Systematic Responses of GILZ Regulatory Network to Alcohol

GILZ 监管网络对酒精的系统响应

• 批准号: 8743169
• 负责人: GUOSHUN WANG
• 金额: $ 20.08万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8743169
• 关键词: Affect; Alcohols; Binding; Binding Sites; Cell physiology; Cells; Cytokine Suppression; Data; Disease; Dose; Elements; Endothelial Cells; Epithelial Cells; Fingerprint; Gene Expression Profile; Gene Targeting; Genes; Genome; Glucocorticoids; Goals; Health; Human; Immune response; Immunosuppression; Inflammation; Inflammatory; Inflammatory Response Pathway; Knowledge; Laboratories; Lead; Leucine Zippers; Mediating; Mediator of activation protein; Molecular; Mutation; Peripheral Blood Mononuclear Cell; Production; Proteins; Publications; Regulation; Research; Role; Sequence Analysis; Signal Pathway; Small Interfering RNA; Steroids; System; Systems Biology; Testing; Therapeutic; Trans-Activators; Up-Regulation; airway epithelium; alcohol abuse therapy; alcohol effect; alcohol exposure; cell type; chromatin immunoprecipitation; cytokine; density; design; immunoregulation; insight; novel; promoter; public health relevance; response; tandem mass spectrometry

DESCRIPTION (provided by applicant): Alcohol has long been associated with anti-inflammation and immunosuppression. The molecular mechanisms underlying these effects are not fully defined. In the preliminary studies, we performed whole-genome high-density microarray analyses on human airway epithelia exposed to varied doses of alcohol. A cluster of alcohol-responsive genes was identified. Among them, glucocorticoid-induced leucine zipper (GILZ), a prominent glucocorticoid (GC) target gene, responded to alcohol in a dose-dependent manner. GILZ is a major mediator to transduce glucosteroid actions in cells. This novel finding reveals a potentially important signaling pathway which may contribute to the alcohol-associated anti-inflammation and immunosuppression. The ultimate goal of this application is to define alcohol-specific GILZ regulatory network at the system level. There are three specific aims: 1) Specific Aim 1: To identify the trans-acting factors which bind to the GILZ gene promoter and are responsible for alcohol-mediated activation of GILZ; Specific Aim 2: To examine GILZ chromosomal occupancy induced by alcohol by chromatin immunoprecipitation sequencing (ChIP-seq) to profile the GILZ-targeting sequences across the genome and to delineate the alcohol-specific GILZ molecular network; 3) Specific Aim 3: To define the GILZ role in inflammatory cytokine response to LPS in multiple types of cells under alcohol exposure. The proposed research will allow us to test the central hypothesis that the alcohol-induced GILZ upregulation contributes to alcohol anti- inflammation and immunosuppression through a specific regulatory network. By completion of this proposal, we will gain the groundbreaking knowledge to help understand how alcohol acts like steroids to modulate cellular functions molecularly. This research will provide new insights into the mechanism of alcohol-induced anti-inflammation and immunosuppression, which may lead to rational design of therapeutics for the treatment of alcohol-associated diseases.

描述(申请人提供)：长期以来，酒精一直与抗炎和免疫抑制联系在一起。这些效应背后的分子机制还没有完全确定。在初步研究中，我们对暴露于不同剂量酒精的人呼吸道上皮细胞进行了全基因组高密度微阵列分析。研究人员发现了一组酒精反应基因。其中，糖皮质激素诱导的亮氨酸拉链基因(GILZ)是糖皮质激素(GC)的重要靶基因，它对酒精的反应呈剂量依赖性。GILZ是细胞内糖皮质激素作用的主要介体。这一新的发现揭示了一个潜在的重要信号通路，该通路可能有助于酒精相关的抗炎和免疫抑制。该应用程序的最终目标是在系统级别定义特定于酒精的GILZ调控网络。有三个特定目的：1)特定目的1：确定与GILZ基因启动子结合并负责酒精介导的GILZ激活的反式作用因子；特定目的2：用染色质免疫沉淀测序(ChIP-SEQ)检测酒精诱导的GILZ染色体占有率，以描绘整个基因组中的GILZ靶向序列，并描绘酒精特异的GILZ分子网络；3)特定目的3：确定GILZ在酒精暴露下多种细胞对内毒素的炎性细胞因子反应中的作用。这项拟议的研究将使我们能够检验这一中心假设，即酒精诱导的GILZ上调通过特定的调节网络有助于酒精抗炎和免疫抑制。通过完成这项提议，我们将获得开创性的知识，以帮助理解酒精是如何像类固醇一样从分子上调节细胞功能的。本研究将为酒精性抗炎和免疫抑制机制的研究提供新的思路，为合理设计酒精性疾病的治疗药物提供理论依据。