Natalie Holman

Research Mentor:

Ed LeCluyse

Clinical Co-mentor:

Paul Watkins

Home Department Toxicology
Project Description Drug-induced liver injury (DILI) remains a major problem in drug safety, impacting patients, physicians and the pharmaceutical industry. Many such reactions are idiosyncratic and poorly understood. To prevent DILI and reduce patient harm, a greater understanding of the pharmacological mechanisms that underlie DILI is needed. Growing evidence suggests that while an initial response begins at the hepatocyte level, communication with the immune system is essential for propagating DILI. We hypothesize that extracellular vesicles called exosomes act as heralds of hepatocellular stress to modulate this reaction. Hepatocyte-derived exosomes (HDE) are capable of immune cell regulation, and we have shown that the number and content of circulating exosomes change significantly during DILI in vivo. Thus, the current project seeks to establish a novel mechanism by which exosomes released from drug-treated hepatocytes can signal to neighboring immune cells and propagate a DILI reaction. To gain specific mechanistic information, we will use a series of in vitro methods to assess the role of rat and human HDE in early DILI events. The objective of this research is to use primary rat and human hepatocytes to demonstrate the following: that HDE release precedes liver injury; HDE relay hepatocellular perturbation signals; and, other relevant cell types in DILI are responsive to HDE. By informing the human relevance of HDE in intrinsic DILI, this work will facilitate evaluation of HDE as a means to predict and explain idiosyncratic DILI.