BIOLOGY OF IL-16 IN IL-1680 AND IL-1614 TRANSGENIC MICE

IL-16是一种由支气管上皮细胞产生的细胞因子，可诱导CD携带细胞的运动反应，并可在哮喘患者的支气管肺泡灌洗液中检测到。我们已经鉴定了80 kDA的IL-16前体分子IL-16/80，生物活性IL-16/14从该前体分子IL-16/80裂解。IL-16/80在哮喘中的生物学活性及其作用机制尚不清楚。我们已经开始了研究，通过产生第一个靶向IL-16/14到支气管上皮的转基因小鼠来表征IL-16的体内效应器功能。转基因阳性阳性动物在用5-羟色胺攻击后以夸大的量在基线产生和分泌生物活性IL-16。转基因动物在RSV感染后还发展出增强的炎症、气道粘液、IFN-γ、IL-6和JE/MCP-1。在这项研究中，我们建议使用这些小鼠和IL-16/80转基因来表征在正常和炎症气道中的体内作用。我们将：目标1：通过定义CC 10-IL-16/14转基因小鼠的组织学、免疫学和生理学以及这些动物在基线和血清素激发后产生的IL-16部分来表征这些小鼠。目标二。表征CCC-10-IL-16/14小鼠对卵清蛋白和呼吸道合胞病毒诱导的气道炎症的反应以及这些模型中产生的IL-16部分。目的3：产生和表征IL- 16/80转基因小鼠，其中CC 10启动子用于在肺中过表达IL-16/80。我们将在基线和血清素激发后表征这些动物的表型以及这些动物产生的IL-16部分。目标4：表征C-10-11- 16/80小鼠对卵清蛋白和呼吸道合胞病毒诱导的气道炎症的反应以及这些模型中产生的IL-16部分。在这些实验中，我们将在体内表征IL-16（IL-16/14）和IL-16/80的C-末端生物活性形式在基线和破坏炎症应激时的效应器功能。我们将在基线和炎症情况下表征这些动物肺中的IL-16部分。这些研究将为IL-16的生物效应器功能以及IL-16前激素在健康和疾病中的加工机制提供深刻的见解。我在实现本提案中概述的目标时获得的经验和技术将补充我以前的研究经验，并将帮助我成长为一名科学家，并最终成为一名独立的研究人员。这些发现将维斯我们对IL-16生物学和哮喘气道炎症和愈合机制的了解产生令人印象深刻的影响。

IL-16 os a cytokine produced by bronchial epithelium which induces motile responses in CD bearing cells, and is detectable in bronchoalveolar lavage fluid of asthmatics. We have identified an 80 kDA IL-16 precursor molecule, IL-16/80 from which bioactive IL-16/14 is cleaved. The biologic activities, in asthma and processing mechanisms of IL-16/80 are unknown. We have initiated studies to characterize the in vivo effector functions of IL-16 by generating the first transgenic mice which target IL-16/14 to the bronchial epithelium. Transgene positive positive animals produce and secrete bioactive IL-16 at baseline in exaggerated amounts after challenge with serotonin. Transgenic animals also develop enhanced inflammation, airway mucous, IFN-gamma, IL-6, and JE/MCP-1 after RSV infections. In this grant we propose to use these mice and IL-16/80 transgenics to characterize the in vivo effects, processing in the normal and inflamed airway. We will: Aim 1: Characterize the CC10-IL-16/14 transgenic mice by defining their histology, immunology and physiology and the IL-16 moieties produced in these animals at baseline and after serotonin challenge. Aim 2. Characterize the responses of CCC-10-IL-16/14 mice to ovalbumin and respiratory syncytial virus induced airway inflammation and the IL-16 moieties produced in these models. Aim 3: Generate and characterize IL- 16/80 transgenic mice in which the CC10 promoter is used to over-express IL-16/80 in the lung. We will characterize the phenotype of these animals at baseline and after serotonin challenge and the IL-16 moieties produced by these animals. Aim 4: Characterize the responses of C-10-11- 16/80 mice to ovalbumin and respiratory syncytial virus induced airway inflammation and the IL-16 moieties produced in these models. In these experiments we will characterize the in vivo the effector functions of the C-terminal bioactive form of IL-16 (IL-16/14) and IL-16/80 at baseline and ruing inflammatory stress. We will characterize the IL-16 moieties in the lungs of these animals at baseline and in the setting of inflammation. These studies will provide profound insights into the biologic effector functions of IL-16 and the mechanisms of processing of the IL-16 pro-hormone in health and disease. The experience and techniques I will gain in achieving the goals outlined in this proposal will compliment my previous research experience and will help me grow as a scientist and ultimately become an independent investigator. These finding swill have impressive implications via-a-vis our knowledge of the biology of IL-16 and mechanisms of airway inflammation and healing in asthma.