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: 7787085
• 负责人: JOSEPH EL EL-KHOURY
• 金额: $ 59.91万
• 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: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787085
• 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; immune activation; 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）：先天免疫系统是使用可溶性组件和蜂窝防御的主机防御的合作网络。先天免疫识别的核心是模式识别受体（PRR），这些受体识别病原体衍生物或通常不存在健康宿主的改变自我成分。已经确定了许多PRR家族，包括定义明确的Toll样和点头样受体（TLR和NLR）。除这些分子外，另一个大型PRR家族是蛋白质的清道夫受体家族。清道夫受体（SRS）是结构无关的受体，具有结合聚苯故配体的能力。这个简单的定义掩盖了SRS作为PRRS -SRS的重要性是原型的多功能受体，通常能够结合病原体和自根的配体。在巡逻病原体进入潜在门户的细胞上发现了SR，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。不同的细胞表达了PRR的独特曲目，包括SR，为它们提供了独特的PRR特征，该标志由细胞类型和原始组织定义。除了充当吞噬/内吞受体的功能外，某些SR还可以独立和合作地与其他PRR家族（例如TLR）对病原体作出反应。因此，通过组合信号传导，SRS有助于微调病原体特异性反应。此外，SR是改良的内源性配体的主要受体类别，可提供先天免疫激活与无菌炎症性疾病之间的联系。然而，尽管SRS在病原体识别中的重要性以及这些分子在炎症中的新作用的出现，但清除剂受体生物学领域仍显着落后于TLR和NLR。具体而言，缺乏研究SR的几种基本试剂，因此在体外和体内限制了许多这些分子的研究。在这里，我们建议专注于开发基于清除仪的试剂。具体而言，我们建议开发试剂，即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SR功能以及3）将利用不同免疫细胞表达的SRS，以将基于纳米粒细胞的基于纳米粒细胞的剂量提供至VIVO中细胞的特定特异性亚型。 相关性（请参阅说明）：通过模式识别受体识别微生物识别后，针对病原体的免疫防御。清道夫受体（SRS）是此类受体的重要家族，涉及对各种病原体的保护。了解SR在免疫中的作用对于推动疫苗发育和生成生物粘液症和新兴传染病的新疗法至关重要。我们建议生成一个全面的试剂小组，以促进研究这些重要的先天免疫受体