COLLAGEN GENE REGULATION DURING ETHANOL INDUCED FIBROSIS

肝纤维化的特征是肝纤维化的沉积增加， I型胶原蛋白。据信，激活的Ito细胞是 负责增加生产的I型胶原蛋白， 纤维化在纤维化刺激后，如乙醇 消耗，伊藤细胞经历了一个转变过程， 从静止的维生素A储存细胞到活化的肌成纤维细胞 就像细胞一样。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， 维生素A是静止的Ito细胞的特征。 此外，本发明还 I型胶原mRNA水平和I型胶原mRNA水平的大幅增加， 在正常的肝脏结构中观察到蛋白质合成， 导致肝功能异常这项研究的长期目标是 是为了了解有助于Ito细胞的分子机制， 纤维化刺激后的激活。 的分子机制 负责通过激活的Ito增加I型胶原合成 细胞将被调查。具体而言，转录调控 α 1（I）胶原基因将在两个新鲜分离的 静止的Ito细胞和激活的Ito细胞，以确定 负责增加I型胶原蛋白的分子机制 在激活的Ito细胞中表达。 重要顺式作用的位置 在α 1（I）基因中的元件，所需的有效转录， Ito细胞及其相应反式作用的鉴定 将确定与顺式作用元件相互作用的因子。 探讨Ito细胞凋亡的分子机制 我们将克隆差异表达的基因，从静止 Ito细胞和激活的Ito细胞。这些基因的作用， 激活过程将被确定。最后，由于伊藤细胞是 由不同的纤维化刺激激活，但表现出类似的 形态和代谢变化，分子机制负责 对于Ito细胞活化，由于不同的纤维化刺激， 追究 差异表达的基因将与 不同的肝纤维化动物模型，以确定 存在共同的基因表达模式。预计该 这项工作的结果将为开发新的 预防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.