TRANSGENIC MOUSE MODEL OF BRONCHIOLITIS OBLITERANS

闭塞性细支气管炎转基因小鼠模型

• 批准号: 6169202
• 负责人: Stuart C Sweet
• 金额: $ 11.73万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6169202
• 关键词: MHC class I antigen; disease /disorder model; genetically modified animals; histology; immune tolerance /unresponsiveness; laboratory mouse; lung transplantation; model design /development; platelet derived growth factor; respiratory epithelium; transplant rejection

This application seeks funding for Dr. Stuart C. Sweet, currently a fellow in Pediatric Pulmonary at Washington University, St. Louis, to seek additional training in cellular immunology. Dr. Sweet's long term interests involve understanding the cellular mechanisms of chronic graft dysfunction in lung transplant recipients. the goal of the project outlined in this application is to develop a murine model system which mimics the most important form of chronic lung transplant graft dysfunction, broncholitis obliterans (BO), which occurs in between 25% and 50% of lung transplant recipients and is th major cuase of late mortality. Although the etiology of BO remains unclear, current evidence implicates two potentially important mechanisms: chronic immune-mediated epithelial injury and over expression of platelet derived growth factor (PCGF). We propose to use transgenic mice to test both of these possiblities. To test whehter an allogeneic immune response is responsible for BO, transgenic mice will be generated which express the mouse class I antigen, L(d) under the control of the Clara cell secretory protein (CCSP) promoter. The CCSP promoter directs expression of genes to the Clara cells which comprise 75% of the bronchiolar epithelial cells in the junctional region between the conducting and respitory bronchioles. The bronchioles. The bronchiolar epitehlium is the primary site where damage is observed in BO. Brocchiolar injury will be induced by adoptive transfer of L(d) reactive lymphocytes; lungs from these animals will be examined for histologic changes similar to BO. To determine whether over-expression is important in the development of BO, trangenic mice will be generated in which PDGF-B expression in the bronchiolar epithelium can be induced by the administration of doxycycline. As above, lngs from these animals will be examined for histologic changes similar to BO. Animals in which both of the potential mechanisms are active will also be evaluated. Determining whether an allogeneic immune response is sufficient to induce the development of BO will be particularly important because at this time enhanced immunosuppression is the predominant therapy for patients with BO. If PDGF over-expression plays an important rolw in the etiology of BO, it will suggest that therapy directed against growth factors may be benfeficial. These animals would then provide a model system in which new forms of therapy may be tested. Dr. Sweet anticipates joining the faculty of the Department of Pediatrics in July 1996, and will be supervised during the period of support by Professor Ted Hansen in the Department of Genetics. The funds provided by this award will facilitate Dr. Sweets's development into an independent scientist.

该申请为Stuart C. Sweet博士寻求资金，目前是研究员 圣路易斯华盛顿大学的小儿肺部寻找 细胞免疫学的额外培训。 Sweet博士的长期 兴趣涉及了解慢性移植的细胞机制 肺移植受者的功能障碍。 项目的目标 此应用程序中概述的是开发一种鼠模型系统 模仿慢性肺移植移植的最重要形式 功能障碍，支气管炎闭塞（BO），发生在25％至 50％的肺移植受者是晚期死亡率的主要库。 尽管BO的病因尚不清楚，但目前的证据涉及 两个潜在的重要机制：慢性免疫介导的上皮 损伤和血小板衍生生长因子（PCGF）的表达。我们 建议使用转基因小鼠测试这两种可能性。 测试同种异体免疫反应是造成BO的原因 将产生转基因小鼠，表达鼠标I类抗原， l（d）在克拉拉细胞分泌蛋白（CCSP）启动子的控制下。 CCSP启动子将基因的表达引向clara细胞 占连接区域的支气管上皮细胞的75％ 在导电和响应支气管之间。 支气管。 这 支气管卵是在BO中观察到损害的主要部位。 Bocchiolar损伤将通过L（d）反应性的过继转移来诱导 淋巴细胞；将检查这些动物的肺部组织学 变化类似于BO。 为了确定过度表达在BO的发展中是否重要， 将生成thrangenic小鼠，其中PDGF-B在该中表达 细支气管上皮可以通过强力霉素的施用来诱导。 如上所述，将检查这些动物的LNG是否有组织学变化 类似于bo。 两种潜在机制的动物 活动还将评估。 确定同种异体免疫反应是否足以诱导 BO的发展将特别重要，因为目前 增强的免疫抑制是BO患者的主要治疗。 如果PDGF过表达在BO的病因中起着重要的作用，则 会表明针对生长因素的治疗可能是 本菲。 这些动物将提供一个模型系统，其中新的 可以测试治疗形式。 Sweet博士期望加入儿科系 1996年7月，将在支持期间受到监督 遗传学系的泰德·汉森教授。 提供的资金 该奖项将使Sweets博士的发展成为独立的发展 科学家。