ALCOHOL INDUCED LIVER FIBROSIS--AN IN VITRO MODEL

描述(改编自《调查者摘要》)：酒精诱导 肝硬变仍然是发病率和死亡率的主要原因。 全世界。肝硬变中I型胶原过度沉积的结果 主要是由于肝脏对其合成和降解的失衡 星状细胞(LSC)。乙醇通过多种机制诱导肝纤维化 这包括：a)细胞氧化还原的变化，自由基的形成，以及 脂质过氧化加剧，所有这些都会导致氧化应激 回应。B)乙醛的形成，这是一种本身就会导致 小鼠胶原蛋白基因(Cla1)在LSC中的转录激活， 和c)酒精引起的肝损伤，导致Kupffer激活 细胞和炎症细胞的到来：细胞产生生长因子和 细胞因子，如白介素6和转化生长因子-β1，已知有助于纤维化的形成 进程。因此，研究人员开发了一种共培养系统，包括 肝细胞和LSC，这模仿了许多生理和生理 这两种细胞类型在体内的关系。PI的初步数据 有力地表明，当肝细胞代谢乙醇时，LSC反应 随着I型胶原蛋白产量的增加。因此，他们的总体具体情况 目的是：a)定义乙醛-、乙醇-和 转化生长因子-β1反应元件，b)确定c/EBPO在 乙醛、乙醇和转化生长因子-β1介导的Cla1上调 吉恩。C)证明氧化应激的产物H202 反应，是一种常见的第二信使引起的三种纤维化 在Colla1基因上调中起关键作用的刺激。d) PI应调查是否存在相互调制 基质金属蛋白酶-I和胶原蛋白1基因。他们的长期目标是定义关键 易受治疗干预影响的监管要素涉及 乙醇诱导的肝纤维化和开发新的策略，基于我们的 发现，诱导胶原降解，同时抑制其产生。

DESCRIPTION (Adapted from the Investigator's Abstract): Ethanol-induced liver cirrhosis continues to be a major cause of morbidity and mortality worldwide. Excess deposition of type I collagen in cirrhotic livers results mainly from the imbalance between its synthesis and degradation by liver stellate cells (LSC). Ethanol induces liver fibrosis by several mechanisms that include: a) changes in cellular redox, formation of free radicals, and increased lipoperoxidation, all of them contribute to the oxidative stress response. b) formation of acetaldehyde, an agent that by itself, induces the transcriptional activation of the mouse collagen gene (colla1) in LSC, and c) ethanol-induced liver injury which results in activation of Kupffer cells and arrival of inflammatory cells: cells produce growth factors and cytokines, such as IL6 and TGF-beta1, known to contribute to the fibrogenic process. Thus, the investigators developed a co-culture system consisting of hepatocytes and LSC, that mimics many of the physical and physiological relationships of these two cell types in vivo. The PI's preliminary data strongly indicate that while hepatocytes metabolize ethanol, LSC respond with increased production of type I collagen. Thus, their overall specific aims are: a) to define the acetaldehyde-, ethanol-, and TGF-beta1-responsive elements, b) to establish the role of c/EBPO on acetaldehyde-, ethanol and TGF-beta1-mediated upregulation of the colla1 gene. c) To demonstrate that H202, a product of the oxidative stress response, is a common second messenger induced by the three fibrogenic stimuli that plays a key role in the upregulation of the colla1 gene. d) The PI shall investigate whether there is a reciprocal modulation of the MMP-I and colla 1 genes. Their long-term goal is to define the key regulatory elements susceptible to therapeutic intervention involved in ethanol-induced liver fibrogenesis and develop new strategies, based on our findings, to induce Collagen degradation while inhibiting its production.