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（由申请方提供）：肝损伤伴随肝星状细胞（HSC）转分化（活化）为肌成纤维细胞，这是导致增殖和迁移增加的肝纤维化的关键事件。这些通风口伴随着细胞-基质相互作用所需的细胞外基质组分的产生的改变和瘢痕组织的过量产生，包括I型胶原蛋白和纤连蛋白。因此，抑制HSC转分化可以防止导致过度胶原沉积、纤维化和肝硬化的后续事件。HSC活化的标志是血小板衍生生长因子-β受体（PDGF-betaR）的上调及其对PDGF-BB的迁移和增殖反应增加。虽然许多研究都集中在PDGF-BB依赖的分子事件导致细胞增殖和迁移，很少有人知道乙醛，乙醇的第一代谢产物，对PDGF-betaR表达和HSC增殖和迁移的作用。此外，ACH和PDGF-BB对HSC基质相互作用的作用仍有待研究。基于我们以前的研究，即乙醛通过活性氧（过氧化氢）的积累发挥其作用，以及本申请中提出的初步结果，我们建议研究乙醛调节HSC中PDGF-β R表达的分子机制。我们还将研究ACH对HSC对PDGF-BB的迁移和增殖反应以及细胞-基质相互作用中PDGF-BB依赖性改变的作用。我们的长期目标是阐明乙醛引发的关键分子事件，这些事件可能导致治疗干预，从而预防和/或改善酒精诱导的肝纤维化和肝硬化。