TLR Transporters in Lupus

项目总结 核酸传感(NA)-TLRs，特别是TLR7和TLR9，在发展中发挥着基础性作用 狼疮的发生和NA-TLR信号的缺失或抑制已被证明具有治疗效果。近期 研究阐明了NA-TLRs从内质网向外转运的机制。 内溶酶体室，在那里它们提供信号来激活细胞和免疫系统。这个项目 将调查内体转运体的作用，这似乎是NA-TLR信号传递所必需的。这些 内体复合体是细胞内转运系统的一部分，是血管发生和功能所必需的 溶酶体相关细胞器。这些复合体的缺乏与一种罕见的隐性疾病有关， 赫尔曼斯基-普德拉克综合征。本项目将研究HPS基因在TLR信号和自身免疫中的作用 具体看AP-3，BLOC-1到-3。这将通过定义这些基因在基因中的作用来实现 狼疮的发展(目标1)，定义AP-3在B细胞中TLR信号转导中的作用(目标2)，并定义如何 这四个基因在TLR的运输和信号传递中发挥作用(目标3)。通过实现这些目标，该项目将 全面介绍LRO生物发生在自身抗体的内体TLR信号转导中的作用 相关的免疫细胞和狼疮的发生发展，通过研究整个动物的免疫功能，并在 细胞水平。这些研究与系统性红斑狼疮相关，并将加深对 疾病的发病机制，以及将这些信息应用于床边的可能性。

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.