ETHANOL-INDUCED CELL CYCLE DAMAGE

乙醇引起的细胞周期损伤

• 批准号: 6094559
• 负责人: JIA LUO
• 金额: $ 7.3万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6094559
• 关键词: astrocytes; cell cycle; cell line; cell proliferation; cyclin dependent kinase; cytogenetics; ethanol; laboratory rat; neuroblastoma; neurogenesis; tissue /cell culture

APPLICANT'S ABSTRACT: Ethanol is a potent teratogen for the developing central nervous system (CNS). Prenatal ethanol exposure disrupts the proliferative activities of neuronal precursors and glia. Analysis of cell cycle kinetics indicate that both in vivo and in vitro ethanol treatment prolong the duration of cell cycle and in particular, the length of the G1- phase. The movement of cells through the cell cycle is regulated by a family of protein kinases known as cyclin-dependent kinases (CDKs). The activity of CDKs is regulated positively by cyclins, and negatively by CDK inhibitors (CKIS). CDK activity is controlled by extracellular signal-related kinases (ERKs). Ethanol can affect ERK activity. We hypothesize (1) that ethanol- induced inhibition of cell proliferation results from disruptions of CDK systems, and (2) that ERK mediates ethanol-induced alternations in CDK systems. The proposed project will rely on two in vitro models, B104 neuroblastoma cells and primary cortical astrocyytes, to examine the effects of ethanol on the ERK and CDK systems. The studies will investigate the effects of ethanol on the activity of ERKS. Other experiments will examine the effects of ethanol (a) on the expression and activity of G1-phase-specific CDKs and (b) the effects of ethanol on the balance between positive (cyclins) and negative (CKIS) regulators of CDKs. Each of the experiments on ethanol-induced alterations of CDK system will be performed with cells in which ERK activity is intact and depleted (using a specific ERK blocker). Thus, we will be able to determine whether the CDK activity is ERK-dependent. Together, the battery of studies represents a systematic investigation of the effects of ethanol on CDK systems and related signal pathways. It will not only explore the mechanism(s) underlying ethanol-induced cell cycle damage, but also provide an important insight into the regulation of cell cycle in neural cells.

申请者摘要：乙醇是一种对发育有强烈致畸作用的物质 中枢神经系统(CNS)。产前酒精暴露扰乱了 神经前体细胞和神经胶质细胞的增殖活性。细胞分析 循环动力学表明，体内和体外乙醇处理 延长细胞周期的持续时间，特别是延长G1- 相位。细胞在细胞周期中的运动受一个家族的调节 一种称为细胞周期蛋白依赖性蛋白激酶(CDKs)的蛋白激酶。的活动 CDKs受细胞周期蛋白正向调节，受CDK抑制剂负向调节 (长江基建)。CDK活性受细胞外信号相关激酶的控制 (Erks)。乙醇可影响ERK活性。我们假设(1)乙醇- CDK的破坏导致对细胞增殖的诱导抑制 系统，以及(2)ERK介导乙醇诱导的CDK改变 系统。 拟议的项目将依赖于两个体外模型，B104神经母细胞瘤 细胞和原代皮质星形胶质细胞，以检测乙醇对 ERK和CDK系统。这些研究将调查乙醇的影响。 关于厄克人的活动。其他实验将检验 乙醇(A)对G1期特异性CDKs表达和活性的影响 乙醇对正(细胞周期蛋白)和负性细胞周期蛋白平衡的影响 (CKIS)CDK的监管机构。乙醇诱导的每一项实验 CDK系统的改变将在ERK活性的细胞中进行 完好无损且耗尽(使用特定的ERK阻滞剂)。因此，我们将能够 以确定CDK活性是否依赖于ERK。 总而言之，这一系列研究代表了对 乙醇对CDK系统及相关信号通路的影响。它不会的 只有探讨乙醇诱导细胞周期损伤的机制(S)， 同时也为细胞周期的调控提供了一个重要的视角 神经细胞。