Author ORCID Identifier
https://orcid.org/0000-0002-5765-2064
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
Dr. Huiping Zhou
Second Advisor
Dr. Rebecca Martin
Third Advisor
Dr. Phillip Hylemon
Fourth Advisor
Dr. Xiang-Yang Wang
Fifth Advisor
Dr. Joseph Landry
Sixth Advisor
Dr. Jasmohan Bajaj
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by multifocal bile duct inflammation, fibrosis, and progression to cirrhosis and liver failure. Currently, there are no effective pharmacological therapies. Although ursodeoxycholic acid has been used to improve bile flow, it does not alter disease course or prevent the need for liver transplantation, which carries a recurrence rate of up to 30%. A deeper understanding of the cellular and molecular mechanisms underlying PSC is essential for developing targeted therapies.
This dissertation investigates two key factors in PSC pathogenesis: sex-dependent immune differences and the spatially dynamic and cell specific roles of the long non-coding RNA H19, which has been shown to exacerbate PSC progression. Using the Mdr2 knock out (Mdr2KO) mouse model, a retrospective human cohort analysis (TriNetX), spectral flow cytometry, immunohistochemistry, and qRT-PCR, we identified several sex-specific immune alterations that may contribute to the disparity in PSC incidence and progression between males and females.
In parallel, we explored H19-mediated transcriptional changes using single-nucleus RNA sequencing (snRNAseq) and spatial transcriptomics (GeoMx Whole Transcriptome Atlas). We found that H19 deletion induces distinct cell-type- and region-specific transcriptional changes in hepatocytes, cholangiocytes, and macrophages. To further understand disease mechanisms, we trained several cell-type specific machine learning models that accurately predict healthy vs. disease-associated cell states (all AUCs > 0.87 when tested against a public human dataset) and classified H19-associated transcriptional changes across several cell types.
To expand spatial insights, we developed a novel computational package for predicting protein-level ligand-receptor interactions between cell types in segmented spatial transcriptomic datasets, including GeoMx. Finally, we conducted an independent analysis of serum bile acid pool alterations across the spectrum of alcohol-associated liver disease (ALD) using targeted LC-MS/MS.
Together, these studies provide new insights into the immune, transcriptional, and spatial regulators of liver disease progression, with a focus on PSC, offer new computational tools for future spatial liver research, and identify the significance of bile acid metabolism in ALD.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
11-14-2025