The endosomal SLC15A4 proton-coupled histidine transporter in lupus

狼疮中的内体 SLC15A4 质子偶联组氨酸转运蛋白

基本信息

批准号：
8598770
负责人：
Argyrios N Theofilopoulos
金额：
$ 24.16万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8598770
关键词：
Address Affect Animal Model Antigen-Antibody Complex Area Autoantibodies Autoimmune Process Autoimmunity Biological Assay Blood Circulation Carrier Proteins Cells Coupled DNA Dendritic Cells Development Disease Endosomes Ethylnitrosourea Event Functional disorder Genes Health Histidine Human Immune Immune system Inflammation Inflammatory Interferon Type I Interferons Intervention Investigation Knowledge Laboratories Lupus Modeling Mouse Strains Mus Mutation Nuclear Nucleic Acids Participant Pathogenesis Pathologic Patients Play Population Production Protons RNA Role Signal Transduction Skin Syndrome System Systemic Lupus Erythematosus TLR7 gene Therapeutic Intervention cell type cytokine high throughput screening in vivo inhibitor/antagonist insight lupus prone mice mouse model novel novel strategies receptor screening sensor small molecule solute

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus in humans and spontaneous mouse models is characterized by autoantibodies to nuclear and cytoplasmic materials that contain RNA, DNA or both, and considerable evidence indicates a direct pathologic role of these autoantibodies. Until recently the mechanisms involved in autoantibody production were to a large extend unclear, however, the emerging knowledge of a diverse array of mammalian sensors for nucleic acids, and the demonstration that these sensors are principal participants in lupus pathogenesis, have now provided a more concise definition of the mechanisms by which this disease is initiated and propagated. Among the innate immune cells implicated in the pathogenesis of lupus is the plasmacytoid dendritic cell (pDC) which constitute a small (<1%), but distinct population of cells that is thought to be activated by nucleic acid-containing immune complex stimulation of endosomal TLRs resulting in the production of disease-promoting type I interferons. Although investigation of the role of pDCs in SLE was previously not possible because of the absence of adequate animal models, recently an ENU mutation in the Slc15a4 gene, called feeble, was discovered that resulted in defective TLR7/9-induced type I interferon production in specifically pDCs. This proposal will utilize this unique model to define the role of pDCs and the production of type I interferons by these cells in animal models of lupus. We will also seek to identify pharmacologic inhibitors of SLC15A4 by high throughput screening. The insights gained from these studies are likely to provide a better understanding of the mechanisms by which innate sensors and cells promote disease, and reveal novel targets for therapeutic intervention.

描述（由申请人提供）：人类和自发小鼠模型中的全身性红斑狼疮的特征在于含有RNA，DNA或两者的核和细胞质材料的自身抗体，并且证据表明这些自身抗体的直接病理作用。直到最近，自身抗体产生涉及的机制尚不清楚，但是，对核酸的多种哺乳动物传感器的新兴知识的知识，并且证明这些传感器是狼疮发病机理中的主要参与者，现在已经对这种疾病提出了这种疾病的定义更加清晰。在与狼疮发病机理有关的先天免疫细胞中，质子乳清细胞类树突状细胞（PDC）构成了一个小（<1％）但众多的细胞群，这些细胞被认为是被含核酸的免疫复合复合物刺激的内体TLR激活，导致疾病疾病型I型I型Interferferferferferferfearmots的内体TLR。尽管由于没有足够的动物模型而无法研究PDC在SLE中的作用，但发现SLC15A4基因中的ENU突变（称为Befeble）被发现导致TLR7/9诱导的I型I型Interferon产生有缺陷的特定PDC。该建议将利用这种独特的模型来定义PDC的作用以及这些细胞在狼疮动物模型中的I型干扰素的产生。我们还将通过高吞吐量筛选来鉴定SLC15A4的药理抑制剂。从这些研究中获得的见解可能会更好地了解先天传感器和细胞促进疾病的机制，并揭示治疗干预的新颖靶标。