Project description
Microenvironmental determinants of cell fate commitment in the mammalian haematopoietic system
The molecular mechanisms underlying cell fate commitment in the mammalian haematopoietic system are poorly understood. The EU-funded ImmuNiche project aims to understand the cell type composition of the mouse bone marrow using single-cell RNA sequencing and high-resolution spatial analysis of gene expression in tissue sections. Using this approach, the project team will examine the co-localisation of haematopoietic cells and other bone marrow cell types and predict niches of haematopoietic progenitors that reveal microenvironmental determinants of haematopoietic cell fate. The project will investigate the pathogenesis of myelodysplastic syndromes (MDS) that give rise to leukaemia with a poor prognosis. The conserved niche regulators of cell fate commitment involved in disease pathogenesis will be established and functionally analysed in murine models of MDS.
Objective
The complex architecture of the mammalian hematopoietic system has been studied for decades, yet the molecular mechanisms underlying cell fate commitment remain poorly understood. Although cytokine signals are major determinants of hematopoietic cell fate, only few niches of stem and progenitor cells have been characterized. Here, we propose to resolve the cell type composition of mouse bone marrow by integrating single-cell RNA-seq with high-resolution spatial analysis of gene expression in tissue sections, visualizing ~250 cell type specific markers by multiplexed single-molecule RNA fluorescent in situ hybridization. This approach will reveal preferential co-localization of hematopoietic cells with other bone marrow-resident cell types, and globally predict niches of hematopoietic progenitor sub-types to pinpoint microenvrionmental determinants of hematopoietic cell fate. Based on this reference we will investigate the role of the microenvironment in the pathogenesis of myelodysplastic syndromes (MDS), representing one of the most frequent blood cell malignancies, commonly giving rise to leukaemia with poor prognosis. To investigate conservation of microenvironmental determinants of normal and malignant hematopoietic differentiation in human, we will apply the same strategy to healthy donors and human MDS patients and compare predicted cell types, differentiation trajectories, and niche interactions to those derived from healthy mice and murine MDS models. This approach will reveal conserved niche regulators of cell fate commitment involved in disease pathogenesis, which we will functionally analyse in murine models to identify novel therapeutic targets for prevention and treatment of MDS. Our approach represents a blueprint for investigating human malignancies of under-characterized tissues by applying cutting-edge high-resolution techniques in combination with advanced computational methods to jointly analyse the murine model and human patient microenvironment.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics RNA
- medical and health sciences clinical medicine oncology leukemia
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-COG - Consolidator Grant
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2018-COG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
97070 Wuerzburg
Germany
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