Project acronym INFANTLEUKEMIA
Project GENOMIC, CELLULAR AND DEVELOPMENTAL RECONSTRUCTION OFINFANT MLL-AF4+ ACUTE LYMPHOBLASTIC LEUKEMIA
Researcher (PI) Pablo Menendez Buján
Host Institution (HI) FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEMIA JOSEP CARRERAS
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Infant cancer is very distinct to adult cancer and it is progressively seen as a developmental disease. An intriguing infant cancer is the t(4;11) acute lymphoblastic leukemia (ALL) characterized by the hallmark rearrangement MLL-AF4 (MA4), and associated with dismal prognosis. The 100% concordance in twins and its prenatal onset suggest an extremely rapid disease progression. Many key issues remain elusive:
Is MA4 leukemogenic?
Which are other relevant oncogenic drivers?
Which is the nature of the cell transformed by MA4?
Which is the leukemia-initiating cell (LIC)?
Does this ALL follow a hierarchical or stochastic cancer model?
How to explain therapy resistance and CNS involvement?
To what extent do genetics vs epigenetics contribute this ALL?
These questions remain a challenge due to: 1) the absence of prospective studies on diagnostic/remission-matched samples, 2) the lack of models which faithfully reproduce the disease and 3) a surprising genomic stability of this ALL.
I hypothesize that a Multilayer-Omics to function approach in patient blasts and early human hematopoietic stem/progenitor cells (HSPC) is required to fully scrutinize the biology underlying this life-threatening leukemia. I will perform genome-wide studies on the mutational landscape, DNA and H3K79 methylation profiles, and transcriptome on a uniquely available, large cohort of diagnostic/remission-matched samples. Omics data integration will provide unprecedented information about oncogenic drivers which must be analyzed in ground-breaking functional assays using patient blasts and early HSPCs carrying a CRISPR/Cas9-mediated locus/allele-specific t(4;11). Serial xenografts combined with exome-seq in paired diagnostic samples and xenografts will identify the LIC and determine whether variegated genetics may underlie clonal functional heterogeneity. This project will provide a precise understanding and a disease model for MA4+ ALL, offering a platform for new treatment strategies.
Summary
Infant cancer is very distinct to adult cancer and it is progressively seen as a developmental disease. An intriguing infant cancer is the t(4;11) acute lymphoblastic leukemia (ALL) characterized by the hallmark rearrangement MLL-AF4 (MA4), and associated with dismal prognosis. The 100% concordance in twins and its prenatal onset suggest an extremely rapid disease progression. Many key issues remain elusive:
Is MA4 leukemogenic?
Which are other relevant oncogenic drivers?
Which is the nature of the cell transformed by MA4?
Which is the leukemia-initiating cell (LIC)?
Does this ALL follow a hierarchical or stochastic cancer model?
How to explain therapy resistance and CNS involvement?
To what extent do genetics vs epigenetics contribute this ALL?
These questions remain a challenge due to: 1) the absence of prospective studies on diagnostic/remission-matched samples, 2) the lack of models which faithfully reproduce the disease and 3) a surprising genomic stability of this ALL.
I hypothesize that a Multilayer-Omics to function approach in patient blasts and early human hematopoietic stem/progenitor cells (HSPC) is required to fully scrutinize the biology underlying this life-threatening leukemia. I will perform genome-wide studies on the mutational landscape, DNA and H3K79 methylation profiles, and transcriptome on a uniquely available, large cohort of diagnostic/remission-matched samples. Omics data integration will provide unprecedented information about oncogenic drivers which must be analyzed in ground-breaking functional assays using patient blasts and early HSPCs carrying a CRISPR/Cas9-mediated locus/allele-specific t(4;11). Serial xenografts combined with exome-seq in paired diagnostic samples and xenografts will identify the LIC and determine whether variegated genetics may underlie clonal functional heterogeneity. This project will provide a precise understanding and a disease model for MA4+ ALL, offering a platform for new treatment strategies.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym ProNANO
Project Protein-based functional nanostructures
Researcher (PI) Aitziber Lopez Cortajarena
Host Institution (HI) ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOMATERIALES- CIC biomaGUNE
Call Details Consolidator Grant (CoG), LS9, ERC-2014-CoG
Summary The precise synthesis of nano-devices with tailored complex structures and properties is a requisite for their use in nanotechnology and medicine. Nowadays, the technology for the generation of these devices lacks the precision to determine their properties, and is accomplished mostly by “trial and error” experimental approaches. Bottom-up self-assembly that relies on highly specific biomolecular interactions of small and simple components, is an attractive approach for nanostructure templating.
Here, we propose to overcome aforementioned challenges by using self-assembling protein building blocks as templates for nanofabrication. In nature, protein assemblies govern sophisticated structures and functions, which are inspiration to engineer novel assemblies by exploiting the same set of tools and interactions to create nanostructures with numerous potential applications in synthetic biology and nanotechnology.
We hypothesize that we can rationally assemble a variety functional nanostructures by the logical combination of simple protein building blocks with specified properties. We propose to use a designed repeat protein scaffold for which we acquired a deep understanding of its molecular structure, stability, function, and inherent assembly properties. Only few conserved residues define the structure of the building block, which allow us to mutate its sequence to modulate assembly properties and to introduce reactive functionalities without compromising the structure of the scaffolding molecule.
First, we will design a collection of protein-based nanostructures. Then, we will introduce reactive functionalities to create hybrid nanostructures with nanoparticles, metals and electro-active molecules. Finally, these conjugates will be used to build nano-devices such as nanocircuits, catalysts and electroactive materials.
The outcome of this project will be a modular versatile platform for the fabrication of multiple protein-based hybrid functional nanostructures.
Summary
The precise synthesis of nano-devices with tailored complex structures and properties is a requisite for their use in nanotechnology and medicine. Nowadays, the technology for the generation of these devices lacks the precision to determine their properties, and is accomplished mostly by “trial and error” experimental approaches. Bottom-up self-assembly that relies on highly specific biomolecular interactions of small and simple components, is an attractive approach for nanostructure templating.
Here, we propose to overcome aforementioned challenges by using self-assembling protein building blocks as templates for nanofabrication. In nature, protein assemblies govern sophisticated structures and functions, which are inspiration to engineer novel assemblies by exploiting the same set of tools and interactions to create nanostructures with numerous potential applications in synthetic biology and nanotechnology.
We hypothesize that we can rationally assemble a variety functional nanostructures by the logical combination of simple protein building blocks with specified properties. We propose to use a designed repeat protein scaffold for which we acquired a deep understanding of its molecular structure, stability, function, and inherent assembly properties. Only few conserved residues define the structure of the building block, which allow us to mutate its sequence to modulate assembly properties and to introduce reactive functionalities without compromising the structure of the scaffolding molecule.
First, we will design a collection of protein-based nanostructures. Then, we will introduce reactive functionalities to create hybrid nanostructures with nanoparticles, metals and electro-active molecules. Finally, these conjugates will be used to build nano-devices such as nanocircuits, catalysts and electroactive materials.
The outcome of this project will be a modular versatile platform for the fabrication of multiple protein-based hybrid functional nanostructures.
Max ERC Funding
1 718 850 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym QnanoMECA
Project Quantum Optomechanics with a levitating nanoparticle
Researcher (PI) Romain Roger Quidant
Host Institution (HI) FUNDACIO INSTITUT DE CIENCIES FOTONIQUES
Call Details Consolidator Grant (CoG), PE2, ERC-2014-CoG
Summary Micro- and nano-mechanical oscillators with high quality (Q)-factors have gained much interest for their capability to sense very small forces. Recently, this interest has exponentially grown owing to their potential to push the current limits of experimental quantum physics and contribute to our further understanding of quantum effects with large objects. Despite recent advances in the design and fabrication of mechanical resonators, their Q-factor has so far been limited by coupling to the environment through physical contact to a support. This limitation is foreseen to become a bottleneck in the field which might hinder reaching the performances required for some of the envisioned applications. A very attractive alternative to conventional mechanical resonators is based on optically levitated nano-objects in vacuum. In particular, a nanoparticle trapped in the focus of a laser beam in vacuum is mechanically disconnected from its environment and hence does not suffer from clamping losses. First experiments on this configuration have confirmed the unique capability of this approach and demonstrated the largest mechanical Q-factor ever observed at room temperature. The QnanoMECA project aims at capitalizing on the unique capability of optically levitating nanoparticles to advance the field of optomechanics well beyond the current state-of-the-art. The project is first aimed at bringing us closer to ground-state cooling at room temperature. We will also explore new paradigms of optomechanics based on the latest advances of nano-optics. The unique optomechanical properties of the developed systems based on levitated nanoparticles will be used to explore new physical regimes whose experimental observation has been so far hindered by current experimental limitations.
Summary
Micro- and nano-mechanical oscillators with high quality (Q)-factors have gained much interest for their capability to sense very small forces. Recently, this interest has exponentially grown owing to their potential to push the current limits of experimental quantum physics and contribute to our further understanding of quantum effects with large objects. Despite recent advances in the design and fabrication of mechanical resonators, their Q-factor has so far been limited by coupling to the environment through physical contact to a support. This limitation is foreseen to become a bottleneck in the field which might hinder reaching the performances required for some of the envisioned applications. A very attractive alternative to conventional mechanical resonators is based on optically levitated nano-objects in vacuum. In particular, a nanoparticle trapped in the focus of a laser beam in vacuum is mechanically disconnected from its environment and hence does not suffer from clamping losses. First experiments on this configuration have confirmed the unique capability of this approach and demonstrated the largest mechanical Q-factor ever observed at room temperature. The QnanoMECA project aims at capitalizing on the unique capability of optically levitating nanoparticles to advance the field of optomechanics well beyond the current state-of-the-art. The project is first aimed at bringing us closer to ground-state cooling at room temperature. We will also explore new paradigms of optomechanics based on the latest advances of nano-optics. The unique optomechanical properties of the developed systems based on levitated nanoparticles will be used to explore new physical regimes whose experimental observation has been so far hindered by current experimental limitations.
Max ERC Funding
1 987 500 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
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.)
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
