Project acronym YinYang
Project Hypothalamic circuits for the selection of defensive and mating behavior in females
Researcher (PI) Susana LIMA
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Country Portugal
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Social interactions can take different courses depending on the internal state of the participants. For instance, a sexually receptive female mouse will allow a male’s attempt to mount her, but a non-receptive female will fight or flee the same male. Here, we propose to determine how neuronal circuits in the female mouse brain support flexible, state-dependent interactions with male conspecifics. It is known that female receptivity depends on the ventrolateral region of the ventromedial hypothalamus. Within this region there is a population of neurons that expresses receptors for the sex hormone progesterone (PR+ neurons), whose levels cycle with reproductive state. In pilot experiments, we found that PR+ neurons are not homogeneous: some respond during receptive behaviors but others respond during defensive or aggressive behaviors. Our main objective is to determine how female hypothalamic PR+ neurons participate in state-dependent behavioral responses to males. Our hypothesis is that two subpopulations of PR+ neurons are differentially modulated by the reproductive cycle and that each sub-population activates a different downstream circuit, one specialized for receptive and the other for defensive behaviors. Our specific aims are to: (1) characterize the functional selectivity of individual female PR+ neurons across the reproductive cycle; (2) map the connectivity of PR+ neurons to their output targets; (3) test the impact of different PR+ output pathways by genetically activating and silencing them; and (4) determine how reproductive hormones modulate the synaptic and intrinsic functional properties of PR+ neurons. These studies will elucidate the neuronal circuit mechanisms of a biologically essential female behavior. More broadly, this work will reveal mechanisms by which neuronal circuits can support flexible state-dependent adaptive behaviors.
Summary
Social interactions can take different courses depending on the internal state of the participants. For instance, a sexually receptive female mouse will allow a male’s attempt to mount her, but a non-receptive female will fight or flee the same male. Here, we propose to determine how neuronal circuits in the female mouse brain support flexible, state-dependent interactions with male conspecifics. It is known that female receptivity depends on the ventrolateral region of the ventromedial hypothalamus. Within this region there is a population of neurons that expresses receptors for the sex hormone progesterone (PR+ neurons), whose levels cycle with reproductive state. In pilot experiments, we found that PR+ neurons are not homogeneous: some respond during receptive behaviors but others respond during defensive or aggressive behaviors. Our main objective is to determine how female hypothalamic PR+ neurons participate in state-dependent behavioral responses to males. Our hypothesis is that two subpopulations of PR+ neurons are differentially modulated by the reproductive cycle and that each sub-population activates a different downstream circuit, one specialized for receptive and the other for defensive behaviors. Our specific aims are to: (1) characterize the functional selectivity of individual female PR+ neurons across the reproductive cycle; (2) map the connectivity of PR+ neurons to their output targets; (3) test the impact of different PR+ output pathways by genetically activating and silencing them; and (4) determine how reproductive hormones modulate the synaptic and intrinsic functional properties of PR+ neurons. These studies will elucidate the neuronal circuit mechanisms of a biologically essential female behavior. More broadly, this work will reveal mechanisms by which neuronal circuits can support flexible state-dependent adaptive behaviors.
Max ERC Funding
1 952 188 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym YOUNGatHEART
Project YOUNGatHEART: CARDIAC REJUVENATION BY EPIGENETIC REMODELLING
Researcher (PI) SUSANA Gonzalez
Host Institution (HI) CENTRO NACIONAL DE INVESTIGACIONESCARDIOVASCULARES CARLOS III (F.S.P.)
Country Spain
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Aging poses the largest risk for cardiovascular disease (CVD) and is orchestrated, to some extent, by epigenetic changes. Despite the significant progress on many fronts in the cardiovascular field, non-inherited epigenetic regulation in cardiac aging and CVD remains unexplored. Dilated Cardiomyopathy (DCM) is a major contributor to healthcare costs and it is the leading indication for heart transplantation. We have recently discovered that adult cardiac-specific deletion of epigenetic regulator Bmi1 in mice induces DCM and heart failure. These unprecedented data support the idea that inadequate epigenetic regulation in adulthood is critical in CVD. In addition, our studies with parabiotic pairing of healthy and DCM-diagnosed mice show that the circulation of a healthy mouse significantly improve the cardiac performance of mouse with DCM. These ground-breaking discoveries suggest that DCM regression, or cardiac rejuvenation, is feasible in terms of epigenetic states. Therefore, YOUNGatHEART will unveil significant breakthrough on (1) how non-inherited epigenetic deregulation induces DCM and (2) how epigenetic remodeling reversed this process. For that, our challenges are: 1A. To decipher how aged-linked cardiac dysfunction contributes to CVD by identifying the epigenetic landscape regulating cardiac aging among species; 1B. To decode how epigenetic deregulation induces DCM by integrating clinical data and samples from DCM-transplanted patients with imaging, transcriptomic, proteomic, and functional approaches from DCM model; and, 2A. To identified systemic factors with anti-cardiomyopathic effects by systematic proteomic screenings after parabiosis and epigenome of the DCM hearts. In sum, YOUNGatHEART puts forward an ambitious but feasible and pioneering program to tackle the epigenetic hallmark in cardiac aging with the final aim (2B) of setting the molecular basis for future therapeutic interventions in CVD.
Summary
Aging poses the largest risk for cardiovascular disease (CVD) and is orchestrated, to some extent, by epigenetic changes. Despite the significant progress on many fronts in the cardiovascular field, non-inherited epigenetic regulation in cardiac aging and CVD remains unexplored. Dilated Cardiomyopathy (DCM) is a major contributor to healthcare costs and it is the leading indication for heart transplantation. We have recently discovered that adult cardiac-specific deletion of epigenetic regulator Bmi1 in mice induces DCM and heart failure. These unprecedented data support the idea that inadequate epigenetic regulation in adulthood is critical in CVD. In addition, our studies with parabiotic pairing of healthy and DCM-diagnosed mice show that the circulation of a healthy mouse significantly improve the cardiac performance of mouse with DCM. These ground-breaking discoveries suggest that DCM regression, or cardiac rejuvenation, is feasible in terms of epigenetic states. Therefore, YOUNGatHEART will unveil significant breakthrough on (1) how non-inherited epigenetic deregulation induces DCM and (2) how epigenetic remodeling reversed this process. For that, our challenges are: 1A. To decipher how aged-linked cardiac dysfunction contributes to CVD by identifying the epigenetic landscape regulating cardiac aging among species; 1B. To decode how epigenetic deregulation induces DCM by integrating clinical data and samples from DCM-transplanted patients with imaging, transcriptomic, proteomic, and functional approaches from DCM model; and, 2A. To identified systemic factors with anti-cardiomyopathic effects by systematic proteomic screenings after parabiosis and epigenome of the DCM hearts. In sum, YOUNGatHEART puts forward an ambitious but feasible and pioneering program to tackle the epigenetic hallmark in cardiac aging with the final aim (2B) of setting the molecular basis for future therapeutic interventions in CVD.
Max ERC Funding
1 861 910 €
Duration
Start date: 2015-11-01, End date: 2020-10-31
Project acronym ZETA-FM
Project Zeta functions and Fourier-Mukai transforms
Researcher (PI) Lenny Taelman
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Country Netherlands
Call Details Consolidator Grant (CoG), PE1, ERC-2019-COG
Summary Arithmetic geometry and the study of derived categories of coherent sheaves are two central areas of research in algebraic geometry. Despite their many points of contact, they have until recently remained largely disjoint.
The zeta function of an algebraic variety over a finite field is one of the most studied invariants in arithmetic geometry, and a conjecture of Orlov predicts that this invariant can be detected by the derived category of coherent sheaves on the variety. In this project, I will prove this for large classes of varieties.
To achieve this, I will enrich a wide range of techniques from arithmetic geometry with ideas that have classically been used in the study of derived categories. In this way, this project will also serve as a catalyst for further interaction between arithmetic geometry and derived categories.
Summary
Arithmetic geometry and the study of derived categories of coherent sheaves are two central areas of research in algebraic geometry. Despite their many points of contact, they have until recently remained largely disjoint.
The zeta function of an algebraic variety over a finite field is one of the most studied invariants in arithmetic geometry, and a conjecture of Orlov predicts that this invariant can be detected by the derived category of coherent sheaves on the variety. In this project, I will prove this for large classes of varieties.
To achieve this, I will enrich a wide range of techniques from arithmetic geometry with ideas that have classically been used in the study of derived categories. In this way, this project will also serve as a catalyst for further interaction between arithmetic geometry and derived categories.
Max ERC Funding
2 000 000 €
Duration
Start date: 2020-09-01, End date: 2025-08-31
Project acronym ZF-MEL-CHEMBIO
Project Chemical Biology in Zebrafish: Drug-Leads and New Targets in the Melanocyte Lineage and Melanoma
Researcher (PI) Eleanor Elizabeth Patton
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Country United Kingdom
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Melanoma (cancer of the melanocyte) kills over 20,000 Europeans each year and incidence continues to rise rapidly. BRAF(V600E) inhibitors have led to clinically significant improvements in outcomes for melanoma patients, yet many patients with metastatic melanoma rapidly succumb to the disease due to eventual chemoresistance, or insensitivity to the drug. Thus, it is critical to identify new therapies that can act alone, or be combined with available treatments for enhanced efficacy and/or to overcome drug resistance.
An important and new therapeutic concept for melanoma is to target the melanocyte lineage. Recent evidence reveals that a melanocyte lineage specific programme maintains melanoma survival, and we have engineered the first animal model in zebrafish to demonstrate that targeting the master melanocyte lineage transcription factor MITF leads to rapid melanoma regression. Thus, understanding and targeting the melanocyte lineage is directly relevant to melanoma, and reveals therapeutically targetable processes.
Our vision is to use live-imaging of the melanocyte lineage as the basis for phenotypic chemical screens in zebrafish to find drugs/leads and identify targetable processes that might elucidate pathways for cancer therapy. Screening for targets of the melanocyte lineage is highly relevant to melanoma because melanocytes are the melanoma cell of origin, and genes that specify the melanocyte stem cells and the lineage during embryogenesis are the same genes that play fundamental roles in cancer. We will use innovative chemical-biology to capture and validate targets in vivo, and perform chemo-preventative and -therapeutic trials in zebrafish melanoma models using known and novel drug-delivery methods.
Ultimately, we aim to translate our most promising drug/leads and targets into the mammalian system, to establish the basis for patent applications and clinical trials.
Summary
Melanoma (cancer of the melanocyte) kills over 20,000 Europeans each year and incidence continues to rise rapidly. BRAF(V600E) inhibitors have led to clinically significant improvements in outcomes for melanoma patients, yet many patients with metastatic melanoma rapidly succumb to the disease due to eventual chemoresistance, or insensitivity to the drug. Thus, it is critical to identify new therapies that can act alone, or be combined with available treatments for enhanced efficacy and/or to overcome drug resistance.
An important and new therapeutic concept for melanoma is to target the melanocyte lineage. Recent evidence reveals that a melanocyte lineage specific programme maintains melanoma survival, and we have engineered the first animal model in zebrafish to demonstrate that targeting the master melanocyte lineage transcription factor MITF leads to rapid melanoma regression. Thus, understanding and targeting the melanocyte lineage is directly relevant to melanoma, and reveals therapeutically targetable processes.
Our vision is to use live-imaging of the melanocyte lineage as the basis for phenotypic chemical screens in zebrafish to find drugs/leads and identify targetable processes that might elucidate pathways for cancer therapy. Screening for targets of the melanocyte lineage is highly relevant to melanoma because melanocytes are the melanoma cell of origin, and genes that specify the melanocyte stem cells and the lineage during embryogenesis are the same genes that play fundamental roles in cancer. We will use innovative chemical-biology to capture and validate targets in vivo, and perform chemo-preventative and -therapeutic trials in zebrafish melanoma models using known and novel drug-delivery methods.
Ultimately, we aim to translate our most promising drug/leads and targets into the mammalian system, to establish the basis for patent applications and clinical trials.
Max ERC Funding
1 865 345 €
Duration
Start date: 2015-09-01, End date: 2022-02-28
Project acronym ZIPgeting
Project Quantitative understanding of target recognition on DNA based on directional zipping processes
Researcher (PI) Ralf SEIDEL
Host Institution (HI) UNIVERSITAET LEIPZIG
Country Germany
Call Details Consolidator Grant (CoG), PE3, ERC-2016-COG
Summary In the recent years a number of protein systems have been identified that recognize long (tens of base pairs) DNA sequences and allow flexible programmability of their target specificity. This promoted an enormous range of applications in genome engineering and synthetic biology. This project aims to decipher the mechanisms by which these proteins recognize their DNA targets in order to develop quantitative models/predictors for target recognition and to avoid off-target effects.
To obtain detailed insight into the targeting mechanisms of different programmable systems in a “bottom-up manner”, cutting-edge single-molecule experiments, such as mechanical DNA twisting combined with single-molecule fluorescence detection will be employed. This will provide a fully quantitative characterization of the targeting process and insight into the mechanisms of allosteric regulation coupled to targeting. The quantitative data will allow to develop physics-based models of the target recognition process. In particular, we will focus on recognition through non-equilibrium, directional zipping along the target sequence – as recently revealed for CRISPR-Cas enzymes – as a promising unifying mechanism. To obtain precise targeting predictors our first-principle models will be tested and refined using high-throughput measurements on many different targets in parallel. Finally, the predictions will be used in order to understand target selection in live cells using single-molecule imaging.
Within the project the following goals are defined:
Goal 1: Quantitative understanding of target binding/degradation for CRISPR-Cas systems
Goal 2: Detailed mechanistic insight into the target recognition process by TALEs
Goal 3: Development of highly parallelized measurements on different target sequences down to the single-molecule level
Goal 4: Target identification in the complex environment of live cells
Summary
In the recent years a number of protein systems have been identified that recognize long (tens of base pairs) DNA sequences and allow flexible programmability of their target specificity. This promoted an enormous range of applications in genome engineering and synthetic biology. This project aims to decipher the mechanisms by which these proteins recognize their DNA targets in order to develop quantitative models/predictors for target recognition and to avoid off-target effects.
To obtain detailed insight into the targeting mechanisms of different programmable systems in a “bottom-up manner”, cutting-edge single-molecule experiments, such as mechanical DNA twisting combined with single-molecule fluorescence detection will be employed. This will provide a fully quantitative characterization of the targeting process and insight into the mechanisms of allosteric regulation coupled to targeting. The quantitative data will allow to develop physics-based models of the target recognition process. In particular, we will focus on recognition through non-equilibrium, directional zipping along the target sequence – as recently revealed for CRISPR-Cas enzymes – as a promising unifying mechanism. To obtain precise targeting predictors our first-principle models will be tested and refined using high-throughput measurements on many different targets in parallel. Finally, the predictions will be used in order to understand target selection in live cells using single-molecule imaging.
Within the project the following goals are defined:
Goal 1: Quantitative understanding of target binding/degradation for CRISPR-Cas systems
Goal 2: Detailed mechanistic insight into the target recognition process by TALEs
Goal 3: Development of highly parallelized measurements on different target sequences down to the single-molecule level
Goal 4: Target identification in the complex environment of live cells
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
