Endolysosomal transporters and systemic autoimmunity

内溶酶体转运蛋白和系统性自身免疫

• 批准号: 9233919
• 负责人: Argyrios N Theofilopoulos
• 金额: $ 42.35万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233919
• 关键词: Adaptive Immune System; Address; Affect; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biological Assay; Biology; Cells; Characteristics; Data; Defect; Dendritic Cells; Detection; Development; Disease; Disease model; Ethylnitrosourea; Event; Functional disorder; Generations; Genetic; Hematopoietic; Histidine; Histologic; Homeostasis; Immune; Impairment; Infection; Inflammation; Inflammatory; Interferon Type I; Interferons; Knowledge; Laboratories; Lead; Lupus; Lysosomes; Modeling; Modification; Mus; Mutagenesis; Mutation; Nuclear Antigens; Nucleic Acids; Organelles; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Peptide Hydrolases; Pharmacology; Production; Protons; Role; Serological; Signal Transduction; Sterility; Stimulus; Syndrome; System; Systemic Lupus Erythematosus; TLR7 gene; Therapeutic; Therapeutic Intervention; Tissues; Toll-like receptors; congenic; cytokine; high throughput screening; inhibitor/antagonist; insight; loss of function mutation; new therapeutic target; novel; receptor; response; sensor; systemic autoimmune disease; trafficking; transcription factor

PROJECT SUMMARY For several decades, this and other laboratories have extensively investigated the causes and immune pathogenesis of systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease. Despite considerable advances, particularly with regard to abnormalities in the adaptive immune system, several questions remained unanswered, including why autoantibodies in this disease are so often directed against nuclear antigens, and what is the initial trigger for these aberrant responses occurring even under sterile conditions? Emerging knowledge of a diverse array of mammalian sensors for nucleic acids, and the demonstration by us and others that these sensors are principal participants in lupus pathogenesis, have now provided new avenues of inquiry as to how this disease (and possibly many others) is initiated. We recently observed that congenic lupus-predisposed mice carrying an inactivating mutation of the proton/histidine transporter SLC15A4 (termed feeble) showed significantly reduced disease manifestations. The feeble mutation, discovered by others through ENU mutagenesis, has been shown to extinguish signaling by the endolysosomal TLR7 and TLR9, together with almost complete absence of production of type I interferons (IFN-I) and other proinflammatory cytokines by plasmacytoid dendritic cells (pDCs) without affecting the development of these cells. Because of the apparent potential to therapeutically intervene with the function of SLC15A4, this proposal will seek to determine how the feeble mutation reduces autoimmunity by defining the functional characteristics of this molecule, the effects of the feeble mutation in lupus-associated innate and adaptive pathogenic responses, and ultimately to utilize high-throughput screening systems to identify pharmacologic inhibitors of this and other molecules necessary for self-nucleic acid sensing. The insights gained from these studies are certain to provide significant data on the biology of endolysosomes, TLRs and SLC15A4, and to reveal novel targets for therapeutic interventions in SLE and other autoimmune diseases.

项目概要 几十年来，该实验室和其他实验室广泛调查了其原因并 系统性红斑狼疮（SLE）的免疫发病机制，原型系统性红斑狼疮 自身免疫性疾病。尽管取得了相当大的进步，特别是在异常方面 对于适应性免疫系统，有几个问题仍未得到解答，包括为什么 这种疾病中的自身抗体常常针对核抗原，最初的抗体是什么？ 即使在无菌条件下也会引发这些异常反应？新兴知识 各种哺乳动物核酸传感器的研究，以及我们和其他人的演示 这些传感器是狼疮发病机制的主要参与者，现在提供了新的 关于这种疾病（可能还有许多其他疾病）如何引发的探究途径。我们最近 观察到携带狼疮失活突变的同类系狼疮小鼠 质子/组氨酸转运蛋白 SLC15A4（称为弱）显示疾病显着减少 表现形式。其他人通过 ENU 诱变发现的微弱突变已被 显示可消除内溶酶体 TLR7 和 TLR9 的信号传导，以及几乎 完全不产生 I 型干扰素 (IFN-I) 和其他促炎细胞因子 由浆细胞样树突状细胞 (pDC) 产生，而不影响这些细胞的发育。因为 考虑到治疗干预 SLC15A4 功能的明显潜力，该提案 将通过定义功能性突变来寻求确定微弱突变如何降低自身免疫性 该分子的特征，狼疮相关先天和微弱突变的影响 适应性致病反应，并最终利用高通量筛选系统 识别该分子和自身核酸所需的其他分子的药理学抑制剂 传感。从这些研究中获得的见解肯定会提供有关以下方面的重要数据： 内溶酶体、TLR 和 SLC15A4 的生物学，并揭示新的治疗靶点 系统性红斑狼疮和其他自身免疫性疾病的干预措施。