Liver Diseases - Drug Discovery and Development Based on Quantitative Systems Pharmacology (QSP)

We are fully integrating human liver microphysiology systems (MPS) designed to recapitulate the human liver acinus as an advanced experimental model for use in the QSP approach for developing repurposed and novel therapeutics for non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), type 2 diabetes (T2D). The human experimental models are combined with computational biology to infer pathways of disease progression from patient RNASeq data and then to predict drugs that have the potential to halt or reverse the disease progression. A computational model of NAFLD disease progression is under development. We also have a new effort to address drug induced liver injury (DILI) coupling our experimental model with a commercial computational model.

Human vascularized liver acinus microphysiology system (vLAMPS) under flow with two compartments: the vascular channel with liver sinusoidal endothelial cells (LSECs) and Kupffer cells; and the hepatic chamber separated from the vascular channel by a PET membrane and containing hepatocytes and Stellate cells. Primary cells and induced pluripotent stem cells (iPSCs) are employed. Immune cells, other circulating cells, as well as molecular factors are delivered to the liver acinus through the vascular channel.

We take advantage of the long history of liver biology and clinical practice at Pitt and UPMC, exemplified by the Pittsburgh Liver Research Center (PLRC) directed by Satdarshan (Paul) Singh Monga, MD, which integrates research and clinical activities in liver diseases. Paul is also an associate director of the UPDDI along with Ivet Bahar, PhD, Chair of the Department of Computational and Systems Biology. The UPDDI has NIH funded programs to develop human liver MPS to model NAFLD and T2D as critical elements of the metabolic syndrome, with strong clinical inputs from Erin Kershaw, MD, Chief of the Division of Endocrinology and Metabolism, Department of Medicine, Jaideep (Jai) Behari, MD, PhD, Director of the UPMC “FLOW” Center (NAFLD Clinic), Department of Medicine, Vijay Yechoor, MD, Division of Endocrinology and Metabolism, Department of Medicine and Ramon Bataller, MD, PhD, Division of Gastroenterology, Hepatology and Nutrition (AFLD Program), Department of Medicine. Key faculty also include Alex Soto-Gutierrez, MD, PhD, Department of Pathology and the McGowan Institute of Regenerative Medicine, Ipsita Banerjee, PhD, Department of Chemical and Petroleum Engineering (Biomedical Engineering), for coupling the liver to a pancreatic islets chip, Lauren Kokai, PhD, Department of Plastic Surgery and co-Director of the Adipose Stem Cell Center, to couple the liver with a white adipose tissue chip, as well as Albert Gough, PhD, Larry Vernetti, PhD, Timothy Lezon, PhD and Mark Miedel, PhD all from the Department of Computational and Systems Biology and the UPDDI. We also have established collaborations with faculty at Carnegie Mellon University in the Biomedical Engineering Department.