Alcohol-Induced Liver Fibrosis: An In Vitro Model

描述（由申请人提供）：酒精性肝硬化仍然是西半球发病率和死亡率的主要原因。 其对肝星状细胞（肝脏中主要的I型胶原产生细胞）的纤维化作用部分由其第一代谢产物乙醛介导。 该化合物通过涉及过氧化氢积累和转化生长因子-β（TGF-β）上调的机制诱导I型胶原基因的转录激活。 然而，这些影响的分子机制仍有待阐明。 因此，在本申请中，我们提出了旨在解开乙醛触发的关键事件的实验，这将直接侵犯胶原基因上调。 具体而言，我们提出以下目标： 1)研究乙醛早期反应导致COL 1A 2上调的关键分子机制。 2)研究乙醛诱导的晚期反应导致TGF-β基因表达上调和HSC启动对该细胞因子更有效反应的分子机制， 3)研究乙醛对HSC内潜伏性TGF-β活化的影响。 更好地表征参与乙酰丙酮依赖性上调I型胶原基因的分子事件，将使我们能够建立治疗干预的关键部位。 此外，从我们的实验中，我们希望确定连接乙酰丙酮酸介导的事件与过氧化氢和TGF-β的途径，导致建立一个自分泌循环，维持纤维化。 我们的长期目标是解开参与乙酰丙酮酸介导的纤维化的分子机制，并开发新的疗法来抑制胶原沉积和/或从肝脏中去除纤维性瘢痕胶原。

DESCRIPTION (provided by applicant): Alcoholic cirrhosis continues to be a major cause of morbidity and mortality in the Western hemisphere. Its fibrogenic actions on hepatic stellate cells, the main type I collagen-producing cells in the liver, are mediated in part, by its first metabolite acetaldehyde. This compound induces the transcriptional activation of the type I collagen genes by a mechanism involving accumulation of hydrogen peroxide and up-regulation of transforming growth factor-beta (TGF-beta). However, molecular mechanisms underlying these effects remain to be elucidated. Thus, in this application we propose experiments aimed at unraveling key events triggered by acetaldehyde that will directly infringe upon collagen gene upregulation. Specifically, we propose the following aims: 1) To investigate key molecular mechanisms involved in the early response to acetaldehyde leading to COL1A2 upregulation. 2) To investigate molecular mechanisms involved in the late response to acetaldehyde leading to upregulation of TGF-beta gene expression and priming of HSC to respond more efficiently to this cytokine and 3) To study the role of acetaldehyde in the activation of latent TGF-beta in HSC. A better characterization of molecular events involved in acetaldehyde-dependent up-regulation of the type I collagen genes will allow us to establish key sites for therapeutic intervention. Moreover, from our experiments we expect to define pathways connecting acetaldehyde-mediated events with hydrogen peroxide and TGF-beta leading to the establishment of an autocrine loop that sustains fibrogenesis. Our long-term goal is to unravel molecular mechanisms involved in acetaldehyde-mediated fibrogenesis and develop novel therapies to inhibit collagen deposition and/or remove fibrous scar collagen from the liver.