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MODULATION OF TISSUE INFLAMMATION BY RP105/TLR4

RP105/TLR4 对组织炎症的调节

基本信息

批准号：
7650337
负责人：
Christopher L Karp
金额：
$ 8.78万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2008-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7650337
关键词：
Age Antibodies Arthritis Autoimmune Diseases Autoimmune Process B Cell Proliferation B-Lymphocytes Binding Cells Complex Dendritic Cells Dependence Dose Endotoxins Failure Fibronectins Genetic Goals Hand Heparitin Sulfate Homologous Gene Hyaluronan Immune response Infection Infection Control Inflammation Inflammatory Inflammatory Response Injury Lead Leishmania Ligands Light Literature Localized Lymphocyte Antigen 96 Mediating Microbe Molecular Molecular Profiling Mus Myeloid Cells Natural Immunity Organ Pathology Pattern Physiological Play Process Reagent Receptor Signaling Renaissance Research Role Sepsis Signal Pathway Signal Transduction Specificity Splenomegaly Sterility Structure Surface TLR4 gene Tissues Toll-Like Receptor Pathway Toll-like receptors Turpentine autoimmune arthritis in vivo in vivo Model inhibitor/antagonist macrophage microbial mouse model novel pathogen programs response success

项目摘要

Activation of Toll-like receptor (TLR signaling) by conserved microbial molecular signatures promotes the induction of both innate and adaptive immune responses. Such responses need to be kept under tight control. Immune responses that are delayed or of insufficient vigor can lead to a failure to control infection. On the other hand, excessive or inappropriate inflammation can be harmful or even fatal. The hyperinflammatory responses that characterize sepsis provide a paradigmatic example, as do the more localized inappropriate inflammatory processes associated with arthritis. In addition to signaling the presence of microbial products, the TLR pathway is also involved in signaling the presence of altered or damaged self. A variety of molecular patterns generated during tissue inflammation have been shown to signal through TLR4, the most robustly signaling of the TLRs. We recently discovered a novel endogenous inhibitor of TLR4 signaling in myeloid cells: the TLR4 homolog RP105. The central hypothesis underlying these studies is that RP105 acts to mute injurious tissue inflammatory responses through modulation of TLR4 signaling driven by endogenous ligands unmasked by tissue injury. The long-term goal of this research program is to define the molecular mechanisms that underlie dysregulation of tissue inflammatory responses in organ-specific autoimmune diseases such as the autoimmune arthritides. The studies in this proposal will employ genetic approaches to define the role of RP105 (and TLR4) in two well-defined mouse models of microbial productindependent, localized, inflammatory tissue injury: (1) sterile inflammation induced by oil of turpentine; and (2) antibody-induced arthritis.

Toll样受体（TLR信号传导）通过保守的微生物分子标记的激活促进了诱导先天性和适应性免疫应答。这种反应需要严格控制控制免疫反应延迟或活力不足可能导致无法控制感染。另一方面，过度或不适当的炎症可能是有害的，甚至是致命的。高炎症脓毒症的特征性反应提供了一个典型的例子，与关节炎相关的不适当的炎症过程。除了发出信号表明存在除了微生物产物外，TLR途径还参与了改变或受损自身的信号传导。在组织炎症过程中产生的各种分子模式已被证明可以通过 TLR 4是TLR中信号传导最强的。我们最近在骨髓细胞中发现了一种新的内源性TLR 4信号抑制剂：同源物RP 105。这些研究的核心假设是RP 105可以抑制有害的通过内源性配体驱动的TLR 4信号转导调节的组织炎症反应被组织损伤所掩盖这项研究计划的长期目标是确定器官特异性自身免疫性疾病中组织炎症反应失调的机制自身免疫性关节炎等疾病。本提案中的研究将采用遗传学方法为了确定RP 105（和TLR 4）在两种明确的微生物产物独立小鼠模型中的作用，局部炎性组织损伤：（1）由松节油诱导的无菌性炎症; (2)抗体诱发的关节炎