Liver fibrosis caused by excessive alcohol consumption, viral hepatitis, autoimmune diseases and non-alcoholic steatohepatitis (NASH) can progress to cirrhosis and its multiple complications, and represents a massive health care burden worldwide. It is characterized by aberrant signaling by growth factor receptor tyrosine kinases (RTKs) and Gi-coupled chemokine/cytokine family of GPCRs, e.g., the CCRs), incited by chronic injury/inflammation, causing excessive deposition of extracellular matrix, mainly produced by activated hepatic stellate cells (HSCs). In response to fibrogenic stimuli, quiescent HSCs transform into a collagen- producing myofibroblast-like cell. A key profibrotic trigger for this critical transformation is the PI3K-Akt pathway, whereas a key antifibrotic stimulus is cAMP. The PI3K-Akt pathway is also critical for chemotaxis of KCs, which play another set of critical role in liver fibrosis. The precise mechanism(s) that coordinately drives unrestricted PI3K-Akt signaling and simultaneously reduces cAMP downstream of these diverse classes of receptors culminating into liver fibrosis remains unknown. Recently a novel signaling complex comprised of G protein subunit, G?i and GIV, its non-receptor GEF has been identified, which inhibits cAMP production, and enhances PI3K-Akt signals initiated by both growth factor receptor receptors and GPCRs. It is hypothesized that these signaling programs driven by the GIV-Gi signaling axis activates HSCs and KCs and drives liver fibrosis, and that inhibiting this axis may halt and reverse fibrosis. To test this hypothesis, the expression, posttranslational modifications and G-protein binding properties of GIV will be investigated during the course of acute and chronic liver injury in murine models and in clinical samples from human subjects (Aim 1);GIV's impact on liver fibrosis and pro- and antifibrotic signaling programs in HSCs and KCs downstream of fibrogenic receptors, e.g., TGF?R, PDGFR and CCRs and on cellular processes e.g., collagen production, apoptosis, chemotaxis, and proliferation will be interrogated by inducing liver injury in wild-type and HSC/KC-specific GIV- /- mice and HSCs/KCs isolated from them, respectively (Aim 2);if the Gi-GIV complex is required for liver fibrosis, and whether targeted inhibition of the Gi-GIV interface could serve as a strategy to inhibit and/or reverse fibrosis will be interrogated in murine models of cirrhosis using highly specific small molecule inhibitors of the interface for targeted disruption of the functional complex in the liver (Aim 3); and finally, whether the abundance of GIV in liver biopsies can predict the progression to cirrhosis and thereby, serve as a prognostic marker will be evaluated in a historic cohort of human subjects with chronic viral hepatitis who had a variable time-line to advanced fibrosis and cirrhosis (Aim 4). Insights gained will elucidate the role of this novel Gi-GIV signaling complex i liver fibrosis from a molecular and cellular level, to whole animal level, and finally, to the leve of its broader implications in a human liver cirrhosis, and help determine if the complex could serve as a marker and as a therapeutic target, thereby presenting an opportunity for personalized medicine.
Liver fibrosis and its end stage, cirrhosis, represent a massive health care burden worldwide and identification of key signaling molecules that can be effectively exploited to alter the course of all-cause liver fibrosis remains the cornerstone of developing targeted molecular therapy against cirrhosis. The overall goal of the studies planned in this application is to expose how hepatic stellate cells, the major culprit in orchestrating livr fibrogenesis, utilize the G protein pathways to intercept signals triggered by multitude of cytokines and growth factors and simultaneously modulate pro- and anti- fibrogenic signaling networks to drive hepatic fibrosis. This study seeks to discover unique G-protein signaling complexes assembled in response to fibrogenic insult which will help decipher, access, and manipulate the stellate cell's complex signaling code, serve as attractive and effective therapeutic targets to arrest/reverse fibrogenesis, and also serve as markers for predicting liver fibrosis.
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