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Xinran Huang

DPhil Student

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:

  1. 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?
  2. Does p53 guard HSC genome integrity or is it dispensable in the HSC stage?
  3. 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.