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An investigation of the Ciliary Protein PKHD1 in Cyst development in liver disease: clues to the pathogenesis of Biliary Atresia

Blair-Reid, Sarah Alexandra (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

Biliary atresia is a common form of paediatric liver disease, with progressive, inflammatory obliteration of the biliary tree, leading to liver failure early in life. Mutations in PKHD1, encoding the ciliary protein fibrocystin, are associated with autosomal recessive polycystic kidney disease (ARPKD), a ciliopathy with clinical features that resemble biliary atresia. The hepatic developmental defects detectable in a significant number of infants with ARPKD are thought to be caused by dysfunction in the structure and function of primary cilia. The pathogenetic mechanism of both disorders is thought to be dysregulation of epithelial cell growth and tubulomorphogenesis. Preliminary investigations uncovered an association of PKHD1 sequence variants in a subset of biliary atresia patients with renal cysts, promoting further investigation to determine the functional role of fibrocystin in epithelial cells from renal and biliary tubules. Immunohistochemical studies, using a monoclonal antibody raised against wildtype fibrocystin, showed that it localises specifically to intrahepatic bile ducts. Absence of fibrocystin staining in end-stage liver tissue reflects ongoing damage to the intrahepatic biliary tree, rather than a phenomenon specific to biliary atresia. Studies utilising the Pkhd1 \(^{del2/del2}\) mouse model of ARPKD revealed 17β-estradiol sensitive centrosomal overduplication underlies the dysregulation of epithelial cell growth in renal tubules, however this does not appear to be in synergy with \(Pkhd1\) knockdown. Therefore, it remains uncertain whether sequence variants of PKHD1 are associated with biliary atresia.

Type of Work:Ph.D. thesis.
Supervisor(s):Afford, Simon C
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of immunity and infection
Subjects:RC Internal medicine
RJ Pediatrics
Institution:University of Birmingham
ID Code:1173
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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