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

IL-16os是一种由支气管上皮产生的细胞因子，可诱导CD细胞的运动反应，可在哮喘患者的支气管肺泡灌洗液中检测到。我们已经确定了一个80kda的IL-16前体分子IL-16/80，从中可以切割出具有生物活性的IL-16/14。IL-16/80在哮喘中的生物学活性及其作用机制尚不清楚。我们已经开始研究IL-16在体内的效应功能，建立了第一个以IL-16/14为靶点的转基因小鼠。转基因阳性动物在用5-羟色胺攻击后，在基线水平产生和分泌具有生物活性的IL-16。在RSV感染后，转基因动物还会出现炎症、呼吸道粘液、干扰素-γ、IL-6和乙脑/单核细胞趋化蛋白-1的增强。在这项资助中，我们建议使用这些小鼠和IL-16/80转基因来表征体内效应，包括在正常和发炎的呼吸道中的作用。我们将：目标1：通过定义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5-羟色胺攻击后产生的IL-16部分来表征转基因小鼠。目的2.研究CCC-10-IL-16/14小鼠对卵清蛋白和呼吸道合胞病毒诱导的呼吸道炎症的反应以及在这些模型中产生的IL-16部分。目的：建立并鉴定使用CC10启动子在肺内过表达IL-16/80的转基因小鼠。我们将表征这些动物在基线和5-羟色胺攻击后的表型，以及这些动物产生的IL-16部分。目的：研究C-10-11-16/80小鼠对卵清蛋白和呼吸道合胞病毒诱导的呼吸道炎症的反应以及在这些模型中产生的IL-16部分。在这些实验中，我们将在体内表征C端生物活性形式的IL-16(IL-16/14)和IL-16/80在基线和正常炎症应激时的效应功能。我们将在基线和炎症背景下确定这些动物肺中IL-16的含量。这些研究将对IL-16的生物效应功能和IL-16激素前体在健康和疾病中的加工机制提供深刻的见解。我将在实现本提案中概述的目标中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调查人员。这些发现将通过我们对IL-16生物学和哮喘的呼吸道炎症和愈合机制的了解而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.