hypothesis that epigenetic mechanisms are involved in this process. Thus, the overarching aim of EPIFISH is to ascertain the importance of epigenetics in fish domestication using the Nile tilapia (Oreochromis niloticus) as model species. Specific objectives are i) to determine how selection affects the miRNA transcriptome and the epigenetic landscape during domestication, ii) to perform a functional characterization of miRNA variants and epigenetic alleles associated with growth, and iii) to validate them as potential epigenetic markers for future selective breeding programmes. The identification of epigenetic markers will be a ground-breaking element of EPIFISH with major impact on aquaculture biotechnology, since they will enable the development and application of epigenomic selection as a new feature in future selective breeding programmes. Moreover, the project outcomes will provide novel mechanistic insights into the role of epigenetics in fish domestication, which will surely open new horizons for future frontier research in epigenetics, namely transgenerational inheritance and nutritional epigenetics.
Summary
Aquaculture is the fastest growing food production sector in the world, since there is an increasing demand for fish protein to feed a growing global population, which cannot be met by fisheries. In order to ensure the sustainability of this sector it is critical to domesticate and selectively improve the major commercial fish species. To date, the genetic markers used in selective breeding of fish account only for a fraction of the observed phenotypic variation. EPIFISH is a scientifically innovative and timely project that will address fish domestication and selection from a new perspective using a multidisciplinary approach. The rapid pace of substantial phenotypic changes during adaptation to new environmental conditions in fish undergoing domestication raises the original hypothesis that epigenetic mechanisms are involved in this process. Thus, the overarching aim of EPIFISH is to ascertain the importance of epigenetics in fish domestication using the Nile tilapia (Oreochromis niloticus) as model species. Specific objectives are i) to determine how selection affects the miRNA transcriptome and the epigenetic landscape during domestication, ii) to perform a functional characterization of miRNA variants and epigenetic alleles associated with growth, and iii) to validate them as potential epigenetic markers for future selective breeding programmes. The identification of epigenetic markers will be a ground-breaking element of EPIFISH with major impact on aquaculture biotechnology, since they will enable the development and application of epigenomic selection as a new feature in future selective breeding programmes. Moreover, the project outcomes will provide novel mechanistic insights into the role of epigenetics in fish domestication, which will surely open new horizons for future frontier research in epigenetics, namely transgenerational inheritance and nutritional epigenetics.
Max ERC Funding
1 996 189 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym ImPRESS
Project Imaging Perfusion Restrictions from Extracellular Solid Stress
Researcher (PI) Kyrre Eeg Emblem
Host Institution (HI) OSLO UNIVERSITETSSYKEHUS HF
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary Even the perfect cancer drug must reach its target to have an effect. The ImPRESS project main objective is to develop a novel imaging paradigm coined Restricted Perfusion Imaging (RPI) to reveal - for the first time in humans - vascular restrictions in solid cancers caused by mechanical solid stress, and use RPI to demonstrate that alleviating this force will repair the cancerous microenvironment and improve therapeutic response. Delivery of anti-cancer drugs to the tumor is critically dependent on a functional vascular bed. Developing biomarkers that can measure how mechanical forces in a solid tumor impair perfusion and promotes therapy resistance is essential for treatment of disease.
The ImPRESS project is based on the following observations; (I) pre-clinical work suggests that therapies targeting the tumor microenvironment and extracellular matrix may enhance drug delivery by decompressing tumor vessels; (II) results from animal models may not be transferable because compressive forces in human tumors in vivo can be many times higher; and (III) there are no available imaging technologies for medical diagnostics of solid stress in human cancers. Using RPI, ImPRESS will conduct a comprehensive series of innovative studies in brain cancer patients to answer three key questions: (Q1) Can we image vascular restrictions in human cancers and map how the vasculature changes with tumor growth or treatment? (Q2) Can we use medical engineering to image solid stress in vivo? (Q3) Can RPI show that matrix-depleting drugs improve patient response to conventional chemo- and radiation therapy as well as new targeted therapies?
The ImPRESS project holds a unique position to answer these questions by our unrivaled experience with advanced imaging of cancer patients. With successful delivery, ImPRESS will have a direct impact on patient treatment and establish an imaging paradigm that will pave the way for new scientific knowledge on how to revitalize cancer therapies.
Summary
Even the perfect cancer drug must reach its target to have an effect. The ImPRESS project main objective is to develop a novel imaging paradigm coined Restricted Perfusion Imaging (RPI) to reveal - for the first time in humans - vascular restrictions in solid cancers caused by mechanical solid stress, and use RPI to demonstrate that alleviating this force will repair the cancerous microenvironment and improve therapeutic response. Delivery of anti-cancer drugs to the tumor is critically dependent on a functional vascular bed. Developing biomarkers that can measure how mechanical forces in a solid tumor impair perfusion and promotes therapy resistance is essential for treatment of disease.
The ImPRESS project is based on the following observations; (I) pre-clinical work suggests that therapies targeting the tumor microenvironment and extracellular matrix may enhance drug delivery by decompressing tumor vessels; (II) results from animal models may not be transferable because compressive forces in human tumors in vivo can be many times higher; and (III) there are no available imaging technologies for medical diagnostics of solid stress in human cancers. Using RPI, ImPRESS will conduct a comprehensive series of innovative studies in brain cancer patients to answer three key questions: (Q1) Can we image vascular restrictions in human cancers and map how the vasculature changes with tumor growth or treatment? (Q2) Can we use medical engineering to image solid stress in vivo? (Q3) Can RPI show that matrix-depleting drugs improve patient response to conventional chemo- and radiation therapy as well as new targeted therapies?
The ImPRESS project holds a unique position to answer these questions by our unrivaled experience with advanced imaging of cancer patients. With successful delivery, ImPRESS will have a direct impact on patient treatment and establish an imaging paradigm that will pave the way for new scientific knowledge on how to revitalize cancer therapies.
Max ERC Funding
1 499 638 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym NterAct
Project Discovery and functional significance of post-translational N-terminal acetylation
Researcher (PI) Thomas ARNESEN
Host Institution (HI) UNIVERSITETET I BERGEN
Call Details Consolidator Grant (CoG), LS1, ERC-2017-COG
Summary In mammalian cells, N-terminal (Nt) acetylation is one of the most abundant protein modifications. It is catalysed by N-terminal acetyltransferases (NATs) and mostly occurs co-translationally. However, in contrast to the defined co-translational NATs, post-translational NATs which have crucial regulatory roles are mostly unexplored. Distinct peptide hormones regulate appetite, metabolism, sexual behaviour and pain, and their biological activity is critically modulated by post-translational Nt-acetylation. However, the identity of the NAT responsible for this modification, ‘HormNat’, is unknown, thus the molecular and physiological ramifications of this regulatory circuit remain elusive. Another example is actin, a key regulator of cell motility and cell division. The actin N-terminus is crucial for actin function and in mammals actin is modified by an unknown post-translational NAT, ‘ActNat’. Hence, the objectives of this project are to identify these human NATs acting post-translationally, and to investigate their molecular mechanisms, regulation and impact.
We will identify the novel NATs by a combination of classical and newly developed in-house tools like in vitro acetylation assays, unique bisubstrate analogues, Nt-acetylation specific antibodies, and targeted mass spectrometry. Interestingly, Nt-acetylation is considered irreversible, but there is reason to believe that specific substrates are Nt-deacetylated. Elucidation of post-translational NATs and the reversible nature of Nt-acetylation would represent a new era in the field of protein and peptide regulation and identify key cellular and organismal switches.
Summary
In mammalian cells, N-terminal (Nt) acetylation is one of the most abundant protein modifications. It is catalysed by N-terminal acetyltransferases (NATs) and mostly occurs co-translationally. However, in contrast to the defined co-translational NATs, post-translational NATs which have crucial regulatory roles are mostly unexplored. Distinct peptide hormones regulate appetite, metabolism, sexual behaviour and pain, and their biological activity is critically modulated by post-translational Nt-acetylation. However, the identity of the NAT responsible for this modification, ‘HormNat’, is unknown, thus the molecular and physiological ramifications of this regulatory circuit remain elusive. Another example is actin, a key regulator of cell motility and cell division. The actin N-terminus is crucial for actin function and in mammals actin is modified by an unknown post-translational NAT, ‘ActNat’. Hence, the objectives of this project are to identify these human NATs acting post-translationally, and to investigate their molecular mechanisms, regulation and impact.
We will identify the novel NATs by a combination of classical and newly developed in-house tools like in vitro acetylation assays, unique bisubstrate analogues, Nt-acetylation specific antibodies, and targeted mass spectrometry. Interestingly, Nt-acetylation is considered irreversible, but there is reason to believe that specific substrates are Nt-deacetylated. Elucidation of post-translational NATs and the reversible nature of Nt-acetylation would represent a new era in the field of protein and peptide regulation and identify key cellular and organismal switches.
Max ERC Funding
1 999 273 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym PI3K-III COMPLEX
Project The PI3K-III complex: Function in cell regulation and tumour suppression
Researcher (PI) Harald Alfred Stenmark
Host Institution (HI) UNIVERSITETET I OSLO
Call Details Advanced Grant (AdG), LS3, ERC-2008-AdG
Summary Phosphoinositides (PIs), phosphorylated derivatives of phosphatidylinositol (PtdIns), control cellular functions through recruitment of cytosolic proteins to specific membranes. Among the kinases involved in PI generation, the PI3K-III complex, which catalyzes conversion of PtdIns into PtdIns 3-phosphate (PI3P), is of great interest for several reasons. Firstly, it is required for three topologically related membrane involution processes - the biogenesis of multivesicular endosomes, autophagy, and cytokinesis. Secondly, through its catalytic product this protein complex mediates anti-apoptotic and antiproliferative signalling. Thirdly, several subunits of the PI3K-III complex are known tumour suppressors, making the PI3K-III complex a possible target for cancer therapy and diagnostics. This proposal aims to undertake a systematic analysis of the PI3K-III complex and its functions, and the following key questions will be addressed: How is the PI3K-III complex recruited to specific membranes? How does it control membrane involution and signal transduction? By which mechanisms do subunits of this protein complex serve as tumour suppressors? The project will be divided into seven subprojects, which include (1) characterization of the PI3K-III complex, (2) detection of the PI3K-III product PI3P in cells and tissues, (3) the function of the PI3K-III complex in downregulation of growth factor receptors, (4) the function of the PI3K-III complex in autophagy, (5) the function of the PI3K-III complex in cytokinesis, (6) the function of the PI3K-III complex in cell signalling, and (7) dissecting the tumour suppressor activities of the PI3K-III complex. The analyses will range from protein biochemistry to development of novel imaging probes, siRNA screens for novel PI3P effectors, functional characterization of PI3K-III subunits and PI3P effectors in cell culture models, and tumour suppressor analyses in novel Drosophila models.
Summary
Phosphoinositides (PIs), phosphorylated derivatives of phosphatidylinositol (PtdIns), control cellular functions through recruitment of cytosolic proteins to specific membranes. Among the kinases involved in PI generation, the PI3K-III complex, which catalyzes conversion of PtdIns into PtdIns 3-phosphate (PI3P), is of great interest for several reasons. Firstly, it is required for three topologically related membrane involution processes - the biogenesis of multivesicular endosomes, autophagy, and cytokinesis. Secondly, through its catalytic product this protein complex mediates anti-apoptotic and antiproliferative signalling. Thirdly, several subunits of the PI3K-III complex are known tumour suppressors, making the PI3K-III complex a possible target for cancer therapy and diagnostics. This proposal aims to undertake a systematic analysis of the PI3K-III complex and its functions, and the following key questions will be addressed: How is the PI3K-III complex recruited to specific membranes? How does it control membrane involution and signal transduction? By which mechanisms do subunits of this protein complex serve as tumour suppressors? The project will be divided into seven subprojects, which include (1) characterization of the PI3K-III complex, (2) detection of the PI3K-III product PI3P in cells and tissues, (3) the function of the PI3K-III complex in downregulation of growth factor receptors, (4) the function of the PI3K-III complex in autophagy, (5) the function of the PI3K-III complex in cytokinesis, (6) the function of the PI3K-III complex in cell signalling, and (7) dissecting the tumour suppressor activities of the PI3K-III complex. The analyses will range from protein biochemistry to development of novel imaging probes, siRNA screens for novel PI3P effectors, functional characterization of PI3K-III subunits and PI3P effectors in cell culture models, and tumour suppressor analyses in novel Drosophila models.
Max ERC Funding
2 272 000 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym ProstOmics
Project 'Tissue is the issue': a multi-omics approach to improve prostate cancer diagnosis
Researcher (PI) May-Britt Tessem
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary Overtreatment in prostate cancer (PCa) is a burden for health care economy and for quality of life. Correct diagnosis of early stage PCa is challenging given the limitations of the currently available clinical tools and the biological understanding of PCa. In this inter-disciplinary project, I propose an innovative approach enabling several cutting-edge ‘omics’ technologies (spatial metabolomics, genomics, transcriptomics) as well as histopathology to be performed on the same tissue sample. My goal is to reveal the molecular mechanisms of novel, but also promising metabolite biomarkers (citrate, polyamines, succinate and zinc) and their connection to recurrence, tissue heterogeneity and immune responses in complex human tissues. Such markers can personalize PCa diagnosis, open up new treatment strategies and fundamentally change the view of how to analyze tissue samples in the future. Furthermore, I want to demonstrate that citrate and polyamines are reliable prognostic markers that can be analyzed both in tissue and in patients in vivo by MR spectroscopic imaging. This work is made possible by the availability of high-quality fresh frozen tissue biobanks of prostatectomy biopsies with 5-10 years of follow-up data (N=1000)/slices (N=1000) and targeted in vivo snap-shot biopsies from clinical MR guided procedures (N=100). Among other techniques, I will implement high speed MALDI imaging (RapifleX MALDI TissueTyper) to the multi-omics protocol to study the spatial distribution and provide high resolution metabolic maps for each cell type, and which can be matched to both histopathology and MR Imaging. Multi-disciplinary platforms on large cohorts are needed to explore the clinical potential of the suggested molecular mechanisms. I expect that this ambitious proposal will address the diagnostic challenges of PCa and will further inspire the clinic and scientific community to follow the multi-omics approach within diagnosis and cancer research.
Summary
Overtreatment in prostate cancer (PCa) is a burden for health care economy and for quality of life. Correct diagnosis of early stage PCa is challenging given the limitations of the currently available clinical tools and the biological understanding of PCa. In this inter-disciplinary project, I propose an innovative approach enabling several cutting-edge ‘omics’ technologies (spatial metabolomics, genomics, transcriptomics) as well as histopathology to be performed on the same tissue sample. My goal is to reveal the molecular mechanisms of novel, but also promising metabolite biomarkers (citrate, polyamines, succinate and zinc) and their connection to recurrence, tissue heterogeneity and immune responses in complex human tissues. Such markers can personalize PCa diagnosis, open up new treatment strategies and fundamentally change the view of how to analyze tissue samples in the future. Furthermore, I want to demonstrate that citrate and polyamines are reliable prognostic markers that can be analyzed both in tissue and in patients in vivo by MR spectroscopic imaging. This work is made possible by the availability of high-quality fresh frozen tissue biobanks of prostatectomy biopsies with 5-10 years of follow-up data (N=1000)/slices (N=1000) and targeted in vivo snap-shot biopsies from clinical MR guided procedures (N=100). Among other techniques, I will implement high speed MALDI imaging (RapifleX MALDI TissueTyper) to the multi-omics protocol to study the spatial distribution and provide high resolution metabolic maps for each cell type, and which can be matched to both histopathology and MR Imaging. Multi-disciplinary platforms on large cohorts are needed to explore the clinical potential of the suggested molecular mechanisms. I expect that this ambitious proposal will address the diagnostic challenges of PCa and will further inspire the clinic and scientific community to follow the multi-omics approach within diagnosis and cancer research.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym SWEETOOLS
Project Smart Biologics: Developing New Tools in Glycobiology
Researcher (PI) Milan Vrabel
Host Institution (HI) USTAV ORGANICKE CHEMIE A BIOCHEMIE, AV CR, V.V.I.
Call Details Starting Grant (StG), LS9, ERC-2015-STG
Summary Glycans are ubiquitous biomolecules found throughout all kingdoms of life. Early studies contributed considerably to our appreciation of glycan functions by showing that abnormalities in the glycosylation can develop into pathogenesis and severe dysfunctions. Despite the crucial role of sugars in many biological events we still do not have adequate tools to decipher their complexity. To unveil the mysteries in the rapidly emerging field of glycobiology we aim in this proposal to develop new tools that will help us to study and understand these important biomolecules. To realize this, we plan to combine the unique targeting capability of biologics with the inhibitory effect of small molecules into robust constructs with advanced properties. The biological part of the construct will be evolved using synthetic peptide libraries ensuring high selectivity toward particular sugar processing enzymes. The second part of the construct will consist of small molecular inhibitor warhead that will be designed and synthesized based on crystal structure-aided analyses. To merge these two moieties we aim to develop a new target enzyme–templated fluorogenic in situ click chemistry methodology that will enable us to easily monitor and screen whole peptide–small molecule bioconjugate libraries as highly selective inhibitors and manipulators of sugar processing enzymes. In addition, we aim to create new multivalent heteroglycosystems by using bioorthogonal reactions on peptide library scaffold. These structures will enable us to study polyvalent carbohydrate–protein interactions and to generate novel therapeutics such as influenza virus entry blockers. Our goal is to develop a new class of smart bioconjugate probes that will help us to answer fundamental questions in glycobiology. The outcomes of this project will significantly deepen our knowledge of glycoconjugates and in the long term, will allow for the design of efficient vaccines and for the development of selective therapeutics.
Summary
Glycans are ubiquitous biomolecules found throughout all kingdoms of life. Early studies contributed considerably to our appreciation of glycan functions by showing that abnormalities in the glycosylation can develop into pathogenesis and severe dysfunctions. Despite the crucial role of sugars in many biological events we still do not have adequate tools to decipher their complexity. To unveil the mysteries in the rapidly emerging field of glycobiology we aim in this proposal to develop new tools that will help us to study and understand these important biomolecules. To realize this, we plan to combine the unique targeting capability of biologics with the inhibitory effect of small molecules into robust constructs with advanced properties. The biological part of the construct will be evolved using synthetic peptide libraries ensuring high selectivity toward particular sugar processing enzymes. The second part of the construct will consist of small molecular inhibitor warhead that will be designed and synthesized based on crystal structure-aided analyses. To merge these two moieties we aim to develop a new target enzyme–templated fluorogenic in situ click chemistry methodology that will enable us to easily monitor and screen whole peptide–small molecule bioconjugate libraries as highly selective inhibitors and manipulators of sugar processing enzymes. In addition, we aim to create new multivalent heteroglycosystems by using bioorthogonal reactions on peptide library scaffold. These structures will enable us to study polyvalent carbohydrate–protein interactions and to generate novel therapeutics such as influenza virus entry blockers. Our goal is to develop a new class of smart bioconjugate probes that will help us to answer fundamental questions in glycobiology. The outcomes of this project will significantly deepen our knowledge of glycoconjugates and in the long term, will allow for the design of efficient vaccines and for the development of selective therapeutics.
Max ERC Funding
1 405 625 €
Duration
Start date: 2016-02-01, End date: 2021-01-31
Project acronym TICE
Project TRANSCRIPTOMICS IN CANCER EPIDEMIOLOGY
Researcher (PI) Eiliv Lund
Host Institution (HI) UNIVERSITETET I TROMSOE - NORGES ARKTISKE UNIVERSITET
Call Details Advanced Grant (AdG), LS7, ERC-2008-AdG
Summary NOWAC is the first prospective study with a globolomic design. This is an extension of the current cohort study with its questionnaire information and biological material for analysis of biomarkers, proteomics and single nucleotide polymorphisms (SNPs). The design of NOWAC adds biological material for analysis of the transcriptome in prospectively collected buffered peripheral blood samples, the postgenome biobank. Further, both peripheral blood and tumor tissue are collected from breast cancer patients diagnosed within the cohort together with matched controls. The latter biological material gives a new multidimensional design with a unique biological material at the end-point. The transcriptomic analysis will include both mRNA and miRNA as new technology (microarray and massive parallel sequencing) allows large scale studies. miRNAs could be promising markers for pathways analysis related to the carcinogenic process and for diagnosis and screening tests of breast cancer. These high-troughput technologies have analyses challenges both in bioinformatics and biostatistics therefore success depends on the development of new analytical strategies.This novel design is the observational counterpart to systems biology, or systems epidemiology. Systems epidemiology will seek to understand biological processes by integrating observational derived pathways information into the current prospective design. A true interdisciplinary approach has been implemented. The upside is the potential for an improved understanding of causality in epidemiology by opening up for quantification of traditional criteria of biological plausibility in a more complete biological model. The postgenome biobank with 50 000 participants out of the 172 000 participants in NOWAC and its unique national design and richness of biological material makes it a very strong case for interdisciplinary collaboration based on a population-based study representative of the real and complex lifestyle environment.
Summary
NOWAC is the first prospective study with a globolomic design. This is an extension of the current cohort study with its questionnaire information and biological material for analysis of biomarkers, proteomics and single nucleotide polymorphisms (SNPs). The design of NOWAC adds biological material for analysis of the transcriptome in prospectively collected buffered peripheral blood samples, the postgenome biobank. Further, both peripheral blood and tumor tissue are collected from breast cancer patients diagnosed within the cohort together with matched controls. The latter biological material gives a new multidimensional design with a unique biological material at the end-point. The transcriptomic analysis will include both mRNA and miRNA as new technology (microarray and massive parallel sequencing) allows large scale studies. miRNAs could be promising markers for pathways analysis related to the carcinogenic process and for diagnosis and screening tests of breast cancer. These high-troughput technologies have analyses challenges both in bioinformatics and biostatistics therefore success depends on the development of new analytical strategies.This novel design is the observational counterpart to systems biology, or systems epidemiology. Systems epidemiology will seek to understand biological processes by integrating observational derived pathways information into the current prospective design. A true interdisciplinary approach has been implemented. The upside is the potential for an improved understanding of causality in epidemiology by opening up for quantification of traditional criteria of biological plausibility in a more complete biological model. The postgenome biobank with 50 000 participants out of the 172 000 participants in NOWAC and its unique national design and richness of biological material makes it a very strong case for interdisciplinary collaboration based on a population-based study representative of the real and complex lifestyle environment.
Max ERC Funding
2 300 000 €
Duration
Start date: 2009-01-01, End date: 2014-06-30
Project acronym ToMeTuM
Project Towards the Understanding a Metal-Tumour-Metabolism
Researcher (PI) Vojtech Adam
Host Institution (HI) VYSOKE UCENI TECHNICKE V BRNE
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary A tumour cell uses both genetic and protein weapons in its development. Gaining a greater understanding of these lethal mechanisms is a key step towards developing novel and more effective treatments. Because the metal ion metabolism of a tumour cell is not fully understood, we will address the challenge of explaining the mechanisms of how a tumour cell copes both with essential metal ions and platinum based drugs. The metal-based mechanisms help a tumour to grow on one side and to protect itself against commonly used metal-based drugs. On the other side, the exact description of these mechanisms, which are being associated with multi-drug resistance occurrence and failure of a treatment, still remains unclear. We will reveal the mechanism of the as yet not understood biochemical and molecularly-biological relationships and correlations between metal ions and proteins in a tumour development revealing the way how to suppress the growth and development of a tumour and to markedly enhance the effectiveness of a treatment.
To achieve this goal, we will focus on metallothionein and its interactions with essential metals and metal-containing anticancer drugs (cisplatin, carboplatin, and oxaliplatin). Their actions will be monitored both in vitro and in vivo. For this purpose, we will optimize electrochemical, mass spectrometric and immune-based methods. Based on processing of data obtained, new carcinogenetic pathways will be sought on cell level and proved by genetic modifications of target genes. The discovered processes and the pathways found will then be tested on two animal experimental models mice bearing breast tumours (MCF-7 and 4T1) and MeLiM minipigs bearing melanomas.
The precise description of the tumour related pathways coping with metal ions based on metallothioneins will direct new highly effective treatment strategies. Moreover, the discovery of new carcinogenetic pathways will open a window for understanding of cancer formation and development.
Summary
A tumour cell uses both genetic and protein weapons in its development. Gaining a greater understanding of these lethal mechanisms is a key step towards developing novel and more effective treatments. Because the metal ion metabolism of a tumour cell is not fully understood, we will address the challenge of explaining the mechanisms of how a tumour cell copes both with essential metal ions and platinum based drugs. The metal-based mechanisms help a tumour to grow on one side and to protect itself against commonly used metal-based drugs. On the other side, the exact description of these mechanisms, which are being associated with multi-drug resistance occurrence and failure of a treatment, still remains unclear. We will reveal the mechanism of the as yet not understood biochemical and molecularly-biological relationships and correlations between metal ions and proteins in a tumour development revealing the way how to suppress the growth and development of a tumour and to markedly enhance the effectiveness of a treatment.
To achieve this goal, we will focus on metallothionein and its interactions with essential metals and metal-containing anticancer drugs (cisplatin, carboplatin, and oxaliplatin). Their actions will be monitored both in vitro and in vivo. For this purpose, we will optimize electrochemical, mass spectrometric and immune-based methods. Based on processing of data obtained, new carcinogenetic pathways will be sought on cell level and proved by genetic modifications of target genes. The discovered processes and the pathways found will then be tested on two animal experimental models mice bearing breast tumours (MCF-7 and 4T1) and MeLiM minipigs bearing melanomas.
The precise description of the tumour related pathways coping with metal ions based on metallothioneins will direct new highly effective treatment strategies. Moreover, the discovery of new carcinogenetic pathways will open a window for understanding of cancer formation and development.
Max ERC Funding
1 377 495 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
