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

描述（由申请人提供）：肝纤维化是一个重要的医学问题，具有显著的发病率和死亡率。肝纤维化，无论病因如何，其特征是I型胶原蛋白沉积增加，破坏肝脏的正常结构，导致器官的病理生理损伤。肝星状细胞（HSC）（以前称为伊藤细胞、脂肪储存细胞、肝周膜细胞和脂肪细胞）是肝脏中主要的细胞类型，在肝纤维化期间负责过多的胶原合成。在纤维化刺激后，HSC经历转化或激活过程，从静止的、非增殖的、储存维生素a的细胞转变为激活的肌成纤维细胞样细胞。与HSC激活相关的是细胞形态的改变、增殖的增加和基因表达模式的改变，其中包括I型胶原合成和沉积的急剧增加。造血干细胞在体内被激活时观察到的许多分子变化，在造血干细胞在塑料上培养时也发现了。因此，培养HSC为研究HSC活化提供了方便的模型体系。在HSC激活后发生的众多变化中，有两个主要事件高度影响了该细胞的纤维原细胞特性。首先，HSC开始表达丰富的细胞外基质蛋白，其中I型胶原蛋白占主导地位，从而直接成为纤维性细胞。其次，HSC开始有效地增殖，扩大了肝脏中纤维化细胞的数量。细胞激活后控制HSC中I型胶原合成的分子机制以及控制HSC增殖的增殖信号通路尚不清楚。本研究旨在探讨HSC活化后细胞内增殖信号和胶原基因表达的分子机制。具体而言，我们将研究FAK - PI3K - Akt - p70s6k信号通路在HSC增殖中的作用及其在调节胶原基因表达中的作用。预计这些研究将确定潜在的治疗靶点，并为开发旨在预防肝纤维化进展的新疗法提供基础。

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.