Role of Acetaldehyde on PDGF-BB-induced HSC Migration

乙醛对 PDGF-BB 诱导的 HSC 迁移的作用

• 批准号: 7050518
• 负责人: MARCOS ROJKIND
• 金额: $ 32.51万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050518
• 关键词: acetaldehyde; alcoholic liver cirrhosis; cell differentiation; cell migration; cell proliferation; cytoskeletal proteins; extracellular matrix; fibrogenesis; glycoproteins; hydrogen peroxide; integrins; laboratory mouse; liver cells; membrane proteins; molecular pathology; pathologic process; platelet derived growth factor; receptor expression; tissue /cell culture

DESCRIPTION (provided by applicant): 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, inhibition 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 mechanisms whereby 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.

描述（由申请人提供）：肝损伤伴随着肝星状细胞（HSC）的反式分化（激活）到肌纤维细胞中，这是肝纤维发生中的关键事件，导致增殖和迁移增加。这些通风孔伴随着细胞矩阵相互作用所需的细胞外基质成分的改变以及疤痕组织过多的产生，包括I型胶原蛋白和纤连蛋白。因此，抑制HSC反式分化可以防止随后的事件导致过度胶原蛋白沉积，纤维化和肝硬化。 HSC激活的标志是血小板衍生的生长因子-BETA受体（PDGF-BETAR）的上调及其对PDGF-BB的迁移和增生反应的增加。尽管许多研究都集中在导致细胞增殖和迁移的PDGF-BB依赖性分子事件上，但对于乙醇（乙醇的第一个代谢产物）在PDGF-BetAR表达和HSC增殖和迁移方面的作用知之甚少。此外，ACH和PDGF-BB在HSC基质相互作用上的作用仍有待研究。基于我们以前的研究，即乙醛通过积累活性氧（过氧化氢）和本应用中提出的初步结果来研究其某些作用，我们建议研究分子机制，从而调查乙醛在HSC中调节PDGF-betar在HSC中的表达。我们还将研究ACH对HSC对PDGF-BB的迁移和增殖反应的作用，以及细胞 - 基质相互作用中PDGF-BB依赖性改变。我们的长期目标是揭开乙醛触发的关键分子事件，这可能导致治疗性干预，从而预防和/或改善酒精诱导的肝纤维化和肝硬化。