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Toll-like receptor 9: trafficking and signaling

Toll 样受体 9：运输和信号转导

基本信息

批准号：
8384885
负责人：
CYNTHIA A LEIFER
金额：
$ 31.92万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8384885
关键词：
Accounting Address Adjuvant Affect Allergic Disease Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Biological Assay Bypass Carbohydrates Cell Fractionation Cells Communicable Diseases Cytoplasmic Tail DNA Data Dendritic Cells Development Discrimination Dominant-Negative Mutation Endocytosis Endoplasmic Reticulum Endosomes Event Goals Golgi Apparatus Immune response Immune system In Vitro Interphase Cell Knowledge Lysine Lysosomes Malignant Neoplasms Mass Spectrum Analysis Methods Modeling Modification Molecular Movement Mutate Nucleic Acids Pathology Pathway interactions Pattern Peptide Hydrolases Phosphorylation Play Post-Translational Protein Processing Proteins Receptors, Antigen, B-Cell Regulation Role Secretory Cell Signal Transduction Site Small Interfering RNA Systemic Lupus Erythematosus TLR9 gene Testing Therapeutic Tyrosine Ubiquitin Ubiquitination Vaccines base microbial microorganism mutant novel receptor response synergism trafficking

项目摘要

ABSTRACT DNA containing CpG motifs (CpG DNA) has incredible potential to treat cancer, infectious and allergic diseases. Despite this potential, response to our own nucleic acids, including DNA, triggers autoimmune diseases such as systemic lupus erythematosus. Localization and trafficking of the specific receptor, TLR9, may play a key role in self/foreign DNA discrimination. Uncovering the molecular mechanisms of TLR9 trafficking is the first step towards our long term goal of manipulating TLR9 trafficking to achieve modulation of CpG DNA response. We have shown that TLR9 is localized intracellularly, predominantly in the endoplasmic reticulum (ER), prior to CpG DNA stimulation. TLR9 traffics from the ER to endosomes and lysosomes where it co-localizes with endocytosed CpG DNA. These data raise the fundamental questions of what regulates TLR9 access to CpG DNA and how does access affect response to self and microbial DNA? Using new TLR9 trafficking assays, we have accumulated evidence that TLR9 constitutively exits the ER, that CpG DNA induces a secondary TLR9 trafficking event, and that both events occur through traditional cell trafficking pathways. Therefore, we hypothesize that TLR9 constitutively traffics in a highly regulated fashion through the cell secretory pathway from the Golgi complex to endolysosomes and that Golgi transit is a prerequisite for TLR9 response to CpG DNA. We believe that TLR9 trafficking may account for synergy with other TLRs and the autoimmune B cell receptor, and is regulated by post-translational modification of the TLR9 cytoplasmic tail. This hypothesis will be tested in three Specific Aims. First, transfected and endogenous TLR9 trafficking through the Golgi complex will be examined using multiple in vitro approaches including a novel protease cleavage assay. Second, we will examine the mechanism of TLR9-autoimmune B cell receptor synergism. Third, we will determine the role of TLR9 post-translational modification in regulating intracellular trafficking and in TLR-autoimmune B cell receptor synergy. By understanding the mechanism of TLR9 trafficking we can uncover how regulation of response to foreign DNA and lack of response to self-DNA is achieved. This knowledge will provide the basis for the further development of CpG DNA as an adjuvant and therapeutic as well as develop mechanisms to interrupt the cycle of autoimmune pathology.

摘要