The role of lsc/p115-RhoGEF-regulated pathways for development and function of the enteric nervous system in the upper gastrointestinal tract.

• Applicant: Dr. Eugen Zizer
• Subject Area: Gastroenterology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2013 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 247486657

The transit through the gastrointestinal tract (GIT) is partially controlled in the oropharynx and the esophagus tube, however completely autonomous in the stomach, the small and large intestines. Gastrointestinal motility is affected in different sections of the GIT in achalasia, intestinal pseudoobstruction and gastroparesis. In our previous studies we reported an achalasia-like phenotype in the mice lacking the lsc/p115-RhoGEF-protein, which mediates G-protein dependent intracellular pathways and is essential for the activation of RhoGTPases. In particular the lsc/p115-KO mice showed a significant hypogliosis and hypoinnervation in the esophagus tube and the lower esophagus sphincter (LES), but not in the other GIT-sections. In this project, we are going to evaluate the role of lsc/p115-RhoGEF-dependent pathways in the enteric nervous system (ENS) of the upper GIT-sections (esophagus and LES). We intend to analyse the development of the glial cells and neurons in the ENS at the embryonic stage and after birth. lsc/p115-KO glial cells and neurons will be evaluated for the basal and induced proliferation and apoptosis rates, the expression of neurotrophic factors and the interactions between both cell types, respectively. Complementary, we are going to investigate the role of lsc/p115-RhoGEF in the expression of particular proliferation- and differentiation-factors (Sox10, Mash1, phox2b). Here we believe that lsc/p115-RhoGEF is regulating the expression of these proteins. The other part of our investigations include the functional analysis (esophageal manometry and in-vitro contractions measurements): the alterations of the gastrointestinal motility in the upper GIT in lsc/p115-deficient mice will be evaluated so we will be able to determine when the morphological changes in the ENS of the upper GIT result in the functional alterations. By these investigations we intend to clarify the complicated regulation of gastrointestinal motility at physiological and pathophysiological conditions.

• DFG Programme: Research Grants
• Participating Persons: Professor Dr. Tobias Böckers; Professor Dr. Klaus-Dieter Fischer; Professor Dr. Andreas Friebe