Proteome remodeling during hematopoietic stem cell ageing

1 PhD project offered in the IPP summer call 2021

This project is part of the Science of Healthy Ageing Research Programme (SHARP).

Scientific background

Hematopoietic stem cells (HSC) are the cornerstone of the hematopoietic system that sustain blood production over the entire life-span of an organism. During ageing, many of the intrinsic aspects of HSC are affected resulting in a deterioration in their regenerative potential, aberrant differentiation toward myeloid lineage skewing, transcriptional alterations and dysregulation of signaling pathways. Additionally, blood ageing is also the major risk factor for hematologic malignancies, such as acute myeloid leukemia (AML) that are driven by clonal transformation of HSCs. For all these reasons, cell-intrinsic mechanisms of ageing represent important putative targets for therapeutic interventions in order to ameliorate the consequences of ageing on HSCs and on the hematopoietic system.

The Guezguez laboratory generates genetically engineered mouse models to study hematopoietic stem cell activity during ageing and neoplastic transformation toward Leukemia.

The Beli laboratory develops and employs quantitative mass spectrometry-based proteomics approaches to analyse proteome dynamics and cellular signalling mediated by phosphorylation and ubiquitylation.

PhD project: Role of GSK-3 in hematopoietic stem cell ageing     

Recent evidences demonstrated that aberrant activation of the growth-promoting mammalian target of rapamycin (mTOR) pathway plays a central role in cellular senescence and organismal ageing, representing a key molecular driver of stem cell depletion and reduced tissue regenerative capacity. Specifically, mice deficient for thegene GSK-3 (Glycogen Synthase Kinase-3), a master regulator of the mTOR pathway, were shown to display a hematopoietic-ageing phenotype including myeloid-skewing and blood maturation defects. In this project, we will define specific transcriptional changes and proteome remodeling of ageing HSCs in GSK3-deficient mice and characterize the functional role of mTOR inhibitors on ageing-HSCs as therapeutic approach for blood rejuvenation.

If you are interested in this project, please select Borhane Guezguez as your group preference in the IPP application platform.

Publications relevant to the project

Guezguez B., Almakadi M., Benoit YD., Shapovalova Z., Rahmig S., Fiebig-Comyn M., Casado FL., Tanasijevic B., Bresolin S., Masetti R., Doble BW., Bhatia M (2016) GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that is Predictive of Clinical Outcomes of Human Acute Leukaemia. Cancer Cell, 29:61-74 Link

Hildebrandt A, Brüggemann M, Rücklé C, Boerner S, Heidelberger JB, Busch A, Hänel H, Voigt A, Möckel MM, Ebersberger S, Scholz A, Dold A, Schmid T, Ebersberger I, Roignant JY, Zarnack K, König J, Beli P (2019) The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation. Genome Biol, 20:216 Link

Mejia-Ramirez E and Florian MC (2020) Understanding intrinsic hematopoietic stem cell aging. Haematologica, 105:22-37 Link

Contact

Dr Borhane Guezguez (If you are interested in this project, please select Borhane Guezguez as your group preference in the IPP application platform.)

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Prof. Petra Beli

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