The Role of PIAS1 in Immune Regulation

PIAS1 在免疫调节中的作用

• 批准号: 6855857
• 负责人: KE SHUAI
• 金额: $ 23.09万
• 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/6855857
• 关键词: DNA binding protein; Listeria infections; RNA interference; Semliki Forest virus; Vesiculovirus; binding proteins; biological models; gene induction /repression; gene targeting; genetically modified animals; host organism interaction; immune response; immunity; immunoregulation; laboratory mouse; lymphocytic choriomeningitis virus; macrophage; microarray technology; nuclear factor kappa beta; phenotype; protein protein interaction; protein structure function; vaccinia virus

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）：Stat1和NF-kappaB在免疫系统的调节中发挥重要作用。 STAT 和 NF-κB 活性的异常调节与多种人类免疫疾病有关。 Stat1 和 NF-kappaB 的激活在启动先天免疫反应中发挥着核心作用。我实验室的研究已确定 PIAS1（激活 Stat1 的蛋白抑制剂）是 Stat1 和 NF-kappaB 的常见负调节因子。 最近，我们生成了 PIAS1 缺失小鼠。我们的初步研究已经确定了 PIAS1 在免疫反应调节中的生理作用。本研究计划的总体目标是研究PIAS1在免疫调节中的作用。这些研究将增强我们设计治疗传染病的新治疗策略的能力。 我们将表征 Piasl 敲除小鼠的免疫表型，并检查 PIAS1 在病原体先天免疫中的作用。我们将研究 PIAS1 的信号传导特异性。将进行微阵列分析以确定 PIAS1 在调节 IFN 诱导的 Stat1 依赖性基因激活中的特异性。我们将使用体外和体内 DNA 结合测定来检查 Stat1 结合亲和力对 PIAS1 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Stat1依赖性基因激活中PIAS1的特异性。我们将研究涉及PIAS1介导的免疫调节作用的分子机制。具体地，我们将使用基因靶向策略研究PIAS1 SUMO连接酶活性在PIAS1介导的基因调控中的生理重要性。将检查PIAS1介导的NF-κB调节的重要性以及PIAS1调节的Stat1依赖性基因激活在抗病毒应答中的参与。