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ETHANOL-INDUCED CELL CYCLE DAMAGE

乙醇引起的细胞周期损伤

基本信息

批准号：
6371848
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
项目类别：
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/6371848
关键词：
astrocytes cell cycle cell line cell proliferation cyclin dependent kinase cytogenetics ethanol laboratory rat neuroblastoma neurogenesis tissue /cell culture

项目摘要

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.

申请人摘要：乙醇对于发育中的孩子来说是一种强致畸剂。中枢神经系统（CNS）。产前乙醇暴露会破坏神经元前体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G1-的长度阶段。细胞在细胞周期中的运动受到家族的调节称为细胞周期蛋白依赖性激酶 (CDK) 的蛋白激酶。的活动 CDK 受细胞周期蛋白正向调节，并受 CDK 抑制剂负向调节（CKIS）。 CDK 活性由细胞外信号相关激酶控制（ERK）。乙醇会影响 ERK 活性。我们假设 (1) 乙醇- CDK 破坏导致细胞增殖受到抑制 (2) ERK 介导乙醇诱导的 CDK 变化系统。拟议的项目将依赖于两种体外模型：B104 神经母细胞瘤细胞和初级皮质星形胶质细胞，以检查乙醇对 ERK 和 CDK 系统。该研究将调查乙醇的影响关于 ERKS 的活动。其他实验将检验以下效果：乙醇 (a) 对 G1 期特异性 CDK 的表达和活性的影响，(b) 乙醇对阳性（细胞周期蛋白）和阴性之间平衡的影响 (CKIS) CDK 监管机构。乙醇诱导的每个实验 CDK 系统的改变将在 ERK 活性的细胞中进行完整且耗尽（使用特定的 ERK 阻断剂）。这样，我们就能够以确定 CDK 活性是否依赖于 ERK。总之，一系列研究代表了对乙醇对CDK系统和相关信号通路的影响。它不会仅探索乙醇诱导的细胞周期损伤的机制，还提供了对细胞周期调节的重要见解神经细胞。