902C Abramson Research Building 3615 Civic Center Blvd

Genetic liver disease
Biliary atresia
Metabolic liver disease

Liver disease
Biliary atresia
Zebrafish models of disease
Hepatobiliary development

The Matthews laboratory is interested in the pathogenesis of various pediatric liver diseases, using zebrafish as a model organism. Specifically, we are interested in cholestatic diseases such as biliary atresia, and hepatic diseases such as non-alcoholic steatohepatitis (NASH) and other causes of liver steatosis. While NASH is certainly not limited to children, it is becoming an increasingly important disorder in pediatrics.

Several liver diseases, including biliary atresia, affect only infants, suggesting that developmental processes may be important in disease pathogenesis. Thus, a greater understanding of liver development will help us understand these disorders. We have noted that epigenetic defects are associated with biliary atresia and with abnormal biliary development, and we are very interested in understanding the contribution of the epigenome to biliary development. We have also noted an importance of multiple polarity pathways in normal biliary development and in disease pathogenesis, and we are interested in studying the role of cell polarity in biliary development and disease.

We have established several NASH models in zebrafish, and we are studying the influence of multiple pathways on the pathogenesis of NASH. In the near future, we hope to take advantage of the zebrafish system to perform small molecule screens on our NASH models, and we will perform similar studies on our cholestatic models. Such studies could uncover novel treatments for these disorders and further our understanding of pathogenesis.

Adjunct Assistant Professor of Pediatrics at University of Pennsylvania School of Medicine (2014 – 2015)
Assistant Professor of Pediatrics at University of Pennsylvania School of Medicine (2005 – 2014)
MD, University of Washington (1998)
PhD, Pharmacology, University of Washington (1996)
BS, Chemistry; Cell & Molec. Biol, University of Michigan (1990)
Selected Publications
Steven F. Eauclaire, Shuang Cui, Liyuan Ma, James Matous, Florence L. Marlow, Tripti Gupta, Harold A. Burgess, Eliott W. Abrams, Lee D. Kapp, Michael Granato, Mary C. Mullins, and Randolph P. Matthews.. Mutations in vacuolar H(+)-ATPase subunits lead to biliary developmental defects in zebrafish.. Dev Biol. Vol 365(2) . 2012 May:434-444.
Shuang Cui, Louis M. Capecci, Randolph P. Matthews*. Disruption of planar cell polarity activity leads to developmental biliary defects. Dev Biol. Vol 351(2) . 2011 March:229-241.
Shuang Cui, Jessi Erlichman, Pierre Russo, Barbara A. Haber, and Randolph P. Matthews*. Intrahepatic biliary anomalies in a patient with Mowat-Wilson syndrome uncover a role for the zinc finger homeobox gene zfhx1b in vertebrate biliary development. J. Pediatr. Gastroenterol. Nutr.. Vol 52(3) . 2011 March:339-344.
Randolph P. Matthews*, Steven F. EauClaire, Monica Mugnier, Kristin Lorent, Shuang Cui, Megan M. Ross, Zhe Zhang, Pierre Russo and Michael Pack. DNA hypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia. Hepatology. Vol 53(3) . 2011 March:905-14.
Cullinane, A.R., Straatman-Iwanowska, A., Zaucker, A., Wakabayashi, Y., Bruce, C., Luo, G., Rahman, F., Gurakan, F., Utine, E., Ozkan, T.B., Denecke, J., Vukovic, J., Di Rocco, M., Mandel, H., Cangul, H., Matthews, R.P., Thomas, S.G., Rappoport, J., Arias, I.M., Wolburg, H., Knisely, A.S., Kelly, D.A., Mueller, F., Maher, E.R., and Gissen, P.. Mutations in VIPAR lead to arthrogryposis, renal dysfunction, cholestasis (ARC) syndrome via defects in epithelial polarization. Nat Genet. Vol 43. 2010 April:303-312.
Matthews RP, Lorent K, Mañoral-Mobias R, Huang Y, Gong W, Murray IV, Blair IA, Pack M. TNF{alpha}-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase.. Development. Vol 136. 2009 March:865-875.
Hand, N.J., Master, Z.R., EauClaire, S.F., Weinblatt, D.E., Matthews, R.P., and Friedman, J.R.. The microRNA-30 family is required for vertebrate hepatobiliary development. Gastroenterology. Vol 136. 2009 March:1081-1090.
Matthews RP, Plumb-Rudewiez N, Lorent K, Gissen P, Johnson CA, Lemaigre F, Pack M.. Zebrafish vps33b, an ortholog of the gene responsible for human arthrogryposis-renal dysfunction-cholestasis syndrome, regulates biliary development downstream of the onecut transcription factor hnf6.. Development. Vol 132. 2005:5295-5306.
Lorent K, Yeo SY, Oda T, Chandrasekharappa S, Chitnis A, Matthews RP, Pack M.. Inhibition of Jagged-mediated Notch signaling disrupts zebrafish biliary development and generates multi-organ defects compatible with an Alagille syndrome phenocopy.. Development. Vol 131. 2004:5753-5766.
Matthews RP, Russo P, Berry GT, Piccoli DA, Rand EB.. Biliary atresia associated with a fatty acid oxidation defect.. J Pediatr Gastroenterol Nutr. Vol 35. 2002:624-628.
Matthews RP, Lorent K, Russo P, Pack M.. The zebrafish onecut gene hnf-6 functions in an evolutionarily conserved genetic pathway that regulates vertebrate biliary development.. Dev Biol. Vol 274. 2004:245-259.