REDEFINING BILIARY ATRESIA: INTEGRATIVE MODELS AND METHODOLOGIES Restricted; Files Only
Hellen, Dominick (Spring 2024)
Abstract
Biliary atresia (BA) is the most prevalent serious liver disease of infancy, presenting as a fibroinflammatory erasure of the extrahepatic bile duct and rapidly progressing intrahepatic cholangiopathy. Without effective non-surgical therapies, a confirmed etiology, or agreed upon preclinical models, BA is a devastating pediatric disorder with multiple unmeet needs. Addressing these concerns, and led by exome analyses of BA patients, we hypothesized that ciliary genetic perturbations in murine developing cholangiocytes could induce a spectrum of phenotypes that are observed in BA. ARC 1 of this thesis focused on characterizing the developmental, adult, and obstructive phenotypes in livers deficient in the ciliary BA candidate gene; Pkd1l1. Initiated by these findings, ARC 2 outlines the first comprehensive machine-learning platform for quantification of biliary forms, expanding the analyses of Pkd1l1-deficient livers, and several other cholangiopathy models. ARC 3 introduces several new ciliary BA candidate genes, validated through in vitro knockdown within intra- and extrahepatic cholangiocyte organoids. Illustrated in ARCs 1 & 2, the first genetic-based model of BA, the Pkd1l1 liver-restricted deletion mouse, has developmental bile duct paucity, adulthood peribiliary fibroinflammation, and significant exacerbations in the presence of obstruction. In ARC 3, divergent morphological phenotypes were observed within cholangiocyte organoids deficient in the new ciliary BA candidate genes. Selectively, each ciliary candidate gene, those from ARCs 1-3, resulted in a distinct injury to cholangiocyte cells that could initiate disease. This thesis redefines BA as a developmental cholangiopathy, induced, in part, by genetic perturbations in specific ciliary genes essential for biliary tree morphogenesis.
Table of Contents
CHAPTER I. INTRODUCTION
1
CHAPTER II. LIVER-RESTRICTED DELETION OF THE BILIARY ATRESIA CANDIDATE GENE INDUCES BILE DUCT DYSMORPHOGENESIS AND CILIOPATHY
48
CHAPTER III. BiliQML: A supervised machine learning model to quantify biliary forms from digitized whole-slide liver histopathological images
90
CHAPTER IV. ROLES FOR Pkd1l1 IN PATHWAYS MAINTAINING BILIARY MATURATION
133
CHAPTER V. MULTIPLE GENETIC PATHWAYS LEADING TO THE BILIARY ATRESIA PHENOTYPE
162
CHAPTER VI. DISCUSSION
184
CHAPTER VII. OTHER NOTABLE WORK
197
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File download under embargo until 22 May 2026 | 2024-05-06 11:08:23 -0400 | File download under embargo until 22 May 2026 |
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