The Role of PIAS1 in Immune Regulation

PIAS1 在免疫调节中的作用

• 批准号: 6986769
• 负责人: KE SHUAI
• 金额: $ 37.72万
• 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/6986769
• 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（由申请人提供）：STAT1和NF-KAPPAB在免疫系统的调节中起重要作用。 STAT和NF-KAPPAB活动的异常调节与各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方面具有核心作用。我实验室的研究确定了PIAS1（活化STAT1的蛋白质抑制剂）是STAT1和NF-KAPPAB的常见负调节剂。 最近，我们产生了PIAS1 null小鼠。我们的初步研究已经确定了PIAS1在调节免疫反应中的生理作用。该研究建议的总体目标是研究PIAS1在免疫调节中的作用。这些研究将增强我们设计用于治疗传染病的新型治疗策略的能力。 我们将表征PIASL基因敲除小鼠的免疫学表型，并检查PIAS1在对病原体的先天免疫中的作用。我们将研究PIAS1的信号传导特异性。将进行微阵列分析，以定义PIAS1调节IFN诱导的STAT1依赖性基因激活的特异性。我们将使用体外和体内DNA结合测定法检查STAT1结合亲和力对PIAS1特异性的潜在影响。此外，我们还将测试通过基因靶向和RNA干扰方法，PIASY是否影响PIAS1在STAT1依赖性基因激活中的特异性。我们将研究与PIASL介导的免疫调节作用有关的分子机制。具体而言，我们将使用基因靶向策略来研究PIAS1 SUMO连接酶活性在PIASL介导的基因调节中的生理重要性。将检查PIASL介导的NF-KAPPAB调节的重要性以及PIASL调节的STAT1依赖性基因在抗病毒反应中的参与。