Endolysosomal transporters and systemic autoimmunity

内溶酶体转运蛋白和系统性自身免疫

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要几十年来，这个和其他实验室已经广泛调查了原因和全身性红斑狼疮（SLE）的免疫发病机理，原型全身性自身免疫性疾病。尽管取得了长足的进步，尤其是关于异常的自适应免疫系统，几个问题尚未解决，包括为什么这种疾病中的自身抗体经常针对核抗原，最初是什么即使在无菌条件下也会发生这些异常反应的触发？新兴的知识用于核酸的多种哺乳动物传感器以及我们和其他人的演示这些传感器是狼疮发病机理的主要参与者，现在提供了新的关于这种疾病（可能还有许多其他疾病）的探究途径。我们最近观察到，携带着持有灭活突变突变突变的先天狼疮的小鼠质子/组氨酸转运蛋白SLC15A4（称为微弱）显示出明显降低的疾病表现。他人通过ENU诱变发现的微弱突变已经显示内溶血TLR7和TLR9的熄灭信号传导，几乎完全缺乏I型干扰素（IFN-I）和其他促炎细胞因子的产生通过浆细胞样树突状细胞（PDC），而不会影响这些细胞的发展。因为该建议的明显潜力与SLC15A4的功能有关将寻求通过定义功能来确定微弱的突变如何降低自身免疫性该分子的特征，微弱突变在狼疮相关的先天和自适应致病反应，并最终利用高通量筛查系统鉴定自核酸所需的该分子的药理抑制剂感应。从这些研究中获得的见解肯定会提供有关该研究的重要数据内溶性，TLR和SLC15A4的生物学，并揭示治疗性的新靶标 SLE和其他自身免疫性疾病的干预措施。