Hello! My name is Sriram and I’m a rising senior majoring in molecular biology and sociology and minoring in chemistry and neuroscience. This summer, I will be conducting research in the Soto-Gutierrez lab through the Brackenridge Fellowship!
My research is focused on modeling a pediatric liver disease using induced pluripotent stem cells (iPSCs). This disease is called progressive familial intrahepatic cholestasis (PFIC) and is estimated to affect 1 in 50,000 to 1 in 100,000 live births. There are five officially recognized types of PFIC, each characterized by mutations in their respective genes, but they all have one thing in common— cholestasis. Cholestasis describes any impairment in the flow of bile from the liver. Some other shared symptoms include jaundice and pruritus, which is an intense itching sensation throughout the whole body. Existing treatments for PFIC focus on symptom management, unable to target the dysfunctional protein leading to cholestasis. Liver transplantation is one potential cure, but each type of PFIC is often associated with its own unique complicating factors.
In my research, I am focusing on PFIC Type 1 (PFIC1), which results from mutations in the ATP8B1 gene. ATP8B1 encodes the protein FIC1, which is an aminophospholipid translocase. This means that it flips specific phospholipids from the outside leaflet to the inside leaflet of the plasma membrane, maintaining the asymmetry of the membrane. The activity of FIC1 is thought to play a protective role in hepatocytes, or “liver cells.” A unique feature of FIC1 is that it is expressed outside of the liver. This means that PFIC1 differs from the other types of PFIC because it is associated with extrahepatic symptoms, or symptoms not associated with the liver. Some of these include diarrhea, sensorineural hearing loss, and exocrine pancreatic insufficiency.
The models that currently exist for PFIC1 are inadequate and do not replicate the same severity of disease observed in human patients. My goal is to create a more accurate model of PFIC1 using stem cell technology in order to further study the mechanisms of this disease. My project uses genetic reprogramming technology in order to generate patient-specific iPSCs from biopsies taken from real PFIC1 patients. These iPSCs can then be differentiated into human induced hepatocytes to study the molecular changes happening within hepatocytes as a result of the dysfunctional FIC1 protein. By using cells derived from patients suffering from the disease, I hope to better model PFIC1 in vitro and lay the groundwork for further studying the mechanisms of this disease.