MRC DiMeN Doctoral Training Partnership - Understanding spatio-temporal GSK-3β activity in hematopoietic stem cells to improve regenerative medicine

Haematopoietic stem cells (HSCs) are rare, highly potent cells that are responsible for life-long maintenance of our blood system. HSCT (transplantation) was the first regenerative medicine to enter the clinic and is a major component of gene therapy treatments. Unfortunately, issues remain, including our ability to expand these cells pre-transplantation and maintain cells in vitro for gene editing and therapy. Thus, a better understanding of HSC biology will unlock potential new therapeutic approaches for HSCT.

HSCs are highly quiescent but must respond rapidly to stress. Consequently, homeostasis of HSCs is a complex process that must be regulated by signalling. Glycogen Synthase Kinase-3β (GSK-3β) is a master regulator of HSCs, modulating stress responses and self-renewal. Importantly, GSK-3β activity levels regulate HSC expansion, making it a highly promising target. We propose the selective modulation of GSK-3β in time and space as an innovative novel strategy to tackle current obstacles in HSCT. You will take a crucial step towards this by visualising spatio-temporal GSK-3β dynamics in HSCs for the first time. To do this, you will develop targeted strategies to modify GSK-3β function to boost HSCs expansion and maintenance for gene therapy and transplantation. The project aims are to:

Explore spatio-temporal GSK3b activity in healthy human and mouse HSCs during classical and novel expansion protocols.
Determine timeline of changes in GSK-3β activity when HSCs engraft recipients and reform the blood system.