Project acronym ANOREP
Project Targeting the reproductive biology of the malaria mosquito Anopheles gambiae: from laboratory studies to field applications
Researcher (PI) Flaminia Catteruccia
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PERUGIA
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Anopheles gambiae mosquitoes are the major vectors of malaria, a disease with devastating consequences for
human health. Novel methods for controlling the natural vector populations are urgently needed, given the
evolution of insecticide resistance in mosquitoes and the lack of novel insecticidals. Understanding the
processes at the bases of mosquito biology may help to roll back malaria. In this proposal, we will target
mosquito reproduction, a major determinant of the An. gambiae vectorial capacity. This will be achieved at
two levels: (i) fundamental research, to provide a deeper knowledge of the processes regulating reproduction
in this species, and (ii) applied research, to identify novel targets and to develop innovative approaches for
the control of natural populations. We will focus our analysis on three major players of mosquito
reproduction: male accessory glands (MAGs), sperm, and spermatheca, in both laboratory and field settings.
We will then translate this information into the identification of inhibitors of mosquito fertility. The
experimental activities will be divided across three objectives. In Objective 1, we will unravel the role of the
MAGs in shaping mosquito fertility and behaviour, by performing a combination of transcriptional and
functional studies that will reveal the multifaceted activities of these tissues. In Objective 2 we will instead
focus on the identification of the male and female factors responsible for sperm viability and function.
Results obtained in both objectives will be validated in field mosquitoes. In Objective 3, we will perform
screens aimed at the identification of inhibitors of mosquito reproductive success. This study will reveal as
yet unknown molecular mechanisms underlying reproductive success in mosquitoes, considerably increasing
our knowledge beyond the state-of-the-art and critically contributing with innovative tools and ideas to the
fight against malaria.
Summary
Anopheles gambiae mosquitoes are the major vectors of malaria, a disease with devastating consequences for
human health. Novel methods for controlling the natural vector populations are urgently needed, given the
evolution of insecticide resistance in mosquitoes and the lack of novel insecticidals. Understanding the
processes at the bases of mosquito biology may help to roll back malaria. In this proposal, we will target
mosquito reproduction, a major determinant of the An. gambiae vectorial capacity. This will be achieved at
two levels: (i) fundamental research, to provide a deeper knowledge of the processes regulating reproduction
in this species, and (ii) applied research, to identify novel targets and to develop innovative approaches for
the control of natural populations. We will focus our analysis on three major players of mosquito
reproduction: male accessory glands (MAGs), sperm, and spermatheca, in both laboratory and field settings.
We will then translate this information into the identification of inhibitors of mosquito fertility. The
experimental activities will be divided across three objectives. In Objective 1, we will unravel the role of the
MAGs in shaping mosquito fertility and behaviour, by performing a combination of transcriptional and
functional studies that will reveal the multifaceted activities of these tissues. In Objective 2 we will instead
focus on the identification of the male and female factors responsible for sperm viability and function.
Results obtained in both objectives will be validated in field mosquitoes. In Objective 3, we will perform
screens aimed at the identification of inhibitors of mosquito reproductive success. This study will reveal as
yet unknown molecular mechanisms underlying reproductive success in mosquitoes, considerably increasing
our knowledge beyond the state-of-the-art and critically contributing with innovative tools and ideas to the
fight against malaria.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
Project acronym cis-CONTROL
Project Decoding and controlling cell-state switching: A bottom-up approach based on enhancer logic
Researcher (PI) Stein Luc AERTS
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS2, ERC-2016-COG
Summary Cell-state switching in cancer allows cells to transition from a proliferative to an invasive and drug-resistant phenotype. This plasticity plays an important role in cancer progression and tumour heterogeneity. We have made a striking observation that cancer cells of different origin can switch to a common survival state. During this epigenomic reprogramming, cancer cells re-activate genomic enhancers from specific regulatory programs, such as wound repair and epithelial-to-mesenchymal transition.
The goal of my project is to decipher the enhancer logic underlying this canalization effect towards a common survival state. We will then employ this new understanding of enhancer logic to engineer synthetic enhancers that are able to monitor and manipulate cell-state switching in real time. Furthermore, we will use enhancer models to identify cis-regulatory mutations that have an impact on cell-state switching and drug resistance. Such applications are currently hampered because there is a significant gap in our understanding of how enhancers work.
To tackle this problem we will use a combination of in vivo massively parallel enhancer-reporter assays, single-cell genomics on microfluidic devices, computational modelling, and synthetic enhancer design. Using these approaches we will pursue the following aims: (1) to identify functional enhancers regulating cell-state switching by performing in vivo genetic screens in mice; (2) to elucidate the dynamic trajectories whereby cells of different cancer types switch to a common survival cell-state, at single-cell resolution; (3) to create synthetic enhancer circuits that specifically kill cancer cells undergoing cell-state switching.
Our findings will have an impact on genome research, characterizing how cellular decision making is implemented by the cis-regulatory code; and on cancer research, employing enhancer logic in the context of cancer therapy.
Summary
Cell-state switching in cancer allows cells to transition from a proliferative to an invasive and drug-resistant phenotype. This plasticity plays an important role in cancer progression and tumour heterogeneity. We have made a striking observation that cancer cells of different origin can switch to a common survival state. During this epigenomic reprogramming, cancer cells re-activate genomic enhancers from specific regulatory programs, such as wound repair and epithelial-to-mesenchymal transition.
The goal of my project is to decipher the enhancer logic underlying this canalization effect towards a common survival state. We will then employ this new understanding of enhancer logic to engineer synthetic enhancers that are able to monitor and manipulate cell-state switching in real time. Furthermore, we will use enhancer models to identify cis-regulatory mutations that have an impact on cell-state switching and drug resistance. Such applications are currently hampered because there is a significant gap in our understanding of how enhancers work.
To tackle this problem we will use a combination of in vivo massively parallel enhancer-reporter assays, single-cell genomics on microfluidic devices, computational modelling, and synthetic enhancer design. Using these approaches we will pursue the following aims: (1) to identify functional enhancers regulating cell-state switching by performing in vivo genetic screens in mice; (2) to elucidate the dynamic trajectories whereby cells of different cancer types switch to a common survival cell-state, at single-cell resolution; (3) to create synthetic enhancer circuits that specifically kill cancer cells undergoing cell-state switching.
Our findings will have an impact on genome research, characterizing how cellular decision making is implemented by the cis-regulatory code; and on cancer research, employing enhancer logic in the context of cancer therapy.
Max ERC Funding
1 999 660 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym ECMETABOLISM
Project Targeting endothelial metabolism: a novel anti-angiogenic therapy
Researcher (PI) Peter Frans Martha Carmeliet
Host Institution (HI) VIB
Call Details Advanced Grant (AdG), LS2, ERC-2010-AdG_20100317
Summary Current anti-angiogenesis based anti-tumor therapy relies on starving tumors by blocking their vascular supply via inhibition of growth factors. However, limitations such as resistance and toxicity, mandate conceptually distinct approaches. We will explore an entirely novel and long-overlooked strategy to discover additional anti-angiogenic candidates, based on the following innovative concept: ¿rather than STARVING TUMORS BY BLOCKING THEIR VASCULAR SUPPLY, we intend TO STARVE BLOOD VESSELS BY BLOCKING THEIR METABOLIC ENERGY SUPPLY¿, so that new vessels cannot form and nourish the growing tumor. This project is a completely new research avenue in our group, but we expect that it will offer refreshing long-term research and translational opportunities for the field.
Because so little is known on endothelial cell (EC) metabolism, we will (i) via a multi-disciplinary systems-biology approach of transcriptomics, proteomics, computational network modeling, metabolomics and flux-omics, draw an endothelio-metabolic map in angiogenesis. This will allow us to identify metabolic regulators of angiogenesis, which will be further validated and characterized in (ii) loss and gain-of-function studies in various angiogenesis models in vitro and (iii) in vivo in zebrafish (knockdown; zinc finger nuclease mediated knockout), providing prescreen data to select the most promising candidates. (iv) EC-specific down-regulation (miR RNAi) or knockout studies of selected candidates in mice will confirm their relevance for angiogenic phenotypes in a preclinical model; and ultimately (v) a translational study evaluating EC metabolism-targeted anti-angiogenic strategies (pharmacological inhibitors, antibodies, small molecular compounds) will be performed in tumor models in the mouse.
Summary
Current anti-angiogenesis based anti-tumor therapy relies on starving tumors by blocking their vascular supply via inhibition of growth factors. However, limitations such as resistance and toxicity, mandate conceptually distinct approaches. We will explore an entirely novel and long-overlooked strategy to discover additional anti-angiogenic candidates, based on the following innovative concept: ¿rather than STARVING TUMORS BY BLOCKING THEIR VASCULAR SUPPLY, we intend TO STARVE BLOOD VESSELS BY BLOCKING THEIR METABOLIC ENERGY SUPPLY¿, so that new vessels cannot form and nourish the growing tumor. This project is a completely new research avenue in our group, but we expect that it will offer refreshing long-term research and translational opportunities for the field.
Because so little is known on endothelial cell (EC) metabolism, we will (i) via a multi-disciplinary systems-biology approach of transcriptomics, proteomics, computational network modeling, metabolomics and flux-omics, draw an endothelio-metabolic map in angiogenesis. This will allow us to identify metabolic regulators of angiogenesis, which will be further validated and characterized in (ii) loss and gain-of-function studies in various angiogenesis models in vitro and (iii) in vivo in zebrafish (knockdown; zinc finger nuclease mediated knockout), providing prescreen data to select the most promising candidates. (iv) EC-specific down-regulation (miR RNAi) or knockout studies of selected candidates in mice will confirm their relevance for angiogenic phenotypes in a preclinical model; and ultimately (v) a translational study evaluating EC metabolism-targeted anti-angiogenic strategies (pharmacological inhibitors, antibodies, small molecular compounds) will be performed in tumor models in the mouse.
Max ERC Funding
2 365 224 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
Project acronym FastBio
Project A genomics and systems biology approach to explore the molecular signature and functional consequences of long-term, structured fasting in humans
Researcher (PI) Antigoni DIMA
Host Institution (HI) BIOMEDICAL SCIENCES RESEARCH CENTER ALEXANDER FLEMING
Call Details Starting Grant (StG), LS2, ERC-2016-STG
Summary Dietary intake has an enormous impact on aspects of human health, yet scientific consensus about how what we eat affects our biology remains elusive. To address the complex biological impact of diet, I propose to apply an unconventional, ‘humans-as-model-organisms’ approach to compare the molecular and functional effects of a highly structured dietary regime, specified by the Eastern Orthodox Christian Church (EOCC), to the unstructured diet followed by the general population. Individuals who follow the EOCC regime abstain from meat, dairy products and eggs for 180-200 days annually, in a temporally-structured manner initiated in childhood. I aim to explore the biological signatures of structured vs. unstructured diet by addressing three objectives. First I will investigate the effects of the two regimes, and of genetic variation, on higher-level phenotypes including anthropometric, physiological and biomarker traits. Second, I will carry out a comprehensive set of omics assays (metabolomics, transcriptomics, epigenomics and investigation of the gut microbiome), will associate omics phenotypes with genetic variation, and will integrate data across biological levels to uncover complex molecular signatures. Third, I will interrogate the functional consequences of dietary regimes at the cellular level through primary cell culture. Acute and long-term effects of dietary intake will be explored for all objectives through a two timepoint sampling strategy. This proposal therefore comprises a unique opportunity to study a specific perturbation (EOCC structured diet) introduced to a steady-state system (unstructured diet followed by the general population) in a ground-breaking human systems biology type of study. This approach brings together expertise from genomics, computational biology, statistics, medicine and epidemiology. It will lead to novel insights regarding the potent signalling nature of nutrients and is likely to yield results of high translational value.
Summary
Dietary intake has an enormous impact on aspects of human health, yet scientific consensus about how what we eat affects our biology remains elusive. To address the complex biological impact of diet, I propose to apply an unconventional, ‘humans-as-model-organisms’ approach to compare the molecular and functional effects of a highly structured dietary regime, specified by the Eastern Orthodox Christian Church (EOCC), to the unstructured diet followed by the general population. Individuals who follow the EOCC regime abstain from meat, dairy products and eggs for 180-200 days annually, in a temporally-structured manner initiated in childhood. I aim to explore the biological signatures of structured vs. unstructured diet by addressing three objectives. First I will investigate the effects of the two regimes, and of genetic variation, on higher-level phenotypes including anthropometric, physiological and biomarker traits. Second, I will carry out a comprehensive set of omics assays (metabolomics, transcriptomics, epigenomics and investigation of the gut microbiome), will associate omics phenotypes with genetic variation, and will integrate data across biological levels to uncover complex molecular signatures. Third, I will interrogate the functional consequences of dietary regimes at the cellular level through primary cell culture. Acute and long-term effects of dietary intake will be explored for all objectives through a two timepoint sampling strategy. This proposal therefore comprises a unique opportunity to study a specific perturbation (EOCC structured diet) introduced to a steady-state system (unstructured diet followed by the general population) in a ground-breaking human systems biology type of study. This approach brings together expertise from genomics, computational biology, statistics, medicine and epidemiology. It will lead to novel insights regarding the potent signalling nature of nutrients and is likely to yield results of high translational value.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym RNA+P=123D
Project Breaking the code of RNA sequence-structure-function relationships: New strategies and tools for modelling and engineering of RNA and RNA-protein complexes
Researcher (PI) Janusz Marek Bujnicki
Host Institution (HI) INTERNATIONAL INSTITUTE OF MOLECULAR AND CELL BIOLOGY
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Ribonucleic acid (RNA) is a large class of macromolecules that plays a key role in the communication of biological information between DNA and proteins. RNAs have been also shown to perform enzymatic catalysis. Recently, numerous new RNAs have been identified and shown to perform essential regulatory roles in cells.
As with proteins, the function of RNA depends on its structure, which in turn is encoded in the linear sequence. The secondary structure of RNA is defined by canonical base pairs, while the tertiary (3D) structure is formed mostly by non-canonical base pairs that form three-dimensional motifs. RNA is similar to proteins in that the development of methods for 3D structure prediction is absolutely essential to functionally interpret the information encoded in the primary sequence of genes. For proteins there are many freely available methods for automated protein 3D structure prediction that produce reasonably accurate and useful models. There are also methods for objective assessment of the protein model quality. However, there are no such methods for automated 3D structure modelling of RNA. There are only methods for RNA secondary structure prediction and a few methods for manual 3D modelling, but no automated methods for comparative modelling, fold-recognition of RNA, and evaluation of models. Only recently a few methods for de novo folding of RNA appeared, but they can provide useful models only for very short molecules.
Recently, inspired by methodology for protein modelling, we have developed prototype tools for both comparative (template-based) and de novo (template-free) modelling of RNA, which allow for building models for very large RNA molecules. These tools will be further optimized and tested. The major goal is to developed tools for RNA modelling to the level of existing protein-modelling methods and to combine RNA and protein-centric methods to allow multiscale modelling of protein-nucleic acid complexes, either with or without the aid of experimental data. This proposal also includes the development of methods for the assessment of model quality and benchmarking of methods. The software tools and the theoretical predictions will be extensively tested (also by experimental verification of models), optimized and applied to biologically and medically relevant RNAs and complexes.
In one sentence: The aim of this project is to use bioinformatics and experimental methods to crack the code of sequence-structure relationships in RNA and RNA-protein complexes and to revolutionise the field of RNA & RNP modelling and structure/function analyses.
Summary
Ribonucleic acid (RNA) is a large class of macromolecules that plays a key role in the communication of biological information between DNA and proteins. RNAs have been also shown to perform enzymatic catalysis. Recently, numerous new RNAs have been identified and shown to perform essential regulatory roles in cells.
As with proteins, the function of RNA depends on its structure, which in turn is encoded in the linear sequence. The secondary structure of RNA is defined by canonical base pairs, while the tertiary (3D) structure is formed mostly by non-canonical base pairs that form three-dimensional motifs. RNA is similar to proteins in that the development of methods for 3D structure prediction is absolutely essential to functionally interpret the information encoded in the primary sequence of genes. For proteins there are many freely available methods for automated protein 3D structure prediction that produce reasonably accurate and useful models. There are also methods for objective assessment of the protein model quality. However, there are no such methods for automated 3D structure modelling of RNA. There are only methods for RNA secondary structure prediction and a few methods for manual 3D modelling, but no automated methods for comparative modelling, fold-recognition of RNA, and evaluation of models. Only recently a few methods for de novo folding of RNA appeared, but they can provide useful models only for very short molecules.
Recently, inspired by methodology for protein modelling, we have developed prototype tools for both comparative (template-based) and de novo (template-free) modelling of RNA, which allow for building models for very large RNA molecules. These tools will be further optimized and tested. The major goal is to developed tools for RNA modelling to the level of existing protein-modelling methods and to combine RNA and protein-centric methods to allow multiscale modelling of protein-nucleic acid complexes, either with or without the aid of experimental data. This proposal also includes the development of methods for the assessment of model quality and benchmarking of methods. The software tools and the theoretical predictions will be extensively tested (also by experimental verification of models), optimized and applied to biologically and medically relevant RNAs and complexes.
In one sentence: The aim of this project is to use bioinformatics and experimental methods to crack the code of sequence-structure relationships in RNA and RNA-protein complexes and to revolutionise the field of RNA & RNP modelling and structure/function analyses.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
