Taxilin Alpha Regulates DNA-Mediated and Interferon-Dependent Innate Immunity

Taxilin Alpha 调节 DNA 介导和干扰素依赖性先天免疫

• 批准号: 9303580
• 负责人: Shitao Li
• 金额: $ 43.18万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-06 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303580
• 关键词: Animal Model; Autoimmune Diseases; Binding; DNA; DNA Virus Infections; DNA Viruses; Data; Development; Dimerization; Endoplasmic Reticulum; Environment; Genes; Health Sciences; Host Defense; Immune response; Immune signaling; Immunity; In Vitro; Interferon Activation; Interferon Type I; Interferons; Investigation; Knockout Mice; Link; Literature; Mediating; Natural Immunity; Oklahoma; Pathway interactions; Play; Polyubiquitin; Production; Proteomics; Recruitment Activity; Research; Role; Science; Signal Pathway; Signaling Molecule; Specificity; Systemic Lupus Erythematosus; TANK-binding kinase 1; Transgenic Mice; Treatment Efficacy; Universities; Virus Diseases; base; career preparation; dimer; graduate student; improved; in vivo; novel therapeutics; prevent; protein complex; response; undergraduate student

Project summary While exogenous DNA-mediated immune response contributes to host defense, excessive host cytoplasmic DNA can result in autoimmune diseases due to interferon overproduction. Taxilin alpha (TXLNA) has been implied in autoimmune disease caused by cytosolic DNA. However, the role of TXLNA in DNA-mediated innate immunity is unknown. Thus, it is pressing to elucidate the mechanisms of how TXLNA regulates DNA-induced innate immune signaling. This application proposes a hypothesis that TXLNA is a new signaling molecule in DNA-mediated, interferon-dependent innate immunity. Aim 1 will establish TXLNA as a TBK1 regulator in DNA-mediated innate immunity in vitro and in vivo. TXLNA deficiency will establish the requirement and specificity in TBK1-mediated interferon activation in response to DNA. Aim 2 will investigate the mechanisms by which TXLNA regulates TBK1 activity in DNA-mediated innate signaling pathway. We will examine several hypotheses of TXLNA-mediated TBK1 activation and recruitment to STING signalosome. The mechanistic concepts derived from this proposal will advance our current understanding of the regulatory mechanisms in DNA-mediated innate immunity. This project will also provide graduate and undergraduate students with opportunities for significant independent research in preparation for careers in biomedical science.

项目摘要 虽然外源DNA介导的免疫应答有助于宿主防御，但过量的宿主细胞质 由于干扰素的过量产生，DNA可导致自身免疫性疾病。Taxilin alpha（TXLNA） 暗示了由胞质DNA引起的自身免疫性疾病。然而，TXLNA在DNA介导的先天性 免疫力未知。因此，迫切需要阐明TXLNA如何调节DNA诱导的细胞凋亡的机制。 先天免疫信号本申请提出了一种假设，即TXLNA是一种新的信号分子， DNA介导的干扰素依赖性先天免疫。目标1将建立TXLNA作为TBK1调节器， 体外和体内DNA介导的先天免疫。TXLNA缺陷将确定要求， TBK1介导的干扰素激活对DNA应答的特异性。目标2将研究机制 TXLNA在DNA介导的先天性信号通路中调节TBK1活性。我们将研究几个 TXLNA介导的TBK1活化和募集到STING信号体的假说。机械论 从这一建议中得出的概念将促进我们目前对监管机制的理解， DNA介导的先天免疫。该项目还将为研究生和本科生提供 重要的独立研究的机会，为生物医学科学的职业生涯做准备。