COLLAGEN GENE REGULATION DURING ETHANOL INDUCED FIBROSIS

肝纤维化的特征是肝组织中 I型胶原蛋白。据认为，激活的伊藤细胞是 负责I型胶原产量的增加 纤维化。在酒精等致纤维化的刺激下 消费，伊藤细胞经历了一个变化的转变过程 从静止的维生素A储存细胞到激活的肌成纤维细胞- 就像手机一样。激活的Ito细胞比静止的Ito细胞大， 表达细胞骨架蛋白α-平滑肌肌动蛋白，并失去 维生素A储存静止的伊藤细胞所特有的特性。另外， I型胶原mRNA水平和I型胶原蛋白水平的大幅增加 蛋白质的合成在正常的肝脏结构和 导致肝功能异常。这项研究的长期目标是 是为了了解导致伊藤细胞的分子机制 肝纤维化刺激后的激活。分子机制 激活的Ito负责增加I型胶原的合成 牢房将被调查。具体地说，转录调控 将对新分离的两株人的α1(I)胶原基因进行检测 静止的Ito细胞和激活的Ito细胞，以确定 I型胶原增加的分子机制 在激活的Ito细胞中表达。重要的顺位代理的位置 α1(I)基因中高效转录所需的元件 ITO细胞及其相应反式作用基因的鉴定 将确定与顺式作用元件相互作用的因素。 探讨Ito细胞形成的分子机制 激活我们将从静止的克隆差异表达的基因 Ito细胞和激活的Ito细胞。这些基因在人类进化过程中的作用 激活过程将确定。最后，由于Ito单元是 被不同的致纤维化刺激激活，但表现出相似的 形态和代谢变化，相关的分子机制 由于不同的纤维化刺激，Ito细胞将被激活 被调查。差异表达的基因将与 不同的肝纤维化动物模型，以确定 基因表达的共同模式存在。据预计， 这项工作的结果将为小说的开发提供基础 防止肝纤维化进展的治疗策略。

Hepatic fibrosis is characterized by an increase in the deposition of Type I collagen. It is believed that the activated Ito cell is responsible for the increase in production of Type I collagen during fibrogenesis. Following a fibrogenic stimulus, such as ethanol consumption, the Ito cell undergoes a transformation process changing from a quiescent vitamin A storing cell to an activated myofibroblast- like cell. Activated Ito cells are larger than the quiescent Ito cell, express the cytoskeletal protein alpha smooth muscle actin, and lose the vitamin A stores characteristic for quiescent Ito cells. Additionally, a large increase in Type I collagen mRNA levels and in Type I collagen protein synthesis are observed in the normal liver architecture and results in abnormal liver function. The long-term goals of this research are to understand the molecular mechanisms which contribute to Ito cell activation following a fibrogenic stimulus. The molecular mechanisms responsible for increased Type I collagen synthesis by the activated Ito cell will be investigated. Specifically, transcriptional regulation of the alpha 1(I) collagen gene will be examined in both freshly isolated quiescent Ito cells and activated Ito cells in order to determine the molecular mechanisms responsible for the increased Type I collagen expression in activated Ito cells. The location of important cis-acting elements in the alpha 1(I) gene required for efficient transcription in Ito cells and the identification of the corresponding trans-acting factors which interact with the cis-acting elements will be determined. To investigate the molecular mechanisms responsible for Ito cell activation we will clone differentially expressed genes from quiescent Ito cells and activated Ito cells. The roles of these genes in the activation process will be determined. Finally, since Ito cells are activated by different fibrogenic stimuli and yet display similar morphological and metabolic changes, the molecular mechanisms responsible for Ito cell activation as a result of different fibrogenic stimuli will be investigated. Differentially expressed genes will be compared from different animal models of hepatic fibrosis in order to ascertain if a common pattern of gene expression exists. It is anticipated that the results from this work will provide a foundation to develop novel therapeutic strategies to prevent the progression of hepatic fibrosis.