Hepatic fibrogenesis is mediated by the hepatic sinusoidal stellate cell, the major effector cell in the liver during injury. Disruption of this process, is this application's long-term objective. This will require a detailed understanding of the regulatory steps which transform the HSC, devoid of cytokine receptors into an actively proliferating cell expressing the platelet-derived growth factor beta receptor (PDGFbR) capable of responding to PDGF, which is present in its milieu during injury. The transformed cell then upregulates the expression of the insulin-like growth factor II receptor (IGFIIR), which binds latent transforming growth factor beta (TGF beta). This permits TGF beta to become concentrated and available for activation into active TGF beta, the most potent stimulant of collagen matrix synthesis. During liver injury, HSC also expresses the Type I and Type II TGF beta receptors (TGFbR) and can respond to the active form of TGF beta after IGFIIR expression. A unifying hypothesis is needed to explain the sequence of PDGFbR, IGFIIR and TGFbR gene expression in the HSC which are central factors during liver injury and are likely responsible factors for early fibrogenesis and subsequence cirrhosis. The proposal will examine the causal factors responsible for the enhanced cytokine receptor gene expression and TGF beta pericellular concentration, the key features of fibrogenesis. In vitro studies will be done with HSC to determine the 5' promoter regions involved in regulating baseline and stimulated PDGFbR and IGFIIR and Type I and II TGFbR gene promoter activity. HSC extracts will be contrasted between quiescent HSC and HSC activated in vitro or in vivo.
NIH ExPorter
NIH ExPorter