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Characterization of the myddosome, a protein complex that controls TLR signaling

myddosome（一种控制 TLR 信号传导的蛋白质复合物）的表征

基本信息

批准号：
9236656
负责人：
JONATHAN C KAGAN
金额：
$ 44.25万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-13 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9236656
关键词：
Aftercare Antibodies B-Lymphocytes CD14 Antigen Cell-Free System Cells Complex Dangerousness Data Death Domain Detection Disease Endosomes Ensure Enzyme Activation Event Genetic Transcription Goals Human Immune response Immune signaling Immunity In Vitro Infection Inflammasome Inflammation Inflammatory Inflammatory Response Injectable Innate Immune System Intestines Laboratories Life Ligand Binding Ligands Metabolic Metabolism Microbe Modeling Motion Mus Mutation Natural Immunity Organelles Phosphorylation Phosphotransferases Physiological Production Proteins Receptor Activation Receptor Signaling Recruitment Activity Regulation Research Proposals Signal Pathway Signal Transduction Sorting - Cell Movement Spleen TBK1 gene TIRAP gene TLR4 gene Time Tissues Toll-like receptors Tumor Necrosis Factor Receptor Work base cell type commensal microbes cytokine genetic regulatory protein human disease immune activation in vivo macrophage microbial mutant novel pathogenic bacteria protein complex receptor response tool transcription factor

项目摘要

Project Summary: The goal of this proposal is to characterize a protein complex called the myddosome, which is uniquely assembled during Toll-like Receptor (TLR) signal transduction. The myddosome is one of several newly- defined receptor-proximal complexes that control innate immune signal transduction. Analogous complexes operate to control inflammasome assembly and the RIG-I and TNF receptor signaling pathways. A common feature of these complexes is that they operate as organelles that are assembled “on-demand”, or upon ligand binding. As such, these complexes are only present in cells after microbes have been detected, and they may serve as critical hubs for coordinating downstream signaling enzyme activation. Despite the recognition that these organelles control innate immunity, we have little understanding of their regulation (or composition). Our proposal is founded on our recent discovery that the myddosome is assembled within macrophages upon treatment with TLR ligands. This finding is important because it had been unclear whether the myddosome is a pre-existing protein complex, or if it is assembled inducibly. The inducible assembly of this complex provided us with a tool to study its regulation, and we recently identified the TLR sorting adaptor TIRAP as the first regulator of myddosome assembly. These discoveries establish the myddosome as an important model to study receptor-proximal protein complexes that define the signaling pathways of the innate immune system. In this application, we propose to explore how known myddosome components interact to regulate TLR signaling in vitro and in vivo (Aim 1), to explore how a new myddosome component regulates TLR signaling (Aim 2), and to explore the mechanisms underlying several mutant myddosome components that cause mouse or human disease (Aim 3).

项目总结: