Using C. elegans as a Drug-discovery Model for the Childhood Liver Disease Progressive Familial Intrahepatic Cholestasis 3
Year: 2019
Type: dissertation
Abstract: Progressive familial intrahepatic cholestasis 3 (PFIC3) is a rare liver disease with limited treatment options. PFIC3 is caused by mutations in the phosphatidylcholine transporter, ABCB4. ABCB4 transports phosphatidylcholine to the cell surface to alleviate the hepatotoxicity of bile acids. The C. elegans homologue of ABCB4, PGP-14, is a probable phosphatidylcholine transporter whose mutations lead to sphingomyelin deficit in the pharynx. We postulate that sphingomyelin abundance sensitizes wild type worms to hydrophobic nematocidal molecules including wact-190. In my project, I exploited C. elegans pgp-14 mutants to identify drugs that circumvent the loss of phosphatidylcholine transporters. I screened 2,560 compounds and identified three robust suppressors of pgp-14’s wact-190 resistance: terconazole, nicardipine and amiodarone. I found that terconazole alone can suppress the sphingomyelin deficit of pgp-14 mutants. Therefore, terconazole may induce phosphatidylcholine transport in C. elegans. This work has the potential to make an impact on the health of children afflicted with PFIC3.
Source: TSpace (University of Toronto)
Author: Duhyun Han
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3217795159