Project R-13257

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

Damage to mammalian genomes is unavoidable, arising from reactions with endogenous chemicals, namely reactive oxygen species, or exposures to environmental genotoxins. To prevent the harmful consequences of DNA damage, organisms have evolved DNA repair mechanisms. The enteric nervous system (ENS), also referred to as the 'second brain', is a major division of the autonomic nervous system, controlling the operation of the gastrointestinal tract. Unlike the main central nervous system components, the ENS is not protected by the blood-brain barrier or skeletal structures like those that surround the brain and spinal cord. The ENS is therefore more vulnerable to the genotoxic effects of circulating or consumed agents such as inflammatory molecules, pathogens, and environmental contaminants. These characteristics of the ENS render it very sensitive to DNA damage, suggesting it requires enhanced DNA repair mechanisms. To date, the importance of DNA repair in the ENS remains basically underexplored. I propose to investigate the role of a key DNA repair protein, Apex1, as a guardian of the ENS genome. By inactivating gene expression in the ENS during embryogenesis or in adulthood, I will generate two distinct Apex1 knock-out (KO) mouse models to evaluate its developmental and neuroprotective role, respectively. 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 the KO models.

01 November 2022 - 31 October 2023