The Role of PIAS1 in Immune Regulation

PIAS1 在免疫调节中的作用

• 批准号: 7324793
• 负责人: KE SHUAI
• 金额: $ 35.93万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7324793
• 关键词: Affect; Affinity; Antiviral Response; Binding; Biological Assay; DNA Binding; Gene Activation; Gene Expression Regulation; Gene Targeting; Genes; Goals; Human; Immune; Immune System Diseases; Immune response; Immune system; In Vitro; Infection; Knockout Mice; Laboratories; Ligase; Macrophage Activation; Mediating; Microarray Analysis; Molecular; NF-kappa B; Natural Immunity; Numbers; Phenotype; Physiological; Play; Proteins; RNA Interference; Regulation; Research Proposals; Role; Signal Transduction; Specificity; Testing; Viral; base; design; in vivo; infectious disease treatment; inhibitor/antagonist; macrophage; microbial; novel therapeutics; pathogen

DESCRIPTION (provided by applicant): Stat1 and NF-kappaB play important roles in the regulation of the immune system. Abnormal regulation of STAT and NF-kappaB activities has been associated with various human immune disorders. The activation of Stat1 and NF-kappaB has a central role in initiating the innate immune response. Studies from my laboratory have identified PIAS1 (protein inhibitor of activated Stat1) as a common negative regulator of Stat1 and NF-kappaB. Recently, we have generated PIAS1 null mice. Our preliminary studies have identified a physiological role of PIAS1 in the regulation of immune responses. The overall goal of this research proposal is to study the role of PIAS1 in immune regulation. These studies will enhance our ability to design novel therapeutic strategies for the treatment of infectious diseases. We will characterize the immunological phenotypes of Piasl knockout mice and examine the role of PIAS1 in innate immunity to pathogens. We will study the signaling specificity of PIAS1. Microarray analysis will be performed to define the specificity of PIAS1 in regulating the IFN-induced Stat1-dependent gene activation. We will examine the potential effect of Stat1 binding affinity on the specificity of PIAS1 using in vitro and in vivo DNA binding assays. In addition, we will test if PIASy affects the specificity of PIAS1 in Stat1-dependent gene activation by gene targeting and RNA interference approaches. We will examine the molecular mechanisms involved in the PIASl-mediated effect in immune regulation. Specifically, we will investigate the physiological importance of the PIAS1 SUMO ligase activity in PIASl-mediated gene regulation using a gene targeting strategy. The significance of the PIASl-mediated NF-kappaB regulation and the involvement of PIASl-regulated Stat1-dependent gene activation in antiviral response will be examined.

描述（申请人提供）：Stat 1和NF-κ B在免疫系统的调节中起重要作用。STAT和NF-κ B活性的异常调节与各种人类免疫疾病相关。Stat 1和NF-kappaB的激活在启动先天性免疫应答中具有核心作用。我实验室的研究已经确定PIAS 1（活化Stat 1的蛋白抑制剂）是Stat 1和NF-κ B的共同负调节因子。 最近，我们已经产生了PIAS 1 null小鼠。我们的初步研究已经确定了PIAS 1在免疫应答调节中的生理作用。这项研究的总体目标是研究PIAS 1在免疫调节中的作用。这些研究将提高我们设计治疗传染病的新治疗策略的能力。 我们将描述PIAS 1基因敲除小鼠的免疫表型，并研究PIAS 1在先天免疫中对病原体的作用。我们将研究PIAS 1的信号特异性。将进行微阵列分析，以确定PIAS 1在调节IFN诱导的Stat 1依赖性基因激活中的特异性。我们将使用体外和体内DNA结合试验研究Stat 1结合亲和力对PIAS 1特异性的潜在影响。此外，我们将通过基因靶向和RNA干扰方法测试PIASy是否影响PIAS 1在Stat 1依赖性基因激活中的特异性。我们将研究PIASl介导的免疫调节作用中涉及的分子机制。具体地，我们将使用基因靶向策略研究PIAS 1 SUMO连接酶活性在PIAS 1介导的基因调控中的生理重要性。将检查PIAS 1介导的NF-κ B调节的意义和PIAS 1调节的Stat 1依赖性基因活化在抗病毒应答中的参与。