Cholangiopathies - Nicholas F. LaRusso

Programs

Dr. LaRusso's Cholangiopathies Laboratory has two major parallel programs focused on cholangiocyte pathobiology, each supported by an R01 grant from the National Institute of Diabetes and Digestive and Kidney Diseases.

Cyst and cystic diseases

One program of the Cholangiopathies lab is cholangiociliopathies, a group of incurable genetic diseases manifesting as biliary cysts with or without fibrosis. Autosomal recessive and autosomal dominant polycystic kidney disease are two examples of cholangiociliopathies that the lab studies.

The Cholangiopathies lab has shown that:

• Cholangiocyte cilia are mechano-, chemo- and osmo-sensors.
• Exosomes (biliary vesicles derived from cholangiocyte multivesicular bodies, or MVBs) interact with cilia, triggering changes in cAMP that affect expression of selected microRNAs (miR-15a).
• Cystic cholangiocytes from the PCK rat, a model of ARPKD, have increased cAMP, decreased miR-15a, overexpressed Cdc25A (a cell cycle protein targeted by miR-15a) and increased Hedgehog (Hh) components (Ptc, Smo and Gli-2).
• Pharmacologic reduction of cAMP and upregulation of miR-15a with accompanying decrease of Cdc25A inhibits cell proliferation and cyst growth in vitro; in PCK rats, octreotide reduces cholangiocyte cAMP and inhibits hepatic cystogenesis.

Microbial infections

The second program of the Cholangiopathies lab is the interaction between cholangiocytes and Cryptosporidium parvum (C. parvum), an emerging pathogen that causes intestinal and biliary cryptosporidiosis.

Recent evidence from the Cholangiopathies lab indicates that:

• The cellular expression and regulation of key receptors (toll-like receptors, or TLRs) and specific intracellular signaling pathways (NF-kB activation) are involved in cholangiocyte C. parvum recognition and strategic defense.
• Endogenous microRNA (miRNA)-mediated post-transcriptional gene regulation is involved in cholangiocyte defense responses to C. parvum infection.