Role of Acetaldehyde on PDGF-BB-induced HSC Migration and Proliferation.

肝损伤伴随着肝星状细胞(HSC)的转分化(激活)为 肌成纤维细胞，肝纤维化过程中的一个关键事件，导致增殖和迁移增加。这些 通风口伴随着细胞所需的细胞外基质成分的产生的变化- 基质相互作用和瘢痕组织的过度产生，包括I型胶原和纤维连接蛋白。因此， 抑制HSC反式分化可防止后续事件导致胶原过量 沉积、纤维化和肝硬变。HSC活化的一个标志是上调了血小板衍生的生长 因子-β受体(PDGF-Betar)及其对PDGF-BB增强的迁移和增殖反应。 尽管许多研究都集中在导致细胞增殖的PDGF-BB依赖的分子事件上 和迁移，关于乙醇的第一代谢物乙醛对PDGF-1的作用知之甚少。 Betar的表达与HSC的增殖和迁移此外，ACH和PDGF-BB在HSC- 基质相互作用仍有待研究。基于我们之前的研究，即乙醛 通过积累活性氧物种(过氧化氢)和 在本申请中给出的初步结果我们建议研究分子机制，其中 乙醛对HSC中PDGF-β表达的调节作用我们还将研究ACH在 HSC对PDGF-BB的迁移和增殖反应及对PDGF-BB依赖性改变的影响 细胞-基质相互作用。我们的长期目标是揭开乙醛引发的关键分子事件 可导致治疗性干预，从而预防和/或改善酒精性肝 纤维化和肝硬变。

Liver injury is accompanied by trans-differentiation (activation) of hepatic stellate cells (HSC) into myofibroblasts, a key event in liver fibrogenesis that results in increased proliferation and migration. These vents are accompanied by alterations in the production of extracellular matrix components required for cell- matrix interactions and excess production of scar tissue, including type I collagen and fibronectin. Thus, nhibition of HSC trans-differentiation could prevent the subsequent events leading to excess collagen deposition, fibrosis and cirrhosis. A hallmark of HSC activation is the up-regulation of platelet-derived growth factor-beta receptor (PDGF-betaR) and their increased migratory and proliferative response to PDGF-BB. Although many studies have focused on PDGF-BB-dependent molecular events leading to cell proliferation and migration, little is known regarding the role of acetaldehyde, the first metabolite of ethanol, on PDGF- betaR expression and HSC proliferation and migration. Moreover, the role of ACH and PDGF-BB on HSC- matrix interactions remains to be investigated. Based on our previous studies, namely that acetaldehyde exerts some of its action via the accumulation of reactive oxygen species (hydrogen peroxide) and the preliminary results presented in this application we propose to investigate molecular mechanismswhereby acetaldehyde modulates the expression of PDGF-betaR in HSC. We will also study the role of ACH on the migratory and proliferative responses of HSC to PDGF-BB and on the PDGF-BB-dependent alterations in cell-matrix interactions. Our long term goal is to unravel key molecular events triggered by acetaldehyde that could lead to therapeutic intervention and thus, to prevention and/or amelioration of alcohol-induced liver fibrosis and cirrhosis.