Romina Fiorotto, PhD

Project Title: Mechanisms of vascular Dysfunction in Cystic Fibrosis-related Liver Disease

Cystic fibrosis-associated liver disease (CFLD) affects up to 30% of patients with cystic fibrosis (CF). A severe form of portal hypertension in the absence of cirrhosis, characterized by obliterative portal venopathy, has recently been described in CF patients undergoing liver transplantation. Recent work has shown that endothelial cells do express CFTR, however, the pathogenetic mechanism of non-cirrhotic portal hypertension in CF is unknown. Moreover, our preliminary data show that CFLD is linked to intestinal dysbiosis. The hypothesis of this project is that vascular dysfunction in CFLD results from an increased inflammatory reaction to gut-derived bacterial products in the endothelial cells of the portal vein radicles. This project aims at understanding the mechanisms leading to the portal vascular dysfunction in CF and how defective CFTR function affects the physiology of the endothelium. Single cell transcriptomics will be used to characterize the portal inflammation and endothelial damage in CFTR-defective mice. In vivo treatments will be used to evaluate how modulation of the gut microbiota and intestinal permeability could prevent the vascular damage. We will also use human induced pluripotent stem cells-derived endothelial and biliary cells to understand the function of CFTR in the endothelium and the relationship between endothelial cells and the biliary epithelium. This project is designed to unveil the presence of pathogenetic cross talk mechanisms between biliary and endothelial cells that are activated in response to gut-derived factors and possibly causing liver vascular disease in patients with CF.