The liver is the largest internal organ, accounting for approximately 2-3% of the average body weight, and is involved in a variety of important functions such as digestion, metabolism, detoxification, production of vital proteins, coagulation, and immune response. Understanding the complex anatomy and physiology of the liver has been a long-standing challenge for scientists and physicians who struggle to identify underlying causes for many types of liver disease. There are over 100 types of liver disease with different risk factors that can lead to cirrhosis and liver failure. To better understand the physiology of the liver and the pathogenesis of various types of liver disease, I have applied novel systems biology approaches to investigate the mechanisms of liver regeneration and pathologies.
In Chapter 1, I investigated the priming phase of liver regeneration in the complement-knockout mice. The complement system, part of the innate immune system, has been recently shown to successfully promote the early phase, or priming phase, of liver regeneration, during which complex regulation of signaling pathways and other molecular events occur. To better understand the role of the complement system in this complex biological process, I analyzed transcriptomic and metabolomic measurements during the several time points of the priming phase of liver regeneration to identify novel biomarkers and relevant biological pathways. I also supplemented the results with protein-protein interaction network, correlation analysis, and literature knowledge to derive a comprehensive mechanism.
In Chapters 2 and 3, I investigated the complex pathogenesis of biliary atresia, a rare disease of the liver and the bile ducts. Biliary atresia has unknown etiologies and multiple disease forms based on the heterogeneous phenotypes that are difficult to diagnose. To better elucidate the pathogenesis of this disease, I analyzed different high-throughput molecular data such as genome-wide association study, mRNA sequencing, target genome sequencing, and whole exome sequencing. I also integrated novel biomarkers from these datasets with a protein-protein interaction network to reconstruct a disease specific network that is both highly interpretable and enriched in important biological functions, including inflammation, immunity, fibrosis, and development.