Date of Award

2022

Embargo Period

8-13-2027

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Don C. Rockey

Second Advisor

Antonis Kourtidis

Third Advisor

Carol Feghali-Bostwick

Fourth Advisor

Robin C. Muise-Helmericks

Fifth Advisor

Stanley Hoffman

Sixth Advisor

Stephen Duncan

Abstract

Cirrhosis, the final stage of liver fibrosis, is one of the leading causes of death in the United States and worldwide. Its pathogenesis revolves around repeated cycles of injury, inflammation, and the wound healing response, which ultimately cause fibrosis and end-organ dysfunction. Historically, fibrosis and cirrhosis were viewed as irreversible, but current evidence suggests otherwise. Studies have identified the hepatic stellate cell (HSC) as the primary effector of liver fibrosis. Of mesenchymal origin, HSCs are “quiescent” in normal liver, but after injury, they transform to an “activated” state by transdifferentiating into extracellular matrix (ECM)-secreting myofibroblasts. Given the evidence that the HSC is the effector cell in liver fibrosis, it is critical to better understand the mechanisms leading to its activation and its function during this process. Although compounds targeting HSC activation have been promising in animal models, none have been translated to the clinic. Thus, there is an ongoing need for research to better understand HSC biology. Our laboratory investigates the process of HSC activation by focusing on the link between the extracellular matrix (ECM), and the cytoskeleton, which are connected by transmembrane receptors called integrins and multiprotein complexes termed focal adhesions (FAs). Since integrins are important in HSC activation and fibrogenesis, we hypothesized that paxillin, a key downstream effector in integrin signaling, may be critical in the process of HSC activation and liver fibrosis. Using a cell-culture based model of HSC activation and two in vivo models of liver injury, we have shown that paxillin is upregulated in activated HSCs. Overexpression of paxillin in vitro augmented functional phenotypes associated with HSC activation, including increased cell migration, proliferation, attachment, and ECM production (particularly type I collagen). Adenoviral-mediated delivery of paxillin in vivo revealed that paxillin overexpression drives increased fibrosis compared to control mice. Mechanistically, we show that paxillin stimulates actin polymerization and ERK activation, eventually causing an increase in type I collagen expression. The results in this thesis highlight a novel role for paxillin in HSC biology and liver fibrosis and provide a potential mechanism by which paxillin regulates HSC activation.

Rights

All rights reserved. Copyright is held by the author.

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Available for download on Friday, August 13, 2027

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