Role of ISG12 in cellular innate immune responses

ISG12 在细胞先天免疫反应中的作用

• 批准号: 7849979
• 负责人: Douglas W Leaman
• 金额: $ 18.19万
• 依托单位: UNIVERSITY OF TOLEDO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849979
• 关键词: Ablation; Antiviral Agents; Antiviral Response; Apoptotic; Bacteria; Cells; ERG gene; Exhibits; Gene Expression Profiling; Genes; Human; Immune; Immune response; Individual; Interferon Type I; Interferons; Invaded; Knock-out; Lead; Malignant - descriptor; Mediating; Mitochondria; Natural Immunity; Organism; Physiological; Play; Process; Production; Proteins; RNA Interference; Role; Stimulus; Virus; Virus Diseases; cell type; cytokine; improved; knockout gene; microorganism; mitochondrial membrane; pathogen; protein function; public health relevance; research study; response

DESCRIPTION (provided by applicant): Interferons (IFNs) are multifunctional cytokines that play a critical role in innate immunity. Type I IFNs (IFNs-1, -2, -I and others) exhibit immunomodulatory, antiproliferative and antiviral activities, although gene knockout experiments have suggested that, among these effects, the antiviral function is most critical for survival. IFNs elicit their effects through the induction of discreet subsets of early response genes, known collectively as IFN-stimulated genes (ISGs). To date, however, the precise functions of many individual ISGs remain poorly understood. We have performed extensive gene expression profiling of genes regulated by type I IFNs in a variety of normal and malignant human cell types. These studies have highlighted large repertoires of both common (e.g. induced in all cell types) and unique (cell-specific) ISGs. Here, we propose to assess the physiological function of the protein encoded by the ISG12a gene, an IFN-induced gene that was implicated in our gene array studies as an ISG strongly induced in all cell types. Our recent studies have shown that the ISG12a protein is localized to the mitochondrial membrane, and that ectopic ISG12a expression results in a sensitization of cells to other apoptotic stimuli. Since apoptotic responses to virus are an important component of an overall IFN response, we hypothesize that ISG12a influences the ability of cells to respond to viral infections by impacting mitochondrial function, and possibly regulating apoptotic responses. Thus, we propose to evaluate the physiological importance of endogenous ISG12a in both IFN-dependent mitochondrial responses and in antiviral effects by conducting exploratory studies that encompass these specific aims: Aim 1. To determine the significance of ISG12a in IFN-induced cellular and mitochondrial changes Aim 2. To determine the significance of ISG12a induction on antiviral and other innate immune responses PUBLIC HEALTH RELEVANCE: The ability of the body to respond to invading organisms, including virus and bacteria, depends on the coordinated actions of both immune cells and other cell types in the body. Production of interferon by virally infected cells upregulates the body's ability to sense and respond not only to other viruses, but also to other invading microorganisms. We have identified an interferon-induced protein, called ISG12a, that we feel is involved in this sensitization process, and better understanding of ISG12a's effects on cells should lead to improved understanding of how the body regulates responses to virus and other pathogens.

说明(申请人提供)：干扰素(IFN)是一种多功能细胞因子，在先天性免疫中发挥关键作用。I型IFN(IFNS-1、-2、-I等)具有免疫调节、抗增殖和抗病毒活性，尽管基因敲除实验表明，在这些作用中，抗病毒功能是最关键的。干扰素通过诱导早期反应基因的谨慎子集，统称为干扰素刺激基因(ISGs)来诱导它们的效应。然而，到目前为止，人们对许多单独的ISG的确切职能仍然知之甚少。我们在各种正常和恶性人类细胞中对I型干扰素调控的基因进行了广泛的基因表达谱分析。这些研究突出了大量常见的(如在所有细胞类型中诱导的)和独特的(细胞特异性的)ISG。在这里，我们建议评估由ISG12a基因编码的蛋白质的生理功能，ISG12a基因是干扰素诱导的基因，在我们的基因阵列研究中被认为是在所有类型的细胞中强烈诱导的ISG。我们最近的研究表明，ISG12a蛋白定位于线粒体膜，异位表达ISG12a导致细胞对其他凋亡刺激的敏感性。由于对病毒的凋亡反应是整个干扰素反应的重要组成部分，我们假设ISG12a通过影响线粒体功能并可能调节凋亡反应来影响细胞对病毒感染的反应能力。因此，我们建议通过围绕以下特定目标的探索性研究来评估内源性ISG12a在干扰素依赖的线粒体反应和抗病毒效应中的生理重要性：目的1.确定ISG12a在干扰素诱导的细胞和线粒体变化中的意义目的2.确定ISG12a诱导对抗病毒和其他先天免疫反应的意义公共卫生相关性：机体对包括病毒和细菌在内的入侵生物的反应能力取决于免疫细胞和体内其他细胞类型的协调作用。受病毒感染的细胞产生的干扰素不仅提高了人体对其他病毒的感知和反应能力，也增强了对其他入侵微生物的感知和反应能力。我们已经确定了一种名为ISG12a的干扰素诱导蛋白，我们认为它参与了这一致敏过程，更好地了解ISG12a对细胞的影响应该有助于更好地理解身体如何调节对病毒和其他病原体的反应。