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1.

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

Regulation of synaptic development and plasticity by molecular pathways linked to human evolution

  • 2 Million
  • France
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Regulation of synaptic development and plasticity by molecular pathways linked to human evolution
Company Name INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Funded By 38
Country France , Western Europe
Project Value 2 Million
Project Detail

The synapse is a nanoscale machine, which transfers, integrates and stores information in brain circuits. Its function relies on multimolecular networks of interactions whose composition and dynamics shape synaptic transmission. A large body of evidence indicates that synapses specialized in humans. Human synapses are more densely distributed along dendrites and their period of maturation is protracted compared to rodent or non-human primate synapses. The rules governing their plasticity also differ from the other mammalian species studied so far. These traits contribute to the formation and function of complex circuits supporting human cognitive abilities. Yet, the underlying molecular mechanisms are not known. Here we will investigate the role of molecular pathways linked to human evolution in the regulation of synaptic development and plasticity. The proposed research takes advantage of my previous work on Slit-Robo Rho GTPAse-activating protein 2 (SRGAP2), one of the few genes specifically duplicated in humans, and the only one implicated at synapses so far. We will use the duplications of SRGAP2 as a thread to uncover i) fundamental mechanisms of synaptic development and plasticity, and ii) regulations specific to human synapses. To achieve our goals, we will employ a multi-disciplinary approach based on in vivo manipulations in intact mouse cortical circuits, mass spectrometry, live-cell single-molecule super-resolution microscopy, electrophysiology, and engineering of cortical neurons derived from human pluripotent stem cells. The combination of mouse and human models will allow us to establish a robust framework to bridge the gap in knowledge between cellular neurobiology and human brain evolution, and better understand synaptic dysfunctions in neurodevelopmental disorders.

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Contact Details

Company Name INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Address Rue De Tolbiac 101 75654 Paris
Web Site https://cordis.europa.eu/project/rcn/219889/factsheet/en

2.

Masarykova univerzita

SIGNALING PROPENSITY IN THE MICROENVIRONMENT OF B CELL CHRONIC LYMPHOCYTIC LEUKEMIA

  • 1 Million
  • Czech Republic
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SIGNALING PROPENSITY IN THE MICROENVIRONMENT OF B CELL CHRONIC LYMPHOCYTIC LEUKEMIA
Company Name Masarykova univerzita
Funded By 38
Country Czech Republic , Eastern Europe
Project Value 1 Million
Project Detail

B cell chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults. CLL cells are characterized by their universal dependency on pro-survival and pro-proliferative signals from immune niches. To achieve this they constantly re-circulate between blood and lymph nodes, which is inhibited by novel microenvironment-targeting therapies such as “BCR inhibitors”. We aim to reveal how the malignant B cells change the propensity of their signalling pathways in response to the different microenvironments such as peripheral blood vs lymph node to obtain the proliferative signals. This is of major relevance for CLL, but also transferable to the biology of some other B cell malignancies and/or normal B cells. We analyzed the “finger print” of microenvironmental interactions in many CLL samples at various times during the disease course or during therapy. The obtained data led us to hypothesize on the mechanisms of regulation of signalling propensity of two pathways that are responsible for proliferation and survival of CLL cells, namely B Cell Receptor (BCR) signalling and signals from T-cells mediated by CD40/IL4. In aim 1 we hypothesize that CD20 is one of the key proteins involved in CLL cell activation, and influences BCR and interleukin signalling (see figure). This has important therapeutic implication since CD20 is used as a therapeutic target for 20 years (rituximab), but its function in CLL/normal B cells is unknown. In aim 2 we hypothesize that miR-29 acts a key regulator of T-cell signalling from CD40 and down-stream NFkB activation (see figure). This represents the first example of miRNAs‘ role in the propensity of T-cell interaction, and could be also utilized therapeutically. In aim 3 we will integrate our data on microenvironmental signaling (aim 1+2) and develop a first mouse model for PDX that would allow stable engraftment of primary CLL cells. Currently, CLL is non-transplantable to any animal model which complicates studies of its biology.

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Contact Details

Company Name Masarykova univerzita
Address Zerotinovo Namesti 9 60177 Brno Stred
Web Site https://cordis.europa.eu/project/rcn/219810/factsheet/en

3.

UNIVERSITA DEGLI STUDI DI TRENTO

Studying the role of Quiescent Cancer Stem Cells in GBM development using a novel in vivo cell cycle-based approach

  • 183,473
  • Italy
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Studying the role of Quiescent Cancer Stem Cells in GBM development using a novel in vivo cell cycle-based approach
Company Name UNIVERSITA DEGLI STUDI DI TRENTO
Funded By 38
Country Italy , Western Europe
Project Value 183,473
Project Detail

Glioblastoma (GBM) is the most common and aggressive high-grade primary brain tumour in adults. More than 90% of the patients shows recurrence of the disease with a survival of 2 years despite a multitherapeutic approach consisting of a first surgical resection of the brain lesion followed by radio- and chemo-therapy. GBM patients die because of the cancer relapse that evolve becoming not sensitive to the classical therapies. A sub-population of quiescent/slow cycling cancer stem cells (CSCs) has been proposed to be the origin of the cancer relapse. The features and role of that specific population of CSCs within GBM is still not well characterised. The aim of the proposed project is to first clarify the cell cycle state of CSCs within GBM induced in mouse models in addition to their contribution and role in cancer development. To achieve this goal, I will use a cell cycle-based approach together GBM mouse models to: characterise the cell cycle state of CSCs within tumour (Aim 1); analyse the contribution of quiescent and proliferating CSCs during cancer development and their molecular features using a novel cell cycle-based lineage tracing approach (Aim 2); analyse the effect of selective ablation of each CSCs sub-subpopulation in cancer growth a novel cell cycle-based cellular ablation (Aim 3). Using a cell cycle point of view, the obtained results will be fundamental for the definition and the role of the different CSCs co-existing within glioma. In particular, the findings will open new avenue in the study of the role of quiescent or proliferating cells within GBM and give the possibility to others in the field for testing for example which cells contribute to cancer relapse after the initial tumour treatment (mass debulking and following radio- and chemo-therapy) or even design new drugs targeting specific CSC types.

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Contact Details

Company Name UNIVERSITA DEGLI STUDI DI TRENTO
Address Via Calepina 14 38122 Trento
Web Site https://cordis.europa.eu/project/rcn/223131/factsheet/en

4.

OKINLAB GMBH

Fully-automated software platform with 3D freeform configurator for design and production of individual and affordable furniture

  • 3 Million
  • Germany
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Fully-automated software platform with 3D freeform configurator for design and production of individual and affordable furniture
Company Name OKINLAB GMBH
Funded By 38
Country Germany , Western Europe
Project Value 3 Million
Project Detail

Mass customization is finding its way into innumerable areas of daily life, e.g. textiles, shoes, as consumer strive for individuality. 84 million customers bout furniture online in the EU. The preconditions for mass furniture are enabled by digitization. Yet there is no solution for affordable individualized furniture representing a tremendous unexploited market. FORMBAR, our novel parametric design software based on mathematical-physical-architectural principles, is the enabling technology allowing customers for the first time to freely shape their furniture individually. In this Phase 2 project FORMBAR will be 100% automated. With simple mouse movements, the customer designs a photo-realistically rendered 3D model and thus constantly inspects his created piece of furniture visually with regard to the selected materiality and colour. By directly integrating the machine specifications into the design process, the self-generated 3D piece of furniture is automatically converted into an optimized cutting pattern and produced cost-effectively using state-of-the-art CNC milling machines. The generated milling data are sent to one of the more than 100 carpenters of OKINLAB in close vicinity to the customer. FORMBAR covers the entire furniture manufacturing process 100% automated, from design to production, in a single application. In combination with mathematically implied algorithms, OKINLAB can guarantee the functionality as well as the producibility of the furniture while at the same time implementing a scalable business model. With FORMBAR mass customization of individual furniture becomes affordable for the first time. OKINLAB with its team of 16 employees from software development, architecture, design, marketing, has developed a configurator in the past selling more than 1,500 pieces of furniture as of today. By automation of FORMBAR costs of the furniture is reduced by 50% opening the technology for the mass market with a potential of €25.3 billion.

Sector Administration & Marketing

Contact Details

Company Name OKINLAB GMBH
Address Ursulinenstrasse 35 66111 Saarbrucken
Web Site https://cordis.europa.eu/project/rcn/223011/factsheet/en

5.

KINGS COLLEGE LONDON

Modelling in vivo lineage reprogramming of human astrocytes into induced neurons in the adult mouse brain

  • 224,934
  • United Kingdom
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Modelling in vivo lineage reprogramming of human astrocytes into induced neurons in the adult mouse brain
Company Name KINGS COLLEGE LONDON
Funded By 38
Country United Kingdom , Western Europe
Project Value 224,934
Project Detail

Studies during last decade have shown that the genetic programs underlying cell identity are plastic even in fully differentiated cells. Direct lineage reprogramming takes advantage of this plasticity to induce cell fate conversions from one cell type into another. The host laboratory is among those who have pioneered successful lineage reprogramming of glial cells into induced functional neurons in vitro and in vivo. These studies have largely focused on murine glia. While there is sparse evidence that also human glia can be reprogrammed into induced neurons, it is unclear whether such lineage conversion can occur within the constraints of the in vivo tissue context by fully integrated mature human glia. In this project I propose an experimental model to study direct lineage reprogramming of human astrocytes into induced neurons at distinct developmental stages within the context of the adult mouse brain in vivo. This model is based on previous findings that show that human astroglial progenitors can integrate into the mouse brain following grafting, maintaining hallmarks that are specific to human astroglia which differ markedly in their complexity from their murine counterparts. Here I will combine this model system with the directed glial differentiation of induced human pluripotent stem cells (hiPSC) and state-of-the-art genome-editing via CRISPR-Cas9 technology. This will enable me to derive transplantable glial progenitors that can be induced to undergo lineage conversion in a humanized in vivo context at distinct maturation stages. With this approach I will obtain important insights into the fundamental question of how the state of maturation and functional integration determines the capacity of human astroglia to undergo lineage conversion into functional neurons in vivo. I expect that the data resulting from this approach will have important implications towards the translation of direct lineage reprogramming into new strategies for brain repair.

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Contact Details

Company Name KINGS COLLEGE LONDON
Address Strand Wc2r 2ls London
Web Site https://cordis.europa.eu/project/rcn/222791/factsheet/en

6.

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS

Control of Central Nervous Sytem inflammation by meningeal macrophages, and its impairment upon aging

  • 184,708
  • France
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Control of Central Nervous Sytem inflammation by meningeal macrophages, and its impairment upon aging
Company Name CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Funded By 38
Country France , Western Europe
Project Value 184,708
Project Detail

Immune responses within the central nervous system (CNS) can drive fatal neuroinflammation and age-related neurodegeneration as seen in the EU but are also crucial to prevent microbial spread into the CNS. It is thus important to understand and control the parameters involved in CNS inflammation. Most studies have focused on the contribution of immune cells localized within the CNS parenchyma. While searching for novel strategies to control neuroinflammation, we and others have found that the nature and activation state of immune cells at the brain surface can profoundly influence CNS inflammation. The parenchyma is enveloped by membranes referred to as the meninges that harbor a vast network of macrophages juxtaposed to blood vasculature, thus ideally positioned to detect pathogens and orchestrate immune cell recruitment into the CNS. The overarching goal of this project is to understand the role of resident meningeal macrophages in initiating and controlling CNS inflammation. To this end, I intend to study the heterogeneity of myeloid subpopulations at steady-state and their differential ability to mount an immune response following a microbial challenge. Furthermore, I will define how natural inflammatory aging impairs the induction of CNS immune responses by meningeal macrophages, and will propose strategies to restore CNS immunity at the brain borders to protect this vital organ. This will be accomplished using combinatorial approaches, including transcriptomics, flow cytometry, histo-cytometry and intravital imaging. Macrophages will be manipulated using transcranial drug delivery and transgenic mice. Sharing skills, expertise, and tools with my host institution will be a key component of this project. Understanding meningeal immunity will open avenues for the treatment of CNS inflammation and neurodegeneration, in line with the H2020 goals of promoting research excellence in the EU to deliver solutions to important societal challenges.

Sector Administration & Marketing

Contact Details

Company Name CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Address Rue Michel Ange 3 75794 Paris
Web Site https://cordis.europa.eu/project/rcn/222766/factsheet/en

7.

TECHNION RESEARCH AND DEVELOPMENT FOUNDATION LTD

Brain Cancer Therapy Monitoring using a Novel Quantitative and Rapid Magnetic Resonance Imaging-based Method

  • 27 Million
  • Israel
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Brain Cancer Therapy Monitoring using a Novel Quantitative and Rapid Magnetic Resonance Imaging-based Method
Company Name TECHNION RESEARCH AND DEVELOPMENT FOUNDATION LTD
Funded By 38
Country Israel , Western Asia
Project Value 27 Million
Project Detail

Glioblastoma multiforme (GBM) is the most common type of brain tumor found in adults and is fatal in all cases. A very promising therapeutic approach for GBM is the use of oncolytic viruses (OVs) that selectively infect, replicate in, and destroy tumor cells, while sparing the surrounding normal cells. Nevertheless, to achieve successful oncolytic virotherapy, frequent non-invasive monitoring of the process must be performed. This is crucial for gaining a better understanding of the interactions between the virus and its tumor-host and predicting a therapeutic response. Thus, the development of a non-invasive method, capable of accurately quantifying the location and extent of the viral spread in the tumor is highly required and is of great importance. Accordingly, the main research goal of this action is to develop a magnetic resonance imaging (MRI)- based method for accurate, quantitative, and rapid imaging of OVs delivery, and spread in clinically relevant tumor models. The devised interdisciplinary methodology includes: genetically modifying the therapeutic virus to be detectable in MRI; developing machine learning methods to increase the speed, specificity, and sensitivity in image-monitoring the virus; and evaluating the established methods using mice models of brain tumor therapy. The allocated training and research environment is optimal for achieving the proposal goals: an outgoing phase at Harvard Medical School, a secondment at a leading clinical MRI company (Insightec), enhancing translation potential, and a return phase at a leading university (Technion), ensuring the transport of knowledge back to the EU. The envisioned technology could be expanded to various additional clinical conditions, and its dissemination could improve patient care. The unique skill set to be acquired by the experienced researcher, would allow claiming a distinct niche of knowledge, increasing competency to a tenure-track position, and a research career in the EU.

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Contact Details

Company Name TECHNION RESEARCH AND DEVELOPMENT FOUNDATION LTD
Address The Senate Building Technion City 1 32000 Haifa
Web Site https://cordis.europa.eu/project/rcn/222670/factsheet/en

8.

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE

The mammalian body plan blueprint, an in vitro approach

  • 2 Million
  • United Kingdom
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The mammalian body plan blueprint, an in vitro approach
Company Name THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Funded By 38
Country United Kingdom , Western Europe
Project Value 2 Million
Project Detail

The development of an embryo requires the spatially structured emergence of tissues and organs. This process relies on the early establishment of a coordinate system in the form of three orthogonal axes that act as a reference for laying down the body plan, a template for the organism. Genetic analysis of this process has revealed an underlying transcriptional blueprint that links the coordinate system and the body plan. However, the way in which the gene products contribute to the emergence of the body plan remains an open question. A reason for this is that this process involves feedbacks and integration between the activity of Gene Regulatory Networks (GRNs) and the mechanics of multicellular ensembles, and that probing this relationship is experimentally challenging. In the case of mammalian embryos, which are particularly important as models for human development, our gaps in knowledge of these events are larger than in other organisms. This is partly due to the challenges associated with uterine development but also, and increasingly, because of the cost of mice and the difficulty of obtaining large numbers of embryos, as required for mechanistic experiments. In this project we shall use gastruloids, a novel and versatile Pluripotent Stem Cells based experimental system that we have developed for the study of mammalian development, to gain insights into the molecular and cellular basis underlying the emergence of the mammalian body plan. Gastruloids lack anterior neural structures and over a period of five days become organized in the fashion of a midgestation mouse embryo. We shall use the experimental versatility of the Gastruloid system to probe into the functional relationships between the mechanical activities of multicellular ensembles and the dynamics of GRNs that underlie the emergence of the mammalian body plan.

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Contact Details

Company Name THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Address Trinity Lane The Old Schools Cb2 1tn Cambridge
Web Site https://cordis.europa.eu/project/rcn/222652/factsheet/en

9.

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG

Matching CNS Lineage Maps with Molecular Brain Tumor Portraits for Translational Exploitation

  • 2 Million
  • Germany
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Matching CNS Lineage Maps with Molecular Brain Tumor Portraits for Translational Exploitation
Company Name DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Funded By 38
Country Germany , Western Europe
Project Value 2 Million
Project Detail

Brain tumors represent an extremely heterogeneous group of more than 100 different molecularly distinct diseases, many of which are still almost uniformly lethal despite five decades of clinical trials. In contrast to hematologic malignancies and carcinomas, the cell-of-origin for the vast majority of these entities is unknown. This knowledge gap currently precludes a comprehensive understanding of tumor biology and also limits translational exploitation (e.g., utilizing lineage targets for novel therapies and circulating brain tumor cells for liquid biopsies). The BRAIN-MATCH project represents an ambitious program to address this challenge and unmet medical need by taking an approach that (i) extensively utilizes existing molecular profiles of more than 30,000 brain tumor samples covering more than 100 different entities, publicly available single-cell sequencing data of normal brain regions, and bulk normal tissue data at different times of development across different species; (ii) generates unprecedented maps of normal human CNS development by using state-of-the art novel technologies; (iii) matches these molecular portraits of normal cell types with tumor datasets in order to identify specific cell-of-origin populations for individual tumor entities; and (iv) validates the most promising cell-of-origin populations and tumor-specific lineage and/or surface markers in vivo. The expected outputs of BRAIN-MATCH are four-fold: (i) delivery of an unprecedented atlas of human normal CNS development, which will also be of great relevance for diverse fields other than cancer; (ii) functional validation of at least three lineage targets; (iii) isolation and molecular characterization of circulating brain tumor cells from patients´ blood for at least five tumor entities; and (iv) generation of at least three novel mouse models of brain tumor entities for which currently no faithful models exist.

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Contact Details

Company Name DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Address Im Neuenheimer Feld 280 69120 Heidelberg
Web Site https://cordis.europa.eu/project/rcn/222546/factsheet/en

10.

STICHTING VUMC

Saracatinib Trial tO Prevent FOP

  • 200 Million
  • Netherlands The
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Saracatinib Trial tO Prevent FOP
Company Name STICHTING VUMC
Funded By 38
Country Netherlands The , Western Europe
Project Value 200 Million
Project Detail

Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling and life-shortening congenital syndrome for which no effective therapies exist. Repurposing of AZD0530 (saracatinib, AstraZeneca) would be an ideal solution for de-risking early clinical studies. Using existing assets and investments, this may allow more affordable pricing once an indication is approved. Ectopic bone is formed in soft tissues due to activating mutations in the bone morphogenetic protein receptor kinase ALK2/ACVR1, leading to progressive contractures and early death. Preclinical studies showed AZD0530, previously unexplored in FOP, to be a potent (5nM) inhibitor of ALK2 kinase and ALK2-R206H-mediated neofunction after activin stimulation. In mice, AZD0530 blocked ectopic bone formation preserving limb movement. Hypothesis: AZD0530 will reduce ectopic bone formation and progressive disability in people with FOP. AIM: to provide proof of concept that AZD0530 is an effective drug in the treatment of patients with FOP. Methods: Based on the rarity of the disease and expected drug efficacy (50% reduction in new bone), a phase 2A proof of concept study including a 6 month randomized placebo controlled study and 12 month open label extension study using historical data, is proposed including 16 adults with active FOP disease. The study will be performed in three European FOP expert Centers (Amsterdam The Netherlands – Lead, London UK, and Garmen Partenkirchen Germany). The study will be performed in collaboration with the expert preclinical teams at the Universities of Oxford and Harvard. FOP expert and patient engagement as well as safety will be ensured by establishing advisory, DSM and stakeholder boards. Early involvement of the regulatory agencies are planned. Expectations: we will develop a roadmap for further studies and regulation of this new treatment option in FOP based on the results.

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Contact Details

Company Name STICHTING VUMC
Address De Boelelaan 1117 1081 Hv Amsterdam
Web Site https://cordis.europa.eu/project/rcn/222553/factsheet/en

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