The long-term objective of the proposed research is to understand how the activation of a resident non-parenchymal liver cell, the stellate cell (previously known as lipocyte), is regulated in hepatic fibrosis and cirrhosis. Studies during the recent funding period have led to the cloning and characterization of a novel cDNA termed 'Zf9', its definition as an immediate-early gene induced during stellate cell activation in vivo, and the demonstration of its ability to specifically transactivate key genes regulating fibrogenesis. Zf9 is a member of an enlarging family of """"""""Kruppel-like"""""""" zinc finger transcription factors, which have significant roles in vasculogenesis, erythropoiesis, and lymphopoiesis. Development expression of Zf9 mRNA is tightly restricted to gut, liver and developing mesenchyme suggesting possible key roles in gastrointestinal and hepatic biology. The Hypotheses are: 1) Zf9 is a key regulator of stellate cell activation; 2) Mice lacking Zf9 will have altered gastrointestinal and hepatic morphogenesis, and Zf9 -/- stellate cells will have reduced capacity to activate 3) Targeted overexpression of Zf9 in stellate cells in vivo will enhance their activation.
The Specific Aims to test these hypotheses are: 1) To identify biologic and molecular effects of overexpressing Zf9 in cultured stellate cells. 2) To evaluate the consequences of knocking out Zf9 on embryonic development, and on hepatic injury and fibrosis in Zf9 -/- mice. 3) To examine the effects of targeted overexpression of Zf9 in stellate cells in transgenic mice driven by a stably active promoter (desmin) or one induced during stellate cell activation (alpha sm. muscle actin). The experiments are a direct extension of previously funded studies exploring the role of Zf9 in stellate cell activation, and are immediately relevant to the pathogenesis of cirrhosis in patients with chronic liver injury and fibrosis. The findings could lead to new treatments for this debilitating and incurable condition.
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