Bachelor of Science (Biochemistry and Molecular Biology), University of Melbourne, 2017-2020
Master of Biomedical Science (Cancer Biology and Therapeutics), University of Melbourne, 2020-2022
DPhil candidate in Medical Sciences, University of Oxford, 2022-present
Investigation of p53 function and reliance in haematopoietic stem cells
p53 is a central regulator of cellular fate and holds the balance between longevity and tumour suppression, but it seems to play a more intricate role in haematopoietic stem cells (HSCs). My research aims to investigate p53’s role in HSC longevity, fitness, and genomic stability. I hypothesise that p53 does not affect HSC maintenance or protect HSC genome integrity at the steady state, but acts as a stringent quality control mechanism to eliminate any damaged cells. Specifically, I aim to investigate the following research questions:
- Do HSCs have a Hayflick limit in the ex vivo culturing system and how well can they maintain telomere lengths? Is this affected by p53 status?
- Does p53 guard HSC genome integrity or is it dispensable in the HSC stage?
- Does p53 deficiency create unique vulnerabilities in HSCs?
To address these questions, firstly, I cultured mouse HSCs for up to 6 months, marking the longest ex vivo HSC cultures to date, and they have not yet reached the Hayflick limit. No significant reduction in telomere length was detected during this period. Secondly, I am developing a genetic model to selectively knock-out p53 in the HSC stage, in order to test p53’s importance in protecting HSC genome integrity. Thirdly, I designed and performed ex vivo HSC competitive proliferation assays that suggested a moderate advantage of p53 deficiency. Furthermore, I will perform an ex vivo whole genome CRISPR knock-out screen in p53-/- HSCs to explore p53 functions and potential synthetic lethality with p53 deficiency in HSCs. This work will provide insights into HSC telomere biology and reliance on p53 functions.