Project 458758

Primary sclerosing cholangitis (PSC) is a rare autoimmune liver disease that is characterized by the scarring and narrowing of the bile ducts, ultimately resulting in the retention of bile and a continuous cycle of inflammation in the liver. There is currently no successful treatment or early diagnostic biomarker for PSC. This means that at the time of diagnosis, the disease is often in very progressed states, wherein the only course of action is liver transplantation, and recurrence of PSC is not uncommon. Patients with PSC experience greater risks of developing malignancies and secondary illnesses, such as bile duct cancer and extensive scarring of liver tissue. The underlying mechanism of development is currently not understood, but studies have illustrated that genetics, sex, and inflammatory bowel disease are correlated with PSC onset. We will use cutting-edge technologies and computational biology to map the landscape of the diseased liver of PSC patients at the single-cell level in order to characterize the gene expression profiles of immune and non-immune cells. As a reference, we will be comparing the PSC liver map to that of alternative liver diseases, and donated healthy human livers. It is essential to consider the fact that the dysregulation of macrophages, a class of immune cells involved in promoting and inhibiting inflammation, has been repeatedly implicated in hepatic diseases. However, their role in the development of PSC has not yet been elucidated. To investigate the role of macrophages in PSC pathogenesis, we will employ an animal model that recapitulates the human PSC liver landscape, and evaluate the use of nanoparticles to reprogram macrophages to promote healing and regeneration of the diseased liver. Thus, our data will provide ground-breaking insight into the PSC environment and the mechanisms of disease, as well as pave the way for novel therapeutic development that may lessen the need for liver transplantation.