Role of chemokine monomer-dimer equilibrium in innate immunity and inflammation

趋化因子单体-二聚体平衡在先天免疫和炎症中的作用

基本信息

批准号：
7417794
负责人：
Krishna Rajarathnam
金额：
$ 32.36万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7417794
关键词：
1-Phosphatidylinositol 4-Kinase Affect Affinity Allergic Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Attenuated Bacterial Infections Binding Biological Assay Blood Blood Circulation Blood Vessels Cells Characteristics Chemotaxis Condition Coupled Data Devices Dimerization Disease Drug Design Economics Endothelial Cells Endothelium Equilibrium Event Extracellular Matrix Foundations G-Protein-Coupled Receptors Glycosaminoglycans Goals Homing Host Defense IL8 gene Immune Immunologic Surveillance In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-8 Knowledge Lead Leukocytes Lung Measures Mediating Microfluidics Modeling Molecular Mus Mutation Natural Immunity Neutrophil Infiltration Pathology Pathway interactions Peritoneal Pharmaceutical Preparations Phosphotransferases Physiological Play Population Process Property Protein Family Rate Reagent Recruitment Activity Regulation Relative (related person)Research Research Design Research Personnel Role Signal Transduction Solutions Structure Structure-Activity Relationship Symptoms System Techniques Technology Testing Thinking Tissues Variant Virus Diseases Work abstracting base chemokine chemokine receptor cost design dimer handicapping condition in vivo inhibitor/antagonist innovation migration monomer mortality mutant neutrophil novel pathogen prevent receptor receptor binding response stoichiometry trafficking

项目摘要

DESCRIPTION (provided by applicant): The chemokine CXCL8 (also known as interleukin-8) plays a key role in innate immunity and inflammation by recruiting neutrophils from the bloodstream to tissue damaged by such insults as bacterial infection. Our long-term goal is to understand the molecular mechanisms of CXCL8 function, and so lay the foundation for new anti-inflammatory treatments. CXCL8 exerts its function by binding to G protein-coupled receptors (GPCRs) on neutrophils, and to glycosaminoglycans (GAGs) on the extracellular matrix and endothelium. A fundamental property of chemokines is the ability to exist reversibly as both monomers and dinners. Therefore, knowledge of CXCL8 monomer and dimer binding to GPCRs and GAGs is critical for understanding in vivo neutrophil recruitment. Our hypothesis is that a dynamic equilibrium among four CXCL8 forms, monomers and dinners in solution and monomers and dinners bound to GAG, regulates in vivo neutrophil recruitment. In this project, we will test our hypothesis by characterizing mutants of trapped monomers and dimers and of native CXCL8 that show reduced binding to either GPCRs or GAGs, and mutants of native CXCL8 that show reduced dimerization potency. We will determine how monomer-dimer equilibrium, and the binding interactions of monomers and dimers for GAGs and GPCRs, regulate in vivo CXCL8 function in animal models (Aim 1). We will determine whether monomers and dinners elicit similar signaling events (but with different potencies), or elicit unique signaling events (Aim 2). Finally, by determining how monomers and dimers bind GAGs, we will better define the distribution of monomers and dimers in solution and bound to GAGs (Aim 3). Innovations in our research design include using a combination of biophysical, in vitro cell-based, and in vivo animal-based studies; novel reagents (trapped monomers and dimers); and a novel microfluid device technology to measure chemotaxis. Lay Abstract: Inflammation plays a central role in the pathology of many vascular and allergic diseases, and of bacterial and viral infections. These diseases cause significant infirmity and mortality, and exact a high economic cost. Current medications either treat the symptoms and not the disease, or are nonspecifically targeted to inhibit the immune and inflammatory responses. New drugs that are highly specific designed on the basis of chemokine function should thus provide better treatments for these diseases.

描述（由申请人提供）：趋化因子 CXCL8（也称为白细胞介素 8）通过将中性粒细胞从血流募集到因细菌感染等损伤而受损的组织，从而在先天免疫和炎症中发挥关键作用。我们的长期目标是了解CXCL8功能的分子机制，从而为新的抗炎治疗奠定基础。 CXCL8 通过与中性粒细胞上的 G 蛋白偶联受体 (GPCR) 以及细胞外基质和内皮细胞上的糖胺聚糖 (GAG) 结合来发挥其功能。趋化因子的一个基本特性是能够以单体和晚餐形式可逆地存在。因此，了解 CXCL8 单体和二聚体与 GPCR 和 GAG 的结合对于了解体内中性粒细胞募集至关重要。我们的假设是四种 CXCL8 形式、溶液中的单体和晚餐以及与 GAG 结合的单体和晚餐之间的动态平衡调节体内中性粒细胞的募集。在这个项目中，我们将通过表征被捕获的单体和二聚体以及天然 CXCL8 的突变体（显示出与 GPCR 或 GAG 的结合减少）以及显示出二聚化效力降低的天然 CXCL8 突变体来检验我们的假设。我们将确定单体-二聚体平衡以及 GAG 和 GPCR 单体和二聚体的结合相互作用如何在动物模型中调节体内 CXCL8 功能（目标 1）。我们将确定单体和晚餐是否引发类似的信号事件（但具有不同的效力），或引发独特的信号事件（目标 2）。最后，通过确定单体和二聚体如何结合 GAG，我们将更好地定义溶液中单体和二聚体以及与 GAG 结合的分布（目标 3）。我们研究设计的创新包括结合生物物理、体外细胞和体内动物研究；新型试剂（捕获的单体和二聚体）；以及一种测量趋化性的新型微流体装置技术。摘要：炎症在许多血管和过敏性疾病以及细菌和病毒感染的病理学中起着核心作用。这些疾病导致严重的疾病和死亡，并带来高昂的经济成本。目前的药物要么治疗症状而不是疾病，要么非特异性地抑制免疫和炎症反应。因此，基于趋化因子功能的高度特异性设计的新药应该为这些疾病提供更好的治疗。