Chunyue Yin, PhD's head shot. Alexander Miethke, MD's head shot.Principal Investigators: Chunyue Yin, PhD & Alexander Miethke, MD
Key Personnel: Alexander Valencia, PhD, Shiva Kumar Shanmukhappa, DVM, PhD, Kejian Zhang, MD, MBA

The main function of the liver is to remove toxins and aid in digestion by producing bile which contains bile salts, cholesterol, and various biological wastes. Patients with impaired bile flow have a condition called cholestasis, which results in itching and jaundice that may progress to liver scarring and failure. Medical therapy for cholestasis, and syndromes associated with cholestasis, is often unavailable and many children require liver transplantation. The ability to establish a molecular diagnosis is critical for individualized therapy in children with chronic cholestasis. Over the years, researchers have identified five commonly mutated genes in inherited chronic cholestasis. However, our understanding of the biological function of these known mutations is far from complete. Moreover, more than 70% of the patients do not have mutations in these genes and thus still lack a molecular diagnosis.

To address these urgent issues in the field, we will:
1) perform next-generation sequencing on eight patients with cholestasis to identify new candidate mutations
2) generate zebrafish mutants that carry the same mutations and determine whether and how they impair the bile ducts and bile flow
3) confirm our findings from the zebrafish study in patient’s tissues.

Our research has the potential to transverse the cycle from identifying patients with chronic liver disease to finding the underlying mutations, to validating the mutations in animal model, then to going back to patient diagnosis and care. It can lead to the development of novel diagnostic testing and individualized therapies that are suitable for commercialization. Collectively, advances in understanding of cholestatic diseases will decrease the health costs, and enable personalized treatment to save livers and lives.