The Effects of Alcohol on JNK Mediated Inflammatory Signaling in Glial Cells

酒精对 JNK 介导的胶质细胞炎症信号的影响

基本信息

批准号：
8516407
负责人：
JACK L. LEONARD
金额：
$ 34.57万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516407
关键词：
Affect Alcohol abuse Alcohol consumption Alcohols Astrocytes Autoimmune Process Biological Biological Assay Biology Brain Brain Injuries CXCL10 gene Cells Chemotactic Factors Chronic Clinical Cognitive Competence Cytoskeleton Defect Dementia Disease Progression Disease model Enzyme-Linked Immunosorbent Assay Ethanol Evaluation Experimental Autoimmune Encephalomyelitis Extracellular Matrix Genes Glial Fibrillary Acidic Protein Gliosis Goals ITGAM gene Immune response Immunoblotting Immunosuppressive Agents Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Interleukin-10 JUN gene Lysophospholipids MAPK8 gene Matrix Metalloproteinases Mediating Mediator of activation protein Methodology Metric Microglia Mitogen-Activated Protein Kinases Modeling Multiple Sclerosis Mus Mutant Strains Mice Neonatal Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Pathway interactions Peptide Hydrolases Phosphotransferases Play Production Proteins Rest Role Scaffolding Protein Signal Pathway Signal Transduction Signal Transduction Pathway Stream Stress System Therapeutic Intervention Toll-Like Receptor 2 Toll-like receptors Toxic effect Work alcohol abuse therapy alcohol effect arm astrogliosis brain cell cell motility cell type cytokine extracellular signal-regulated kinase 4 in vivo lysophosphatidic acid mouse model mutant neonate neuroinflammation neuron apoptosis prevent problem drinker public health relevance response stress-activated protein kinase 1 upstream kinase

项目摘要

DESCRIPTION (provided by applicant): One of the major consequences of chronic alcohol abuse in the brain is increased inflammation that leads to neurodegeneration with associated cognitive defects and ultimately dementia. In brain, the neuroimmune system is composed of astrocytes and microglial cells that act in concert to fend off infection, respond to injury and remodel after neuronal damage. Recent work has shown that ethanol elicits a diverse set of responses by the neuroimmune system. Ethanol treatment activates astrocyte signaling pathways mediated by toll-like receptors and up-regulates the secretion of inflammatory mediators regulated by mitogen activated protein kinases (MAPK); the consequence is a chronic increase in release of proinflammatory mediators. The c-Jun NH2-terminal kinase (JNK) signal transduction pathway is one of the MAPK signal transduction pathways that controls the innate immune response and is composed of upstream kinases, JNKs, scaffolding proteins (JIP), and its down stream target, c-Jun. The recent discovery that loss of the JNK1 gene protects the brain against the untoward effects of autoimmune encephalomyelitis highlights the potential role that the JNK signal transduction pathway plays in controlling the neuroimmune response. We hypothesize that ethanol provokes a neuroinflammatory state by altering cytokine production and/or the cellular response of astrocytes and microglial cells through the JNK signal transduction pathway. To explore the effects of alcohol on JNK pathway function in astrocytes and microglial cells, we make use of our colony of JNK pathway mutants that lack one or more of the signaling kinases. We will first define the role of the JNK signal transduction pathway in mediating ethanol-induced cytokine production/secretion by astrocytes. Astrocytes will be prepared from neonates derived from our colony of mouse mutants deficient in one or more of the components in the JNK pathway. The effects of ethanol on resting, TGF-1 and LPS-stimulated cytokine production and secretion will be systematically evaluated. We will then examine the role of the JNK pathway in mediating the ethanol- induced changes in microglial biology. The effects of ethanol on cytokine induced microglial motility, cytokine production by resting, TGF-1 and LPS-stimulated cells, and matrix metalloproteinase (MMP) production will be evaluated. We will finish our studies by evaluating the effects of chronic alcohol treatment on the JNK mediated neuroinflammatory response in vivo, using experimental autoimmune encephalomyelitis (EAE), and lysophosphatidic acid induced reactive gliosis as model diseases. The results of the proposed studies will define the role of JNK dependent cytokine expression in astrocytes and microglial cells and its participation in the neuroinflammatory response associated with alcohol abuse. This discovery will identify the JNK pathway as a potential target for therapeutic intervention that will alleviate or prevent additional brain cell loss in recovering alcoholics and/or to prevent further neurodegeneration.

描述（由申请人提供）：大脑中慢性酒精滥用的主要后果之一是增加炎症，导致神经退行性与相关的认知缺陷和最终痴呆。在大脑中，神经免疫系统由星形胶质细胞和小胶质细胞组成，这些细胞协同作用以抵御感染，对神经元损伤后的损伤做出反应和重塑。最近的工作表明，乙醇引起了神经免疫系统的各种反应。乙醇处理激活由Toll样受体介导的星形胶质细胞信号通路，并上调由有丝分裂原活化蛋白激酶（MAPK）调节的炎症介质的分泌；结果是促炎介体的释放慢性增加。 C-JUN NH2-末端激酶（JNK）信号转导途径是控制先天免疫反应的MAPK信号转导途径之一，由上游激酶，JNKS，jnks，脚手架蛋白（JIP）及其下流流靶组成。最近的发现，JNK1基因的丧失可以保护大脑免受自身免疫性脑脊髓炎的不良影响，这突显了JNK信号转导途径在控制神经免疫反应中起着的潜在作用。我们假设乙醇通过改变细胞因子的产生和/或星形胶质细胞和小胶质细胞通过JNK信号转导途径的细胞反应来激发神经炎症态。为了探索酒精对星形胶质细胞和小胶质细胞中JNK途径功能的影响，我们利用缺乏一个或多个信号激酶的JNK途径突变体的菌落。我们将首先定义JNK信号转导途径在介导乙醇诱导的星形胶质细胞的细胞因子产生/分泌中的作用。将从我们在JNK途径中一个或多个成分中缺乏小鼠突变体菌落的新生儿制备星形胶质细胞。将系统地评估乙醇对静息，TGF-1和LPS刺激的细胞因子产生和分泌的影响。然后，我们将研究JNK途径在介导乙醇诱导的小胶质细胞生物学变化中的作用。将评估乙醇对细胞因子诱导的小胶质细胞运动，静息，TGF-1和LPS刺激的细胞产生的细胞因子的影响，以及基质金属蛋白酶（MMP）的产生。我们将使用实验性自身免疫性脑脊髓炎（EAE）和溶物磷脂酸诱导的反应性神经胶质病作为模型疾病来评估慢性酒精治疗对体内JNK介导的神经炎症反应的影响。拟议的研究的结果将定义JNK依赖性细胞因子在星形胶质细胞和小胶质细胞中的作用，并参与与酗酒有关的神经炎症反应。这一发现将确定JNK途径是治疗干预的潜在靶标，该途径将减轻或防止脑细胞丧失在恢复酒精中毒和/或防止进一步的神经变性中。