PI3-K - Akt - P70S6-kinase Signaling in HSC Fibrogenesis

University Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): Liver fibrosis represents a major medical problem with significant morbidity and mortality. Hepatic fibrosis, regardless of etiology, is characterized by an increased deposition of type I collagen that disrupts the normal architecture of the liver resulting in pathophysiological damage to the organ. The hepatic stellate cell (HSC) (formerly called the Ito cell, fat storing cell, perisinusoidal cell, and lipocyte) is the primary cell-type in the liver responsible for excess collagen synthesis during hepatic fibrosis. Following a fibrotic stimulus the HSC undergoes a transformation or activation process changing from a quiescent, non-proliferative, vitamin A storing cell to that of an activated myofibroblast-like cell. Associated with HSC activation arc changes in cellular morphology, increased proliferation, and changes in the pattern of gene expression that includes a dramatic increase in the synthesis and deposition of type I collagen. Many of the molecular changes that are observed when HSCs are activated in vivo are also found when HSCs are cultured on plastic. Therefore, culturing HSCs provides a convenient model system to study HSC activation. Of the numerous changes that occur following HSC activation two major events occur that highly contribute to the fibrogenlc properties of this cell. First the HSC becomes directly fibrogenic by beginning to express an abundance of extracellular matrix proteins of which type I collagen predominates. Secondly, the HSC begins to proliferate effectively amplifying the population of fibrogenic cells in the liver. The molecular mechanisms that control type I collagen synthesis in the HSC following cellular activation and the proliferative signaling pathways that control HSC proliferation are not well understood. This proposal is aimed at investigating intracellular proliferative signaling and the molecular mechanisms of collagen gene expression following HSC activation. Specifically we will investigate the role of the FAK - PI3K - Akt - p70s6Ksignaling pathway in HSC proliferation and its role in regulating collagen gene expression. It is anticipated that these studies will identify potential therapeutic targets and provide a foundation for the development of novel therapeutics aimed at preventing the progression of hepatic fibrosis. Specific Aims: Specific Aim #1. To determine the role of the FAK- PI3-K- Akt signaling pathway in HSC proliferation. Specific Aim #2. To determine the mechanism how PI3-K- Akt signaling regulates type 1collagen gene expression in HSCs. Specific Aim #3. To determine the role of proliferative signaling in the development of liver fibrosis in vivo.