Collagen Gene Expression During Ethanol-Induced Fibrosis

描述（由申请人提供）：肝纤维化，无论病因如何， 其特征在于I型胶原沉积增加， 肝脏的正常结构导致病理生理损伤， 器官。慢性酒精消耗通常会导致肝纤维化， 与肿瘤生长因子β的合成增加有关 （TGF b），一种有效的纤维化细胞因子，其增强I型胶原基因 表情肝星状细胞（HSC）（正式名称为Ito细胞， 储存细胞，窦周细胞和脂肪细胞）是主要细胞类型， 在肝纤维化过程中，肝脏负责过量的胶原蛋白合成。 在纤维化刺激后，例如过量的乙醇消耗，HSC 经历了从静止的转变或激活过程， 维生素A储存细胞与活化的肌纤维母细胞样细胞的差异。HSC 激活导致细胞形态的变化， 增殖率，以及基因表达模式的变化，包括 I型胶原蛋白的合成急剧增加。此外该 活化的HSC分泌TGF β，一种有效的HSC纤维化细胞因子，和 在细胞表面表达TGF β受体。许多分子变化 当HSC在体内被激活时观察到的， 在塑料上培养。因此，培养HSC提供了一种方便的模型 系统研究HSC活化。控制1型糖尿病的分子机制 细胞活化后，HSC中胶原蛋白的合成并不良好， 明白此外，对TGF β信号通路知之甚少， 在细胞活化后的HSC中或在乙醇诱导的肝脏 疾病该建议旨在研究的分子机制， HSC活化后胶原基因表达及其信号通路 HSC中的TGF β。预计这些研究将提供基础 用于开发旨在预防疾病进展的新疗法， 肝纤维化1.为了分析远端5 'DNase I的作用， 调节al（I）胶原基因表达的超敏位点 HSC激活。2.为了评估SMAD 3在介导TGF β刺激的细胞凋亡中的作用， czl（I）胶原在培养活化的HSC中的表达。3.直接评估 SMAD 3在HSC中调节α 1（I）胶原表达的作用 体内酒精诱导的肝纤维化。4.为了研究 负责α 1（I）胶原基因中TGF β 3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.