SP-A Receptor Regulation in Lung Innate Defense
肺先天防御中 SP-A 受体的调节
基本信息
- 批准号:7122068
- 负责人:
- 金额:$ 35.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-07-01 至 2008-06-30
- 项目状态:已结题
- 来源:
- 关键词:Streptococcus agalactiaealveolar macrophagesbacteria infection mechanismbactericidal immunitybiological modelsbiological signal transductioncell linecell surface receptorsclearance ratecomplement receptorflow cytometryfree radical oxygengene targetinggenetically modified animalslaboratory mousemicroorganism culturephagocytosisphosphatidylinositol 3 kinaseprotein biosynthesisprotein structure functionpulmonary surfactantsreceptor bindingsite directed mutagenesistransfectionwestern blottings
项目摘要
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(申请人提供):这项申请将测试表面活性蛋白-A(SP-A),一种肺集合素,通过调节肺泡巨噬细胞表面受体在保护肺免受细菌感染方面发挥关键作用的假设。本申请提供的初步数据提供了SP-A和补体受体3型(CR3)之间的明确关系,提供了一个强有力的推断,即SP-A的作用是通过CR3介导的。我们认为,SP-A在肺中起着复杂的调节作用,它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、摄取和杀伤。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、脱颗粒和呼吸爆发。CR3介导的吞噬作用在清除B组链球菌(GBS)和流感嗜血杆菌这两种儿童疾病的重要病原体方面起着重要作用。这项应用将利用SP-A合成发生遗传改变的模型,使用SP-A-/-和SP-A+/+小鼠来确定在没有SP-A的情况下,肺泡巨噬细胞上CR3的表达是否发生改变。这一应用将检验核心假设,即SP-A通过调节介导这些事件的表面受体来增强吞噬功能并激活肺泡巨噬细胞。具体目标1将验证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。特定目标2将验证SP-A与肺泡巨噬细胞上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将验证SP-A调理GBS或H.流感激活CR3以增强巨噬细胞吞噬和氧自由基产生的假设。在SP-A-/-、CR3-/-、SP-A-/-CR3-/-和野生型小鼠肺泡巨噬细胞中,重要的信号转导途径将在体外用CR3转基因细胞和体内用肺泡巨噬细胞进行研究。这些研究将有助于阐明SP-A在肺固有防御中的作用,并为未来维持内源性或外源性SP-A以预防细菌感染的发病率提供依据。
项目成果
期刊论文数量(0)
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ANN MARIE LEVINE其他文献
ANN MARIE LEVINE的其他文献
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{{ truncateString('ANN MARIE LEVINE', 18)}}的其他基金
SP-A Receptor Regulation in Lung Innate Defense
肺先天防御中 SP-A 受体的调节
- 批准号:
6765152 - 财政年份:2003
- 资助金额:
$ 35.52万 - 项目类别:
SP-A Receptor Regulation in Lung Innate Defense
肺先天防御中 SP-A 受体的调节
- 批准号:
6904594 - 财政年份:2003
- 资助金额:
$ 35.52万 - 项目类别:
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 - 财政年份:2003
- 资助金额:
$ 35.52万 - 项目类别:
SP-A Receptor Regulation in Lung Innate Defense
肺先天防御中 SP-A 受体的调节
- 批准号:
6677946 - 财政年份:2003
- 资助金额:
$ 35.52万 - 项目类别:
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