Project 1: Pathobiology of Hepatic Epithelia
The long-term objective and specific aim of this project in Dr. LaRusso's Cholangiopathies lab is to test the central hypothesis that normal sensory and transducing activities of cholangiocyte cilia are disrupted in cystic liver disease, leading to altered intracellular signaling and modified miRNA expression, resulting in cholangiocyte hyperproliferation, ductal dysmorphogenesis and hepatic cyst formation.
The specific aims of the hepatic epithelia project are to test three hypotheses:
- Biliary exosomes bind to cholangiocyte cilia with involvement of polycystin 1 (mutated in ADPKD) with or without fibrocystin (mutated in ARPKD), affecting intracellular signaling (cAMP, Hh) and miRNA expression (miR-15a).
- In cystic cholangiocytes, elevated cAMP reduces expression of miR-15a via transcriptional activation of the CREB-ICER-CRE pathway, causing miR-15a target proteins (Cdc25A, Ptc, Erk1) to increase, leading to hyperproliferation.
- Pharmacologic targeting of MEK, Smo and Cdc25A, components of the cAMP, Hh, and cell cycle machinery, respectively, inhibits cholangiocyte hyperproliferation in vitro and reduces hepatic cystogenesis in vivo in rodent models of ARPKD and ADPKD.