Project Details
Projekt
Role of the intestinal antibacterial proteins Regenerating islet-derived 3 beta and gamma (Reg3b and Reg3g) in alcoholic liver disease
Applicant
Dr. Phillipp Hartmann
Subject Area
Gastroenterology
Term
from 2014 to 2016
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 258125387
Alcoholic liver disease leads to serious medical, financial and social problems. The gut-liver axis is a major contributor to the pathogenesis of this disease: Alcoholics display intestinal dysbiosis (suppression of commensal probiotic bacteria) and bacterial overgrowth as well as high plasma levels of endotoxin, a major component of the outer membrane of Gram-negative bacteria. The intended host laboratory of Prof. Schnabl showed additionally that intestinal protein expression of the antimicrobial proteins Regenerating islet-derived 3 beta and gamma (Reg3b and Reg3g) is reduced in alcoholic liver disease. Interestingly, Reg3g protein levels were partially restored and liver injury was alleviated after supplementation with prebiotics. Lower Reg3b and Reg3g levels are furthermore associated with an increased bacterial translocation into the blood stream. We hypothesize that chronic alcohol abuse inhibits intestinal Reg3b and Reg3g expression which leads to intestinal dysbiosis and bacterial overgrowth. This causes increased bacterial translocation into the systemic circulation, measured as increased plasma endotoxin levels that finally (besides alcohol and acetaldehyde themselves) cause liver damage. To investigate the role of Reg3b und Reg3g further, 3 aims shall be achieved: i) Evaluation of alcoholic steatohepatitis following 3 weeks of continuous intragastric ethanol administration using the Tsukamoto-French mouse model in 5 mouse strains, i.e. Reg3b and Reg3g knockout mice, and mice producing these proteins in excess in the intestine (Reg3b and Reg3g transgenic mice) in comparison to wild type mice. ii) Study of alcohol-associated changes in the intestine (including analysis of dysbiosis using modern 454 pyrosequencing, bacterial overgrowth, spatial segregation between intestinal bacteria and the epithelium with Fluorescence in situ hybridization (FISH), and bacterial translocation) in the aforementioned 5 mouse strains. iii) Evaluation of the exact mechanism of suppression of intestinal Reg3b and Reg3g in alcoholic liver disease using a novel intestinal crypt culture system. Research in Schnabl lab has been focusing on the gut-liver axis in alcoholic liver disease for a long time with elaborated techniques. Subsequently, his lab offers optimal conditions in order to learn new methods and to deepen one's knowledge about the exact mechanisms of alcoholic liver disease. The aim of this application is to receive a scholarship in order to be a member of Prof. Schnabl's group in the Division of Gastroenterology at University of California San Diego during a 2-year research period to collaborate on this fascinating and promising subject using the local sophisticated methods.
DFG Programme
Research Fellowships
International Connection
USA
