Collagen Gene Expression During Ethanol-Induced Fibrosis

描述(申请人提供)：肝纤维化，不分病因， 其特征是I型胶原沉积增加，破坏了 肝脏的正常结构导致病理生理损害 管风琴。长期饮酒通常会导致肝纤维化，而且 与肿瘤生长因子β合成增加有关 (TGFb)，一种有效的促纤维化细胞因子，增强I型胶原基因 表情。肝星状细胞(HSC)(正式名称为Ito细胞，脂肪 储存细胞、肝窦周围细胞和脂肪细胞)是 在肝纤维化过程中，导致胶原合成过多的肝脏。 在肝纤维化刺激之后，例如过量的乙醇消费，HSC 经历一种转换或激活过程，从静止的 维生素A储存细胞到激活的肌成纤维细胞样细胞。HSC 激活会导致细胞形态的变化，增加 增殖率和基因表达模式的变化，包括 I型胶原蛋白的合成急剧增加。此外， 激活的HSC分泌TGFb，这是HSC的一种强有力的促纤维化细胞因子，并且 在细胞表面表达TGFb受体。许多分子上的变化 当HSCs在体内被激活时观察到的 在塑料上培养。因此，培养HSCs提供了一种方便的模型。 系统来研究HSC的激活。控制1型的分子机制 细胞激活后肝星状细胞的胶原合成不佳 明白了。此外，人们对转化生长因子b信号通路知之甚少。 在细胞激活后或酒精诱导的肝脏中的HSC 疾病。这项建议旨在研究黄曲霉毒素的分子机制。 肝星状细胞活化后胶原基因的表达及其信号转导途径 TGFb在HSC中的表达。预计这些研究将提供一个基础 用于开发旨在防止病情恶化的新疗法 肝纤维化的症状。1.分析远距离5‘DNase I的作用 调控Al(I)胶原基因表达的过敏性部位 肝星状细胞激活。2.评估Smad3在介导TGFb刺激中的作用 CZL(I)型胶原在培养激活的肝星状细胞中的表达3.直接考核 Smad3在肝星状细胞α1(I)胶原表达调控中的作用 体内酒精诱导的肝纤维化。4.研究分子 在al(I)胶原基因中TGFf3刺激的机制。

DESCRIPTION (provided by applicant): 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. Chronic ethanol consumption often leads to liver fibrosis and is associated with an increase in the synthesis of tumor growth factor beta (TGFb), a potent fibrogenic cytokine that enhances type I collagen gene expression. The hepatic stellate cell (HSC) (formally 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, such as excess ethanol consumption, the HSC undergoes a transformation or activation process changing from a quiescent vitamin A storing cell to that of an activated myofibroblast-like cell. HSC activation results in changes in cellular morphology, an increase in proliferation rate, and changes in the pattern of gene expression that includes a dramatic increase in the synthesis of type I collagen. In addition, the activated HSC secretes TGFb, a potent fibrogenic cytokine for the HSC, and expresses TGFb receptors on the cell surface. 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. The molecular mechanisms that controls type 1 collagen synthesis in the HSC following cellular activation are not well understood. Furthermore, little is known about the pathway for TGFb signaling in the HSC following cellular activation or during ethanol-induced liver disease. This proposal is aimed at investigating the molecular mechanisms of collagen gene expression following HSC activation and the signaling pathway for TGFb in the HSC. It is anticipated that these studies will provide a foundation for the development of novel therapeutics aimed at preventing the progression of hepatic fibrosis. 1. To analyze the role of distant 5' DNase I hypersensitive sites in regulating al (I) collagen gene expression following HSC activation. 2. To assess the role of SMAD3 in mediating TGFb-stimulated expression of czl(I) collagen in culture-activated HSCs. 3. To directly assess the role of SMAD3 in regulating a 1(I) collagen expression in the HSC during alcohol-induced liver fibrosis in vivo. 4. To investigate the molecular mechanism responsible for TGFf3 stimulation in the al (I) collagen gene.