Hepatic accumlation [sic] of myofibroblastic hepatic stellate cells (MF-HSC) is pivotal in the pathogenesis of cirrhosis. Two events are necessary for MF-HSC to accumulate in damaged livers: 1) transition of resident, quiescent HSC (Q-HSC) to MF-HSC, and 2) further expansion of MF-HSC numbers via increased proliferation and/or reduced apoptosis. Our group has identified two novel mediators of MF-HSC accumulation: Rac1 and Hedgehog (Hh). Recently, we have accumulated evidence that the first event (transition to MF-HSC) involves epithelial-to-mesenchymal (EMT) and shown that Hh signaling promotes EMT in another type of resident liver cell (ie, ductular-type progenitors cells (DPC)). Our earlier publications demonstrate that both Rac1 and Hh promote proliferation of MF-HSC while inhibiting their apoptosis. The general goal of this project is to determine if Rac1 and Hh interact to regulate the accumulation of MF-HSC after liver damage. This project evaluates the HYPOTHESIS that Rac1 promotes the activation of the Hh pathway, thereby stimulating signals that promote epithelial-to-mesenchymal transition in Q-HSC, and that enhance the viability of MF-HSC.
Two Specific Aims will be addressed:
Aim 1 will determine if Rac1 inhibits Hedgehog-interacting protein (Hip) to promote Hh signaling-mediatd [sic] EMT in HSC;
Aim 2 will determine the impact of altering Rac1 activity on Hh pathway activation and liver fibrotic response to toxin-induced liver injury. In both in vitro and in vivo model systems, Rac1 signaling will be manipulated via genetic approaches (eg, adenoviral vector-mediated delivery of constitutively active or dominant negative Rac1) and pharmacologic agents (eg, pathway agonists and antagonists). We hope to delineate a signaling cascade by which the cytoskeletal protein Rac1 interacts with a morphogenic signaling pathway (Hh) to reprogram gene expression in Q-HSC, promoting myofibroblastic transition, and enhancing MF-HSC proliferation and survival.
Hepatic stellate cells are the major population of cells in the liver that promote the scarring process leading to cirrhosis. These cells undergo a transformation from a benign, fat-storing state to one that produces scar when subjected to chronic injury, a critical step in the progression to cirrhosis. We propose to study the interaction of two key contributors, Rac1 and Hedgehog, that promote the transformation and growth of these scar-producing stellate cells.
|Coombes, Jason D; Choi, Steve S; Swiderska-Syn, Marzena et al. (2016) Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis. Biochim Biophys Acta 1862:135-44|
|Coombes, J D; Swiderska-Syn, M; Dollé, L et al. (2015) Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice. Gut 64:1120-31|
|Choi, Steve S; Claridge, Lee C; Jhaveri, Ravi et al. (2014) Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication. Clin Sci (Lond) 126:845-55|
|Xie, Guanhua; Choi, Steve S; Syn, Wing-Kin et al. (2013) Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation. Gut 62:299-309|
|Pereira, Thiago A; Xie, Guanhua; Choi, Steve S et al. (2013) Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni. Liver Int 33:149-61|
|Michelotti, Gregory A; Xie, Guanhua; Swiderska, Marzena et al. (2013) Smoothened is a master regulator of adult liver repair. J Clin Invest 123:2380-94|
|Chen, Yuping; Choi, Steve S; Michelotti, Gregory A et al. (2012) Hedgehog controls hepatic stellate cell fate by regulating metabolism. Gastroenterology 143:1319-29.e1-11|
|Chan, Isaac S; Guy, Cynthia D; Chen, Yuping et al. (2012) Paracrine Hedgehog signaling drives metabolic changes in hepatocellular carcinoma. Cancer Res 72:6344-50|
|Arzumanyan, Alla; Sambandam, Vaishnavi; Clayton, Marcia M et al. (2012) Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. Cancer Res 72:5912-20|
|Romac, Joelle M-J; Shahid, Rafiq A; Choi, Steve S et al. (2012) Pancreatic secretory trypsin inhibitor I reduces the severity of chronic pancreatitis in mice overexpressing interleukin-1? in the pancreas. Am J Physiol Gastrointest Liver Physiol 302:G535-41|
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