TYPE I INTERFERONS IN LUPUS

狼疮中的 I 型干扰素

• 批准号: 7141837
• 负责人: Argyrios N Theofilopoulos
• 金额: $ 40.9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141837
• 关键词: cytokine; dendritic cells; genes; genetics; interferons; model; receptor; role

DESCRIPTION (provided by applicant): A large body of research aimed at defining genes contributing to lupus pathogenesis has focused on cytokines and, among them, those encoding the pleiotropic type I and type II interferons (IFNs) have been shown to be key pathogenic effectors. In this proposal, we outline experiments in mouse lupus models to further dissect the mechanisms by which type I IFNs (IFN-alpha/beta) exert their adverse effects, and to devise means to curtail their activity. The hypotheses to be addressed are: a) IFNAR1 deletion reduces lupus development in spontaneous models with diverse genetic abnormalities and disease severity, and a biological blocker of this receptor is effective when applied post-developmentally and at clinically- relevant stages; b) IFN-beta production is required for the IFN-alpha-mediated effects, IFN-alpha/beta and IFN-gamma act coordinately to cause full disease expression, and high levels of the newly identified IFN-lambdas can promote disease in the absence of IFN-alpha/beta or IFN-gamma signaling; c) excessive activation and generation of plasmacytoid dendritic cells (pDCs), the major IFN-alpha/beta producers, are central abnormalities in disease pathogenesis, and d) at the early disease phase, IFN-alpha/beta production and the ensuing autoimmune responses are initiated by endogenous apoptotic materials acting in a TLR-independent pathway, while at the later disease phases, these materials, complexed with autoantibodies, propagate and amplify IFN-alpha/beta production in a TLR-dependent pathway. These studies will advance our knowledge of the mechanisms by which IFNs promote systemic autoimmunity and may contribute to the development of novel therapies for lupus and other autoimmune diseases.

描述（由申请人提供）：一项旨在定义有助于狼疮发病机理的基因的大量研究集中在细胞因子上，其中包括编码多效性I型I型和II型干扰素（IFN）（IFNS）的人已证明是关键的病原体生效。在此提案中，我们概述了小鼠狼疮模型的实验，以进一步剖析I型IFNS（IFN-Alpha/beta）的机制，从而发挥其不良影响，并设计为减少其活性。要解决的假设是：a）IFNAR1缺失减少具有多种遗传异常和疾病严重程度的自发模型中的狼疮的发育，当在临床上相关的阶段应用后，该受体的生物阻滞剂是有效的； b）IFN-Alpha介导的作用，IFN-ALPHA/BETA和IFN-GAMMA法需要协同引起全部疾病表达，而新近鉴定的IFN-LAMBDA可以在没有IFN-Alpha/Beta/Beta/Beta或IFN-Gamma信号传导的情况下促进疾病； c）过度激活和产生过度的激活和产生疾病发病机理的主要异常是疾病发病机理中的核心异常，而在早期疾病阶段，IFN-alpha/beta的产生以及随之而来的自身免疫疾病是由内源性源引发的，而这些apoptotic ersiatient in IFN-Alpha/beta的产生是疾病发病阶段的核心异常，而d）则在这些疾病中引发了这些源自源性的自发性疾病，而这些反应是在这些疾病中引发的，而这些源则是apoptotic intirentiation fe n t t lip the the the fe与自身抗体复合的材料在TLR依赖性途径中繁殖并扩增IFN-α/β产生。这些研究将提高我们对IFN促进系统性自身免疫性的机制的了解，并可能有助于开发狼疮和其他自身免疫性疾病的新型疗法。