Biology subjects

Hurley, E.

Publications and source records attributed to Hurley, E..

2 recordsLinked to original sources

bioRxiv2021

β-Catenin-NFκB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction

Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic knockouts of {beta}-catenin, one with {beta}-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine- supplemented diet. KO2 show gradual liver repopulation with BEC-derived {beta}-catenin- positive hepatocytes, and resolution of injury. KO1 showed persistent loss of {beta}-catenin, NF-{kappa}B activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of {beta}-catenin, NF{kappa}B and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or {beta}-catenin led to NF-{kappa}B activation, DR and inflammation. Thus, we report a novel {beta}-catenin-NF{kappa}B-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF.

pathology↗

bioRxiv2020

mTORC1 and JUN are activated after deletion of Prohibitin 1 in Schwann cells and may link mitochondrial dysfunction to demyelination

Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (Phb1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and JUN are continuously activated in the absence of Phb1, likely due to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and JUN may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria.

neuroscience↗