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Ethanol and MAP Kinase Cascade

乙醇和 MAP 激酶级联

基本信息

批准号：
7803353
负责人：
Shivendra D Shukla
金额：
$ 7.04万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-30 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7803353
关键词：
Acetaldehyde Acute-Phase Proteins Affect Agonist Alcohol withdrawal syndrome Apoptosis Apoptotic CREB1 gene Cell Death Cell Nucleus Chronic Data Development Dimensions Ethanol Event Family Figs - dietary Gene Expression Hepatocyte Histones In Vitro Inflammation JNK-activating protein kinase Knowledge Lipopolysaccharides Liver MAP Kinase Gene MAPK11 gene MAPK14 gene MAPK8 gene MEKs Maps Mediating Mitogen Activated Protein Kinase 1 Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Molecular Mechanisms of Action Nuclear Nuclear Protein Nuclear Proteins Organelles Phosphorylation Phosphotransferases Play Proteins Proteomics Rattus Role SB 203580 Signal Pathway Signal Transduction Stress Techniques Testing Therapeutic Work alcohol effect alcohol research base chromatin remodeling comparative feeding histone modification in vivo inhibitor/antagonist innovation insight kinase inhibitor lipopolysaccharide-binding protein member novel phosphatidylethanol prevent response therapeutic development tool

项目摘要

DESCRIPTION (provided by applicant): Molecular actions of ethanol remain largely unknown. Recent developments indicate that ethanol alters intracellular signaling pathways including those involving members of mitogen activated protein (MAP) kinase family. Based on new supporting data, it is hypothesized that "ethanol modulates p38 MAPK activity leading to downstream activation of nuclear mitogen and stress activated kinase-1 (MSK-1) and phosphorylation of histone-3 as target." An important focus of this renewal application is the ethanol effects on signaling in nucleus and its consequences, e.g., on histone modifications and on apoptosis. In these studies the role of ethanol and ethanol-derived key metabolites [i.e., acetaldehyde (Acet) and phosphatidylethanol (PEth)] will be established. Four specific aims will test this hypothesis using rat hepatocytes and in vivo ethanol-fed rats as models. Aim I will determine the comparative effects of ethanol, Acet and PEth on activation/phosphorylation of p38 MAPK, MSK-1, JNK kinases. In Aim II, effects of ethanol and Acet on nuclear p38 MAPK, MSK-1 and histone-3 phosphorylation will be elucidated using pharmacological inhibitors and antisense strategy and will be correlated to apoptosis. Aim III will determine the "phospho-proteomic map" of nuclear targets affected by the above kinases through functional proteomic technique. These in vitro studies will be extended to in vivo studies in Aim IV, where chronically ethanol fed rat hepatocytes will be used to determine the modulation of p38 MAPK, MSK-1 and histone-3 phosphorylation by ethanol and Acet. The reversibility of the modulatory effects will be also investigated after ethanol withdrawal. Our focus onto nuclear effects of ethanol and its metabolites on specific members of MAPK family highlights a new dimension in ethanol research and will offer novel insight into the molecular mechanisms of ethanol actions at the subcellular organelle level. Histone modifications by ethanol will have mechanistic involvement in chromatin remodeling/gene expression. Relevance of these observations to apoptotic changes will also be established. New knowledge gained from this project will facilitate development of therapeutic tools to prevent and control ethanol-induced cellular damage.

描述（由申请人提供）：乙醇的分子作用在很大程度上仍然未知。最近的研究表明，乙醇改变细胞内信号通路，包括那些涉及丝裂原活化蛋白（MAP）激酶家族成员。基于新的支持数据，假设“乙醇调节p38 MAPK活性，导致核有丝分裂原和应激激活激酶-1（MSK-1）的下游激活以及组蛋白-3的磷酸化作为靶标。“这项更新申请的一个重要焦点是乙醇对细胞核中信号传导的影响及其后果，例如，对组蛋白修饰和细胞凋亡的影响。在这些研究中，乙醇和乙醇衍生的关键代谢物[即，乙醛（Acet）和磷脂酰乙醇（PEth）]。四个具体的目标将测试这一假设，使用大鼠肝细胞和体内乙醇喂养的大鼠作为模型。目的比较乙醇、Acet和PEth对p38 MAPK、MSK-1、JNK激酶激活/磷酸化的影响。在目的II中，将使用药理学抑制剂和反义策略阐明乙醇和Acet对核p38 MAPK、MSK-1和组蛋白-3磷酸化的影响，并将其与细胞凋亡相关。目的III通过功能蛋白质组学技术，确定上述激酶作用的核靶点的磷酸化蛋白质组图谱。这些体外研究将扩展到Aim IV中的体内研究，其中将使用长期乙醇喂养的大鼠肝细胞来确定乙醇和Acet对p38 MAPK、MSK-1和组蛋白-3磷酸化的调节。还将在乙醇停药后研究调节作用的可逆性。我们对乙醇及其代谢产物对MAPK家族特定成员的核效应的关注突出了乙醇研究的新维度，并将在亚细胞器水平上对乙醇作用的分子机制提供新的见解。乙醇对组蛋白的修饰将在染色质重塑/基因表达中具有机制性参与。还将确定这些观察结果与凋亡变化的相关性。从该项目中获得的新知识将促进治疗工具的开发，以预防和控制乙醇诱导的细胞损伤。