The integrity and function of the exocrine pancreas depends on Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) expression in acinar cells.

• Applicant: Professor Dr. Roland M. Schmid
• Subject Area: Gastroenterology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438609576

Cystic fibrosis (CF) is a frequent inherited autosomal recessive disease caused by mutations and dysfunction in the chloride channel CFTR. In the pancreas CFTR is mainly expressed in duct and centro-acinar cells as well as weakly in acinar cells. It is generally believed that the ductal compartment is relevant for the pathophysiology in the pancreas. Almost all patients with CF develop impaired pancreatic function and late stage chronic pancreatitis with pancreatic insufficiency. In addition, there is an association of idiopathic chronic pancreatitis and CFTR mutations. The dogma states the acinar cells are destroyed due to highly viscous pancreatic secretion which causes ductal obstruction. Our preliminary data demonstrate that mice with selective inactivation of the Cftr gene in the pancreas (CftrΔpanc) display maldigestion and malabsorption when exposed to a high fat diet without visible morphological alterations in the pancreas and no signs of pancreatic duct obstruction. Therefore, we postulate a novel so far unknown function of CTFR in acinar cells. Experimental acute pancreatitis takes a more severe course in CftrΔpanc mice with more necrosis and inflammation as well as impaired regeneration with increased acinar-ductal metaplasia. In vitro acini of CftrΔpanc mice display increased spontaneous acinar-ductal metaplasia indicating that the novel unknown function of CFTR in acinar cells is cell autonomous.In the present grant proposal, we will use genetically defined model systems to analyze the effect of CFTR deficiency on pancreatic function and the course of pancreatitis in vivo in acinar cells and duct cells, respectively. The cell autonomous function of CFTR in acinar cells will be characterized in vitro. (i) To investigate whether the observed effects are caused by CFTR deficiency in duct or acinar cells, we will inactivate CFTR using the Cre/lox system in duct or acinar cells and expose these mice to a high fat diet. These experiments will define whether fat-maldigestion and –absorption is caused be impaired duct or acinar cell function. (ii) We will induce experimental pancreatitis with cerulein. These experiments will clarify whether CFTR deficiency in the duct or acinar cells contribute to the phenotype of acute pancreatitis.(iii) We will analyze whether CFTR blocks the expression of pro-inflammatory cytokines in acinar cells. We will use ATAC and RNA-seq analysis to identify chromatin changes associated with the increased expression of pro-inflammatory cytokines in acinar cells in respect to CFTR.(iv) Using ATAC and RNA-Seq analysis we will characterize signaling pathway identified with gene signatures by using pharmacological inhibitors to block spontaneous ADM formation of CFTR deficient acinar cells. These experiments will expand our knowledge and our mechanistic understanding of pancreatic damage caused by CFTR mutations and will finally allow the development of novel treatment strategies.

• DFG Programme: Research Grants