Generation of a comprehensive panel of reagents for research on scavenger recepto

生成用于清除剂受体研究的综合试剂组

基本信息

批准号：
8244402
负责人：
JOSEPH EL EL-KHOURY
金额：
$ 60.07万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8244402
关键词：
Binding Biology Cell Line Cells Dendritic Cells Disease Emerging Communicable Diseases Endocytosis Endothelial Cells Family Flow Cytometry Frozen Sections Generations Host Defense Human Image Immune Immune system Immunity Immunohistochemistry Immunologic Receptors In Vitro Inflammation Inflammatory Instruction Knock-out Libraries Life Ligand Binding Ligands Link Microglia Monoclonal Antibodies Mus Paraffin Embedding Pattern recognition receptor Phagocytes Principal Investigator Property Protein Family Reagent Recombinant Proteins Recombinants Research Role Screening procedure Signal Transduction Sterility Therapeutic Tissues Western Blotting base biodefense cell type combinatorial immune activation in vivo macrophage microbial nanoparticle novel novel therapeutics overexpression pathogen receptor response scavenger receptor small molecule libraries uptake vaccine development

项目摘要

The innate immune system is a cooperative network of host defenses that utilizes both soluble components and cellular defenses. Central to innate immunerecognition are pattern recognition receptors (PRRs)that recognize pathogen derivatives or altered-self components normallyabsent from the healthy host. Numerousfamilies of PRRs have been identified includingthe well-defined Toll-likeand Nod-like receptors (TLRand NLRs). In addition to these molecules another large family of PRRs are the scavenger receptor family of proteins. Scavenger receptors (SRs) are structurally unrelated receptors that share the ability to bind polyanionic ligands. This simple definition belies the importance of SRsas PRRs - SRsare archetypal multifunctional receptors, often able to bind ligands of both pathogen and self-origin. SRsare found on cells that patrol potential portals of pathogen entry such as endothelial cells and phagocytes, including macrophages, dendriticcells andmicroglia. Different cells express distinct repertoires of PRRincludingSRsprovidingthem with a unique PRR signature, defined by both the cell type and the tissue oforigin. In addition to functioning as phagocytic/endocytic receptors, some SRscan both signal independently and cooperatively with other families of PRRs such as the TLRs to respond to pathogens. Thus, through combinatorialsignaling,SRshelp fine-tunepathogen-specific responses. In addition, SRsare the major class of receptors for modified endogenous ligands providinga link between innate immune activation and sterile inflammatorydiseases. However, despite the importance of SRsin pathogen recognition and the emergence of new roles for these molecules in inflammation, the field of scavenger receptor biologyhas significantly lagged behind that of TLRs and NLRs. Specifically, several essential reagents to study SRsare lackingand hence have limited the study of many of these molecules both in vitro and in vivo. Here we propose to focus on developing scavenger-receptor based reagents. Specifically we propose to develop reagents that 1) will facilitate studies of SRbiology and SR-ligand interactions, 2) inhibitthe function of SRsin ligand uptake and signalingand 3) that will utilizethe SRsexpressed by different immune cells to deliver nanoparticle based reagents to specific subpopulations of cells in vivo. RELEVANCE (See instructions): Immune defense against pathogens is initiated after microbial recognition by pattern recognition receptors. Scavenger receptors (SRs) are an important family of such receptors, involved in protection against diverse pathogens. Understanding the role of SRs in immunity is crucial to advance vaccine development and to generate new therapeutics for biodefense and emerging infectious diseases. We propose to generate a comprehensive panel of reagents to facilitate study of these important innate immune receptors

先天免疫系统是宿主防御的协作网络，利用可溶性成分和细胞防御。先天免疫识别的核心是模式识别受体 (PRR)，它识别健康宿主通常不存在病原体衍生物或改变自身的成分。无数家庭已鉴定的 PRR 包括明确定义的 Toll 样和 Nod 样受体（TLR 和 NLR）。在除了这些分子之外，PRR 的另一个大家族是蛋白质清道夫受体家族。清道夫受体 (SR) 是结构上不相关的受体，它们具有结合聚阴离子配体的能力。这个简单的定义掩盖了 SRsas PRR 的重要性 - SRs 是典型的多功能受体，通常能够结合病原体和自身来源的配体。在巡逻潜在门户的细胞上发现了 SR 病原体进入，例如内皮细胞和吞噬细胞，包括巨噬细胞、树突状细胞和小胶质细胞。不同的细胞表达不同的 PRR 库，包括 SR，为它们提供独特的 PRR 特征，由细胞类型和来源组织共同定义。除了吞噬/内吞功能外受体，一些 SRscan 既独立地发出信号，又与其他 PRR 家族（例如 TLR 对病原体做出反应。因此，通过组合信号传导，SR 有助于微调病原体特异性回应。此外，SR 是修饰内源性配体的主要受体，提供了一种连接先天免疫激活和无菌性炎症疾病之间的关系。然而，尽管 SRsin 很重要病原体识别以及这些分子在炎症、清道夫领域中新作用的出现受体生物学明显落后于 TLR 和 NLR。具体来说，几种必需的试剂缺乏SR研究，因此限制了许多这些分子的体外和体内研究。在这里，我们建议重点开发基于清道夫受体的试剂。具体来说，我们建议开发 1) 将促进 SR 生物学和 SR-配体相互作用的研究，2) 抑制 SRsin 功能的试剂配体摄取和信号传导以及 3) 将利用不同免疫细胞表达的 SR 来传递基于纳米颗粒的试剂针对体内特定细胞亚群。相关性（参见说明）：针对病原体的免疫防御是在微生物被模式识别受体识别后启动的。清道夫受体（SR）是此类受体的一个重要家族，参与保护免受多种病原体。了解 SR 在免疫中的作用对于推进疫苗开发和为生物防御和新出现的传染病开发新的疗法。我们建议生成一个全面的试剂组可促进这些重要的先天免疫受体的研究