Endosomal TLR transport in B cell signaling and autoimmunity

B 细胞信号传导和自身免疫中的内体 TLR 转运

• 批准号: 10550242
• 负责人: DWIGHT H KONO
• 金额: $ 48.38万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-12 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10550242
• 关键词: Albinism; Animal Model; Antigen Presentation; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; Biogenesis; Biology; Blood Platelets; Cell physiology; Cells; Ceroid; Coagulation Process; Complex; Data; Defect; Development; Disease; Disease model; Early Endosome; Endoplasmic Reticulum; Endosomes; Functional disorder; Genes; Genetic; Hermanski-Pudlak Syndrome; Histidine; Immune system; Impairment; Kidney Diseases; Ligands; Lung diseases; Lupus; Lysosomes; Mediating; Movement; Mutation; Nature; Nucleic Acids; Organ; Organelles; Pathogenesis; Pathway interactions; Peptides; Phenotype; Predisposition; Production; Proteins; Receptor Activation; Receptor Inhibition; Receptor Signaling; Role; Series; Signal Pathway; Signal Transduction; System; Systemic Lupus Erythematosus; TLR7 gene; Toll-like receptors; Treatment Efficacy; Vesicle; clinically relevant; gene function; insight; interest; lupus prone mice; pathogenic microbe; receptor function; response; systemic autoimmune disease; trafficking

PROJECT SUMMARY Nucleic acid-sensing (NA)-TLRs, notably TLR7 and TLR9, are central players in the pathogenesis of lupus and consequently targeting NA-TLR signaling has been shown to have therapeutic efficacy, but a clinically relevant strategy for specifically inhibiting NA-TLRs has remained elusive. Thus, there is substantial interest in better understanding their basic biology. NA-TLRs are transported from the endoplasmic reticulum to the endolysosomal compartment where they engage ligands and provide signals to activate cells and subsequently the immune system. This project proposes to define the critical endosomal compartments relevant to NA-TLR signaling, B cell activation, autoAb production, and end organ disease. This is based on the premise that endosomal transport of NA-TLRs is similar to the intracellular trafficking system utilized for the biogenesis and function of lysosome-related organelles and that NA-TLRs are a partial form of LROs in NA- TLR-expressing cells. Deficiency of LRO-forming complexes is associated with a rare recessive disorder, called the Hermansky-Pudlak syndrome (HPS) composed of several independent genetic and functional defects that share a common pathway and nearly identical phenotype. This project will use deficiencies in HPS genes as to identify the stages of LRO biogenesis required for NA-TLR signaling and autoimmunity using specifically defects in the AP-3 and BLOC-1 to-3 complexes. 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 B cell TLR transport and signaling (aim 3). This project should yield new insights into the biology of NA-TLR signaling within the endolysosomal compartments and the relevance of these compartments to NA-TLR-mediated B cell activation, autoAb production, and systemic autoimmune disease.

项目总结 核酸感应(NA)-TLRs，特别是TLR7和TLR9，在狼疮和 因此，靶向NA-TLR信号已被证明具有治疗效果，但临床上相关 具体抑制NA-TLRs的战略仍然难以捉摸。因此，人们对更好的产品非常感兴趣。 了解它们的基本生物学。NA-TLRs从内质网运输到 在内溶酶体内，它们与配体结合并提供信号以激活细胞和 随后是免疫系统。该项目建议定义关键的内体隔室 与NA-TLR信号、B细胞激活、自身抗体的产生和终末器官疾病有关。这是基于 假设NA-TLR的内体转运类似于用于 溶酶体相关细胞器的生物发生和功能以及NA-TLRs是NA-TLRs中LRO的一种部分形式。 表达TLR的细胞。LRO形成复合体的缺乏与一种罕见的隐性无序有关， 称为Hermansky-Pudlak综合征(HPS)，由几个独立的遗传和功能性疾病组成 共同的途径和几乎相同的表型的缺陷。该项目将利用HPS中的不足之处 基因识别NA-TLR信号和自身免疫所需的LRO生物发生阶段 具体地说，AP-3和BLOC-1至-3复合体中的缺陷。这将通过定义以下角色来实现 这些基因在狼疮的发生发展中(AIM1)，定义了AP-3在B细胞TLR信号中的作用(AIM2)， 以及确定这四个基因在B细胞TLR运输和信号转导中的作用(目标3)。这个项目应该 对内溶酶体内NA-TLR信号的生物学有了新的见解 这些间隔与NA-TLR介导的B细胞活化、自身抗体的产生和系统的相关性 自身免疫性疾病。