Paul Monga, MD*
Paul Monga, MD*
S422 Biomedical Science Tower
200 Lothrop Street
Pittsburgh, PA 15261
Research: Current research projects are aimed at elucidating the cellular and molecular mechanisms of liver pathophysiology. We are interested in understanding the process of liver regeneration. Using genetic knockout (inducible, conditional) we are in the process of determining the cell-molecule circuitry of the Wnt signaling during liver regeneration process. Similarly, we are interested in the regulation of the process of metabolic zonation where hepatocytes in different zones of the hepatic lobule are bestowed with different functional capacities owing to the differential gene expression. The pericentral gene expression is under the control of Wnt signaling, and the periportal gene signature has been suggested to be under the control of Yap signaling. This process of dynamic interactions between the two signaling pathways is also under investigation. Since hepatic repair after various injuries is dictated by the kind of injury and type of cell affected, several studies have shown the potential of hepatocytes and biliary epithelial cells to transdifferentiate into one another. We are examining the models and the molecular mechanisms that underlie these processes so as to exploit them for regulating repair process. A major sequela of multiple chronic liver diseases is in fact development of hepatic fibrosis. This involves in large part activation of hepatic stellate cells to form activated myofibroblasts, which are the source of collagen and scarring in the liver with the eventual development of cirrhosis. We are examining molecular signals that are relevant in stellate cell activation and biology, which can be targeted for development of anti-fibrotic therapies. Similarly, we are interested in role of macrophages in hepatic injury and repair process and their crosstalk with stellate cells. A common form of hepatic injury is cholestatic, where there is an impairment of bile flow in the liver causing retention of bile acids and injury to hepatic parenchyma as well as breach of blood bile barrier that results in bilirubin and bile acid leaking into systemic circulation. Using animal models, we are looking at novel ways to modulate bile acid metabolism to counteract cholestatic liver injury and repair. Similarly, we are investigating novel mechanisms that underlie the pathogenesis of various cholestatic liver diseases. We have identified the important role of adherens junctions, tight junctions, and desmosomes in maintenance of blood bile barrier through unique mechanisms and crosstalk. We have generated animal models to address such mechanisms and using innovative imaging methodologies like intravital microscopy, we have identified peculiar underpinnings of disorders such as PFIC. We hope to devise novel therapeutic interventions based on new findings. Lastly, we are interested in another relevant sequela of many chronic liver diseases. Liver tumors—especially hepatocellular cancer—develops mostly in the backdrop of chronic liver injury. We are interested in identifying patient-relevant molecular aberrations, and using a reductionist approach, we generate animal models to address biology and therapies. We use sleeping beauty transposon/transposase and hydrodynamic tail vein injections to deliver the plasmids into 1-5% of hepatocytes in a mouse to examine tumorigenesis. Using high throughput analysis of tumors (gene array), we are addressing gene expression changes, which are then correlated with existing human HCC databases, such as TCGA, to address the similarity of the animal model to the human disease. Such validation allows us to more confidently use this model as a representative of a subset of human HCC. Such approaches have also yielded novel information about other liver tumors like hepatoblastomas.
- Collaboration with Dr. Sarangarajan Ranganathan on the Wnt/beta signaling pathway and more recently on the interactions with YAP (NIH funded).
- Collaborating with Dr. Prithu Sundd’s lab to use multi-photon-excitation (MPE) enabled intravital fluorescence microscopy of the liver in live mice to identify the molecular mechanism of blood-bile barrier failure during cholestasis and liver injury.
- Collaboration with Dr. Kari Nejak-Bowen on the role of the Wnt/beta signaling pathway in cholestatic liver diseases, especially in hepatobiliary repair and transdifferentiation.
- Collaboration with Dr. Lans Taylor on applying QSP and the human liver-on-a-chip to explore the mechanisms of hepatocarcinoma disease progression.
- Collaboration with Dr. George Michalopoulos on molecular mechanisms of liver regeneration.
- Collaboration with Dr. Edward Prochownik on the role of Myc in hepatoblastoma.
- Collaboration with Dr. Alex Soto-Gutierrez on the role of beta-catenin mutation in iPS-derived human hepatocytes.
- Collaboration with Dr. Michael Oertel for LCM and imaging of tumors.
- Collaboration with Dr. Nahed Ismail on the Wnt/beta signaling pathway in primary macrophages, hepatocytes, and in vivo following infection with Ehrlichia species that target liver and causes extensive liver injury.