Project R-15607

Resolution of genomic stress as a mechanism to avert gut disorders involving enteric nervous system defects (Research)

The enteric nervous system (ENS), comprised of an integrated network of neuronal and glial cells embedded within the lining of the gastrointestinal (GI) tract, is the largest and most complex unit of the peripheral nervous system. Operating quasi-autonomously, the ENS controls essential GI functions, such as motility, absorption, and immune activity. Disorders involving ENS defects are significant contributors to the worldwide health burden, yet the main mechanisms underlying ENS dysfunction remain largely unknown. Genetic studies of enteric neuropathies and preliminary data presented herein indicate critical contributions of DNA repair factors in ensuring ENS development and performance. DNA repair encompasses diverse molecular pathways that resolve specific forms of DNA damage arising as products of natural events, such as spontaneous decay or reactions with free radicals. The project here will determine the consequences of DNA repair defects in enteric precursor or mature cells on ENS development, ENS structure-function, genomic stress transcriptomic responses, and GI tract operations. Controlled laboratory studies using a range of sophisticated models will identify the major DNA repair pathways for preserving ENS integrity. The investigations will establish the primary genome maintenance mechanisms and associated forms of genomic stress that affect ENS functionality, setting the stage for improved lifestyle practices and therapeutic interventions for diseases of the gut.

01 January 2025 - 31 December 2028