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Deciphering the intrinsic and extrinsic mechanisms shaping aging and leukemic evolution of hematopoietic stem cells at the single cell level

Project description

Haematopoietic stem cells in blood cancers

Mature blood cells have relatively short lifespans so stem cells are required throughout a person’s life. The presence of ‘preleukemic mutations’ in a single haematopoietic stem cell (HSC) enables the cell to form more blood cells than the others, an age-related condition called clonal haematopoiesis. It is a major risk factor for blood cancers, but the mechanisms leading to cancer are unknown. With the support of the Marie Skłodowska-Curie Actions programme, the PRELEUKMEC project aims to develop a method to profile thousands of single HSCs from young and aged patients with clonal haematopoiesis and blood cancers. The approach will reveal cells’ genotypes and protein expression profiles at different time points of differentiation under various culture conditions.

Objective

Clonal Hematopoiesis (CH) is an age related state in which a single and genetically defined Hematopoietic Stem Cell (HSC) contributes more than expected to the hematopoietic pool, due to the selective advantage conferred by genetic variants termed preleukemic mutations (pLMs). CH is a significant risk factor for hematological malignancies such as Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Today, the mechanisms by which pLMs provide selective advantage and why in some cases clones become leukemic is not fully understood. This project focuses on understanding the dynamic changes that occur in human HSCs in aging and disease at the single cell level. Specifically, we wish to answer the following questions: 1) What are the functional consequences of aging on peripheral blood HSCs 2) what are the functional consequences of pLMs in CH, but also in AML and MDS in humans? 3) which microenvironmental factors provide selective advantage to the mutated clones? To answer these questions, we aim at developing a new innovative approach that will allow us to interrogate thousands of single HSCs from young/old/CH/AML/MDS patients to extract their genotype and their dynamic expression profiles at different time point of differentiation, under different culture conditions.
This project will be performed in the Weizmann Institute, one of the world’s leading multidisciplinary basic research institutions in the natural and exact sciences. It will be highly interdisciplinary as it will involve collaboration with renown researchers from the Computer Science and the Chemistry department. In addition to the knowledge acquired in the lab and through the different collaborations, the fellow will benefit from high level training through attendance of various courses, seminars and international conferences. Overall, this project should have great benefit for the career of the fellow.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2022-PF-01

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Coordinator

WEIZMANN INSTITUTE OF SCIENCE
Net EU contribution

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.

€ 200 538,24
Address
HERZL STREET 234
7610001 Rehovot
Israel

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Activity type
Higher or Secondary Education Establishments
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Total cost

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