Krishnanand Padmanabhan

The enteric nervous system (ENS) contains an extensive range of neural subtypes that collectively control essential gut functions largely independent of the central nervous system (CNS). Enteric neuronal diversity is critical for maintaining normal gut function, and a selective dysfunction or local neuronal loss leads to gastrointestinal (GI) disorders. As current treatments of ENS-related disorders are suboptimal, development of novel regenerative approaches has the potential to significantly improve GI health for millions worldwide. As a first milestone towards cell-based regenerative therapies, the Marklund lab recently established a molecular classification of intestinal enteric neurons and discovered that they diversify through a conceptually new stepwise principle during development. The proposed project, DeSTENy, will significantly expand on these discoveries, and investigate how time and spatial context of developing GI tract controls the developing ENS to acquire the appropriate neuron identities at the right time and region within the mouse gut. DeSTENy will integrate cutting-edge regular and spatial single-cell transcriptomics to identify potentially important spatiotemporal driver genes in the ENS of the intestine versus stomach and oesophagus (upper GI-tract). While studies of the developing ENS has been challenged by its inaccessible location within the gut wall, DeSTENy will overcome this limitation by the utilization a precise, rapid and large-scale gene manipulation strategy based on ultrasound-guided transduction of ENS precursor cells followed by temporally controlled gene expression. Apart from transforming our understanding of the largest division of the peripheral nervous system and fundamental developmental processes, DeSTENy will open avenues for regenerative medicine in treating neurological gut disorders, in particular the many affecting the upper GI-tract.