Liver Diseases

Application of biomimetic human liver microphysiology systems (MPS) and quantitative systems pharmacology (QSP) to the development of novel therapeutics for metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and type 2 diabetes (T2D).

We are fully integrating a biomimetic human liver microphysiology system (MPS) designed to recapitulate the human liver acinus as an advanced experimental model for use in the quantitative systems pharmacology (QSP) approach for addressing complexity and heterogeneity and for developing repurposed and novel therapeutics for metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and type 2 diabetes (T2D). We are part of an NIH-funded “clinical trials on a chip (CToC)” precision medicine program coupling the use of liver MPS (patient biomimetic twins (PBTs) with patient-derived iPSC liver cells as a platform for precision therapy to develop MASLD/MASH therapeutics for specific patient cohorts as well as implementing a coupled liver-pancreatic islet platform to study the high comorbidity between MASLD/MASH and T2D. The goal is to harness our coupled QSP and MPS platform and utilize computationally predicted drugs and their combinations as mechanistic probes to modulate key disease phenotypes, providing mechanistic insight into the role disease heterogeneity has in clinically relevant pathophysiology. Biologic drugs now make up more than 50% of the pharmaceutical market. We have initiated a project to evaluate biologic drugs in our MPS biomimetic model by coupling the experimental data with a commercial computational simulation of clinical exposure to identify liabilities of biologic drug-induced liver injury and provide mechanistic insights into observed liver safety signals.

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. The UPDDI has NIH funded programs to develop human liver MPS to model MASLD/MASH 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 (MASLD 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 (MetALD 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.

Healthy and Type 2 Diabetes in the liver- pancreatic islets axis.

Click here and include “Liver Models” in the Additional Gift Instructions to support development of human liver models for research and development of therapies for MASLD, MASH and T2D.