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

• 批准号: 7928276
• 负责人: JOSEPH EL EL-KHOURY
• 金额: $ 61.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928276
• 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; Work; base; biodefense; cell type; combinatorial; in vivo; macrophage; microbial; nanoparticle; novel; novel therapeutics; overexpression; pathogen; receptor; response; scavenger receptor; small molecule libraries; uptake; vaccine development

DESCRIPTION (provided by applicant): The innate immune system is a cooperative network of host defenses that utilizes both soluble components and cellular defenses. Central to innate immune recognition are pattern recognition receptors (PRRs) that recognize pathogen derivatives or altered-self components normally absent from the healthy host. Numerous families of PRRs have been identified including the well-defined Toll-like and Nod-like receptors (TLR and 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 SRs as PRRs - SRs are archetypal multifunctional receptors, often able to bind ligands of both pathogen and self-origin. SRs are found on cells that patrol potential portals of pathogen entry such as endothelial cells and phagocytes, including macrophages, dendritic cells and microglia. Different cells express distinct repertoires of PRR including SRs providing them with a unique PRR signature, defined by both the cell type and the tissue of origin. In addition to functioning as phagocytic/endocytic receptors, some SRs can both signal independently and cooperatively with other families of PRRs such as the TLRs to respond to pathogens. Thus, through combinatorial signaling, SRs help fine-tune pathogen-specific responses. In addition, SRs are the major class of receptors for modified endogenous ligands providing a link between innate immune activation and sterile inflammatory diseases. However, despite the importance of SRs in pathogen recognition and the emergence of new roles for these molecules in inflammation, the field of scavenger receptor biology has significantly lagged behind that of TLRs and NLRs. Specifically, several essential reagents to study SRs are lacking and 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 SR biology and SR-ligand interactions, 2) inhibit the function of SRs in ligand uptake and signaling and 3) that will utilize the SRs expressed 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

描述（由申请人提供）：先天免疫系统是利用可溶性成分和细胞防御的宿主防御协作网络。先天免疫识别的核心是模式识别受体（PRR），它可以识别健康宿主通常不存在的病原体衍生物或自我改变成分。已鉴定出许多 PRR 家族，包括明确定义的 Toll 样和 Nod 样受体（TLR 和 NLR）。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 SR 的重要性，因为 PRR - SR 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。 SR 存在于巡逻病原体进入潜在门户的细胞上，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定义。除了充当吞噬/内吞受体之外，一些 SR 既可以独立发出信号，也可以与其他 PRR 家族（例如 TLR）协作发出信号，以对病原体做出反应。因此，通过组合信号传导，SR 有助于微调病原体特异性反应。此外，SR 是修饰内源性配体的主要受体，在先天免疫激活和无菌性炎症疾病之间提供联系。然而，尽管SR在病原体识别中很重要，并且这些分子在炎症中出现了新的作用，但清道夫受体生物学领域却明显落后于TLR和NLR。具体来说，缺乏研究 SR 的几种必需试剂，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，我们建议开发试剂，1) 将促进 SR 生物学和 SR-配体相互作用的研究，2) 抑制 SR 在配体摄取和信号传导中的功能，3) 将利用不同免疫细胞表达的 SR 来递送基于纳米颗粒的试剂。针对体内特定细胞亚群的试剂。 相关性（参见说明）：针对病原体的免疫防御是在模式识别受体识别微生物后启动的。清道夫受体（SR）是此类受体的一个重要家族，参与防御多种病原体。了解 SR 在免疫中的作用对于推进疫苗开发以及开发生物防御和新发传染病的新疗法至关重要。我们建议生成一套全面的试剂来促进这些重要的先天免疫受体的研究