Project R-14453

The role of the DNA repair protein Apex1 in enteric nervous system development and function (Research)

Damage to mammalian DNA is unavoidable, arising from reactions with endogenous chemicals, namely reactive oxygen species, or exposures to environmental genotoxins. To avoid the harmful consequences of DNA damage, organisms have evolved DNA repair mechanisms. The enteric nervous system (ENS), also called the 'second brain', controls the fundamental operation of the gastrointestinal tract. Unlike the primary central nervous system components, the ENS is not protected by the blood-brain barrier or skeletal structures. The ENS is therefore readily vulnerable to the genotoxic effects of not only endogenous chemicals but circulating or consumed agents such as inflammatory molecules, pathogens, and environmental contaminants. These characteristics suggest that the ENS relies heavily on DNA repair mechanisms to avoid the harmful effects of DNA damage. To date, the importance of DNA repair in the ENS remains largely unexplored. I propose investigating the role of a critical DNA repair protein, Apex1, as a guardian of the ENS genome. I will generate 2 distinct Apex1 knock-out (KO) mouse models to evaluate its developmental and neuroprotective roles by inactivating Apex1 gene expression in the ENS during embryogenesis or adulthood, with the latter model receiving an additional inflammatory insult. To gain molecular insights into the consequences of Apex1 loss on the cellular network within the ENS, I will perform single-cell RNA sequencing on tissue samples from the KO models.

01 November 2023 - 31 October 2027