TLR Transporters in Lupus

项目摘要 核酸敏感（NA）-TLR，特别是TLR 7和TLR 9，在肿瘤的发生发展中起着重要作用。 已经证明，缺失或抑制NA-TLR信号传导具有治疗功效。最近 研究已经阐明了NA-TLR从内质网运输到内质网的机制， 它们在溶酶体内区室中提供信号以激活细胞和免疫系统。这个项目 将研究内体转运蛋白的作用，这似乎是必要的NA-TLR信号。这些 内体复合物是细胞内运输系统的一部分，这些系统是生物发生和功能所必需的。 溶酶体相关的细胞器。这些复合物的缺乏与一种罕见的隐性疾病有关， 赫-普二氏综合征本项目将研究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到-3。这将通过定义这些基因在细胞中的作用来实现。 狼疮的发展（aim 1），定义AP-3在B细胞TLR信号传导中的作用（aim 2），并定义如何 这四个基因在TLR转运和信号传导中起作用（目的3）。通过实现这些目标，该项目将 提供了LRO生物发生在自身抗体的内体TLR信号传导中的作用的全面观点- 相关的免疫细胞和狼疮的发展，通过研究整个动物，免疫功能，并在 细胞水平。这些研究与SLE相关，并将提供对SLE的更多了解。 疾病的发病机制，并有可能将这些信息应用于临床。

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.