Investigating the Impact of Extrinsic Factors on Intestinal Stem Cell Dynamics (360G-Wellcome-109141_Z_15_A)

The rapid turnover of the mammalian intestinal epithelium is fuelled by division of stem cells residing at the bottom of the crypts of Lieberkühn. Our understanding of how stem cells populate the intestine in humans lags behind that of the murine system. In the latter, stem cells populate the crypts by a process of neutral drift. Moreover the number of functional stem cells per crypt and their replacement rate has been quantified in the mouse intestinal epithelium. However, it is not known how extrinsic factors, such as regular drug use, influence these dynamics. In humans, randomised clinical trials have linked low-dose aspirin to a reduction in colorectal cancer incidence and mortality. However, the mechanism is unclear. Since tumours originate from stem cells, I plan to conduct an in vivo study to investigate the impact of aspirin on murine intestinal stem cell dynamics. In the human system, functional stem cell numbers and replacement rates are still not well characterised. Somatic mutations can be used as clonal marks to investigate these parameters in patient samples. I thus aim to find and validate novel human somatic clonal marks and collect data for mathematical modelling of human intestinal stem cell dynamics.