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: 8058800
• 负责人: JOSEPH EL EL-KHOURY
• 金额: $ 59.86万
• 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/8058800
• 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

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组分和细胞防御的宿主防御合作网络。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的病原体衍生物或改变的自我成分。已经鉴定了许多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的清道夫受体家族。清道夫受体（SR）是结构上不相关的受体，其共享结合聚阴离子配体的能力。这种简单的定义掩盖了SR作为PRR-SR的重要性，SR是原型多功能受体，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的潜在门户的细胞上，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，为它们提供由细胞类型和起源组织两者定义的独特PRR签名。除了作为吞噬/内吞受体起作用之外，一些SR可以独立地和与其他PRR家族（例如TLR）合作地发出信号以响应病原体。因此，通过组合信号，SR有助于微调病原体特异性反应。此外，SR是修饰的内源性配体的主要类型的受体，提供先天免疫激活和无菌性炎性疾病之间的联系。然而，尽管SR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，但清道夫受体生物学领域明显落后于TLR和NLR。具体而言，缺乏研究SR的几种必需试剂，因此限制了对许多这些分子的体外和体内研究。在这里，我们建议专注于开发基于清道夫受体的试剂。具体而言，我们提出开发试剂，其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，以及3）将利用由不同免疫细胞表达的SR将基于纳米颗粒的试剂递送至体内特定细胞亚群。 相关性（见说明书）：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）是此类受体的重要家族，参与针对多种病原体的保护。了解SR在免疫中的作用对于推进疫苗开发以及为生物防御和新兴传染病产生新的治疗方法至关重要。我们建议产生一个全面的试剂组，以促进这些重要的先天免疫受体的研究