TLR Transporters in Lupus

狼疮中的 TLR 转运蛋白

• 批准号: 10217974
• 负责人: DWIGHT H KONO
• 金额: $ 38.7万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-28 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217974
• 关键词: Affect; Albinism; Animal Model; Animals; Antigen Presentation; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biogenesis; Blood Platelets; Cell physiology; Cells; Ceroid; Coagulation Process; Complex; Data; Defect; Development; Disease; Disease model; Early Endosome; Endoplasmic Reticulum; Functional disorder; Genes; Hermanski-Pudlak Syndrome; Histidine; Immune; Immune system; Kidney Diseases; Link; Lung diseases; Lupus; Lysosomes; Mediating; Movement; Nature; Nucleic Acids; Organelles; Pathogenesis; Peptides; Play; Predisposition; Production; Proteins; Receptor Activation; Receptor Signaling; Role; Signal Transduction; System; Systemic Lupus Erythematosus; TLR7 gene; Tissues; Toll-like receptors; Treatment Efficacy; Vesicle; clinically relevant; gene function; immune function; pathogenic microbe; receptor; response; systemic autoimmune disease; trafficking

PROJECT SUMMARY Nucleic acid-sensing (NA)-TLRs, particularly the TLR7 and TLR9, play a fundamental role in the development of lupus and deletion or inhibition of NA-TLR signaling has been shown to have therapeutic efficacy. Recent studies have elucidated the mechanism by which NA-TLRs traffick from the endoplasmic reticulum to the endolysosomal compartment where they provide signals to activate cells and the immune system. This project will investigate the role of endosomal transporters that appear to be necessary for NA-TLR signaling. These endosomal complex are part of a intracellular trafficking system required for the biogenesis and function of lysosome-related organelles. Deficiency of these complexes are linked to a rare recessive disorder, Hermansky-Pudlak syndrome. This project will study the role HPS genes in TLR signaling and autoimmunity looking specifically at AP-3, BLOC-1 to-3. This will be accomplished by defining the role of these gene in the development of lupus (aim1), defining the role of AP-3 in TLR signaling in B cells (aim 2), and defining how these four genes function in TLR transport and signaling (aim 3). By accomplishing these aims, this project will provide a comprehensive view of the role of LRO biogenesis in endosomal TLR signaling of autoantibody- relevant immune cells and in the development of lupus, by studying the whole animal, immune function, and at the cellular levels. These studies are relevant to SLE and will provide an increased understanding of the disease pathogenesis with the possibility of applying this information to the bedside.

项目概要 核酸感应 (NA)-TLR，特别是 TLR7 和 TLR9，在发育中发挥着基础作用 狼疮和 NA-TLR 信号传导的缺失或抑制已被证明具有治疗功效。最近的 研究阐明了 NA-TLRs 从内质网运输到 内溶酶体隔室，在那里它们提供激活细胞和免疫系统的信号。这个项目 将研究内体转运蛋白的作用，这似乎是 NA-TLR 信号传导所必需的。这些 内体复合物是生物发生和功能所需的细胞内运输系统的一部分 溶酶体相关细胞器。这些复合物的缺乏与一种罕见的隐性遗传疾病有关， 赫曼斯基-普德拉克综合征。该项目将研究 HPS 基因在 TLR 信号传导和自身免疫中的作用 特别关注 AP-3、BLOC-1 至 3。这将通过定义这些基因在 狼疮的发展（目标 1），定义 AP-3 在 B 细胞 TLR 信号传导中的作用（目标 2），并定义如何 这四个基因在 TLR 转运和信号转导中发挥作用（目标 3）。通过实现这些目标，该项目将 全面了解 LRO 生物发生在自身抗体内体 TLR 信号传导中的作用 通过研究整个动物的免疫功能和在狼疮的发展中相关的免疫细胞 细胞水平。这些研究与 SLE 相关，将加深人们对 SLE 的了解。 疾病发病机制，并有可能将此信息应用于床边。