Summary
Hematopoietic stem cells (HSCs) are a unique population defined by their self-renewal capacity and the potential to give rise to all blood lineages. A complete understanding of the specific mechanisms controlling HSC self-renewal and multipotency is still lacking. This knowledge is fundamental to improve ex vivo HSC expansion with therapeutic purposes and to unveil the mechanisms that promote aberrant cellular growth in leukemia. Long non-coding RNAs (lncRNAs) are emerging as novel players of normal development and physiology and their dysregulation has been associated with multiple cancer types. Recent data suggests that lncRNAs may also act as molecular determinants of the balance between self-renewal and differentiation in HSCs. However, because of traditional limitations in RNA-profiling strategies, current lncRNA catalogs are still incomplete, representing likely only a fraction of the whole lncRNA repertoire expressed in cells. In this proposal, I aim to identify novel lncRNAs specifically involved in the regulation of HSC identity, to ultimately understand their function in normal hematopoiesis and leukemia. For this, I will construct a comprehensive HSC-specific lncRNA catalog through deep total-RNA sequencing of mouse HSCs and their closest cell descendants. I will then infer lncRNA functions through robust computational analyses and validate selected candidates in-vitro. Finally, I will investigate the role of HSC-specific lncRNAs in vivo, using a T-cell acute lymphoblastic leukemia mouse model.
This work will extend our knowledge on lncRNAs, on the molecular mechanisms of HSC identity and on how their dysregulation leads to leukemia. By performing this project I will gain first-hand experience in normal and malignant hematopoiesis while reinforcing my expertise in lncRNA biology. I also expect to reach the highest levels of professional maturity and scientific independence which will allow me to establish a high-profile research group in the near future.
This work will extend our knowledge on lncRNAs, on the molecular mechanisms of HSC identity and on how their dysregulation leads to leukemia. By performing this project I will gain first-hand experience in normal and malignant hematopoiesis while reinforcing my expertise in lncRNA biology. I also expect to reach the highest levels of professional maturity and scientific independence which will allow me to establish a high-profile research group in the near future.
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| Web resources: | https://cordis.europa.eu/project/id/101068212 |
| Start date: | 01-01-2023 |
| End date: | 31-12-2024 |
| Total budget - Public funding: | - 165 312,00 Euro |
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Original description
Hematopoietic stem cells (HSCs) are a unique population defined by their self-renewal capacity and the potential to give rise to all blood lineages. A complete understanding of the specific mechanisms controlling HSC self-renewal and multipotency is still lacking. This knowledge is fundamental to improve ex vivo HSC expansion with therapeutic purposes and to unveil the mechanisms that promote aberrant cellular growth in leukemia. Long non-coding RNAs (lncRNAs) are emerging as novel players of normal development and physiology and their dysregulation has been associated with multiple cancer types. Recent data suggests that lncRNAs may also act as molecular determinants of the balance between self-renewal and differentiation in HSCs. However, because of traditional limitations in RNA-profiling strategies, current lncRNA catalogs are still incomplete, representing likely only a fraction of the whole lncRNA repertoire expressed in cells. In this proposal, I aim to identify novel lncRNAs specifically involved in the regulation of HSC identity, to ultimately understand their function in normal hematopoiesis and leukemia. For this, I will construct a comprehensive HSC-specific lncRNA catalog through deep total-RNA sequencing of mouse HSCs and their closest cell descendants. I will then infer lncRNA functions through robust computational analyses and validate selected candidates in-vitro. Finally, I will investigate the role of HSC-specific lncRNAs in vivo, using a T-cell acute lymphoblastic leukemia mouse model.This work will extend our knowledge on lncRNAs, on the molecular mechanisms of HSC identity and on how their dysregulation leads to leukemia. By performing this project I will gain first-hand experience in normal and malignant hematopoiesis while reinforcing my expertise in lncRNA biology. I also expect to reach the highest levels of professional maturity and scientific independence which will allow me to establish a high-profile research group in the near future.
Status
SIGNEDCall topic
HORIZON-MSCA-2021-PF-01-01Update Date
09-02-2023
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