SP-A Receptor Regulation in Lung Innate Defense

肺先天防御中 SP-A 受体的调节

• 批准号: 7228589
• 负责人: ANN MARIE LEVINE
• 金额: $ 34.49万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228589
• 关键词: 1-Phosphatidylinositol 3-Kinase; A Mouse; Alveolar Macrophages; Bacteria; Bacterial Infections; Bacterial Pneumonia; Binding; Binding Sites; Cell Line; Cell Surface Receptors; Cell surface; Cells; Child; Childhood; Chromosomes, Human, Pair 10; Co-Immunoprecipitations; Collectins; Complement Receptor; Complement Receptor Type 1; Complex; Cytoskeleton; DNA Sequence Rearrangement; Data; Disease; Event; Flow Cytometry; Future; Goals; Haemophilus influenzae; Host Defense; Immunoblotting; In Vitro; Incubated; Laboratories; Ligand Binding; Lung; Macrophage-1 Antigen; Measures; Mediating; Messenger RNA; Modeling; Morbidity - disease rate; Mus; Numbers; Patients; Personal Satisfaction; Phagocytes; Phagocytosis; Play; Production; Proteins; Pulmonary Surfactant-Associated Protein A; Reactive Oxygen Species; Regulation; Respiratory Burst; Role; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Streptococcus; Streptococcus Group B; Surface; Testing; Therapeutic; Wild Type Mouse; base; concept; design; in vivo; killings; macrophage; microbial; microorganism; mutant; pathogen; polypeptide; prevent; receptor; receptor expression; response; surfactant; surfactant protein A receptor; uptake

DESCRIPTION (provided by applicant): This application will test the hypothesis that surfactant protein-A (SP-A), a pulmonary collectin, plays a critical role in protecting the lung from bacterial infection by modulating surface receptors on alveolar macrophages. Preliminary data presented in this application provides a clear relationship between SP-A and complement receptor type 3 (CR3) providing a strong inference that SP-A effects are mediated through CR3. We propose that SP-A serves complex regulatory roles in the lung, binding to cell surface receptors present on alveolar macrophages influencing binding, uptake, and killing of microorganisms. CR3 is an important phagocyte receptor for recognition of microbial pathogens and is responsible for mediating phagocytosis, degranulation, and respiratory bursts by phagocytic cells. CR3 mediated phagocytosis is important in clearance of group B streptococcus (GBS) and Haemophilus influenza, both important pathogens in childhood disease. This application will utilize models in which the synthesis of SP-A is altered genetically, using SP-A-/- and SP-A+/+ mice to determine if CR3 expression on alveolar macrophages is altered in the absence of SP-A. This application will test the central hypothesis that SP-A enhances phagocytosis and activates alveolar macrophages by modulating surface receptors mediating these events. Specific Aim 1 will test the hypothesis that SP-A regulates expression of CR3 on alveolar macrophages by mobilizing intracellular CR3 pools. Specific Aim 2 will test the hypothesis that SP-A binds to CR3 on alveolar macrophages and will determine the specific SP-A domain that enhances CR3 expression. Specific Aim 3 will test the hypothesis that SP-A opsonized GBS or H. influenza activate CR3 to enhance macrophage phagocytosis and oxygen radical production. Signaling pathways important in SP-A enhanced CR3 mediated phagocytosis will be studied in vitro using CR3 transfected cells and in vivo with alveolar macrophages from SP-A-/-, CR3-/-, SP-A-/-CR3-/- and wild type mice. These studies will help clarify the role of SP-A in innate defense of the lung and provide the basis for future therapies to maintain endogenous or supply exogenous SP-A to prevent morbidity from bacterial infection.

描述（由申请人提供）：本申请将检验以下假设：表面活性剂蛋白 A (SP-A)（一种肺集合素）通过调节肺泡巨噬细胞上的表面受体，在保护肺部免受细菌感染方面发挥着关键作用。 本申请中提供的初步数据提供了 SP-A 与补体受体 3 型 (CR3) 之间的明确关系，从而提供了 SP-A 效应是通过 CR3 介导的强有力的推论。 我们认为 SP-A 在肺中发挥着复杂的调节作用，与肺泡巨噬细胞上存在的细胞表面受体结合，影响微生物的结合、摄取和杀死。 CR3是识别微生物病原体的重要吞噬细胞受体，负责介导吞噬细胞的吞噬作用、脱颗粒和呼吸爆发。 CR3 介导的吞噬作用对于清除 B 族链球菌 (GBS) 和流感嗜血杆菌（这两种儿童疾病的重要病原体）非常重要。 该应用将利用 SP-A 合成经过基因改变的模型，使用 SP-A-/- 和 SP-A+/+ 小鼠来确定肺泡巨噬细胞上的 CR3 表达在没有 SP-A 的情况下是否发生改变。 该应用将测试 SP-A 通过调节介导这些事件的表面受体来增强吞噬作用并激活肺泡巨噬细胞的中心假设。 具体目标 1 将检验 SP-A 通过动员细胞内 CR3 池来调节肺泡巨噬细胞上 CR3 表达的假设。 具体目标 2 将测试 SP-A 与肺泡巨噬细胞上的 CR3 结合的假设，并将确定增强 CR3 表达的特定 SP-A 结构域。 具体目标 3 将检验 SP-A 调理 GBS 或流感嗜血杆菌激活 CR3 以增强巨噬细胞吞噬作用和氧自由基产生的假设。 SP-A 增强 CR3 介导的吞噬作用中重要的信号通路将在体外使用 CR3 转染细胞进行研究，并在体内使用来自 SP-A-/-、CR3-/-、SP-A-/-CR3-/- 和野生型小鼠的肺泡巨噬细胞进行研究。 这些研究将有助于阐明 SP-A 在肺部先天防御中的作用，并为未来维持内源性或供应外源性 SP-A 以预防细菌感染发病的治疗奠定基础。