Intestinal serotoninergic activity modulates the intensity of DNA damage

Abstract

Serotonin (5-HT) is neurohormone with multiple effects in mammals. The intestinal 5-HT synthesis is initiated by the enzyme tryptophan hydroxylase I (Tph1) activity on tryptophan. This neuropeptide is believed to promote colon cancer. However, our unpublished findings (FAPESP 2014/ 06428-5) demonstrate that this neurohormone inhibits not only the formation of colon preneoplastic lesions but also modulates the intensity of DNA double-strand breaks (DSBs). This project will investigate the modulatory effects of 5-HT on the intensity of DNA damage-related irradiation in colonocytes. It will be explored by mechanistic experiments that expose mouse models with (KO) or without (WT) Tph1 deletion to irradiation along with pharmacological treatments modulating the serotonergic activity in the colon. Molecular biology methods will determine both the intensity of DNA damage and the activation or silencing of genomic repair mechanisms. This project has the potential to reveal a new 5-HT activity during the DNA damage in colonocytes. (AU)