TRANSGENIC MOUSE MODEL OF BRONCHIOLITIS OBLITERANS

闭塞性细支气管炎转基因小鼠模型

• 批准号: 2886046
• 负责人: Stuart C Sweet
• 金额: $ 8.58万
• 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 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2886046
• 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.

本申请旨在为Stuart C博士提供资金。很好，现在是一个 圣路易斯华盛顿大学儿科肺科，寻求 细胞免疫学的额外培训。 斯威特医生的长期 兴趣包括了解慢性移植的细胞机制 肺移植受者的功能障碍。 该项目的目标 本申请概述的是开发一种鼠模型系统，其 模拟了慢性肺移植的最重要形式 功能障碍，闭塞性支气管炎（BO），发生在25%和 50%的肺移植受者是晚期死亡的主要原因。 虽然BO的病因尚不清楚，但目前的证据表明， 两个潜在的重要机制：慢性免疫介导的上皮细胞 损伤和血小板衍生生长因子（PCGF）的过度表达。我们 我建议使用转基因小鼠来测试这两种可能性。 为了测试同种异体免疫反应是否是BO的原因， 将产生表达小鼠I类抗原的转基因小鼠， L（d）在Clara细胞分泌蛋白（CCSP）启动子的控制下。 CCSP启动子引导基因表达至Clara细胞， 包括交界区75%的细支气管上皮细胞 传导细支气管和呼吸细支气管之间。 细支气管。 的 细支气管上皮是BO中观察到损伤的主要部位。 通过过继性转移L（d）反应性蛋白， 淋巴细胞;将检查这些动物的肺组织学 类似于BO的变化。 为了确定过度表达在BO的发展中是否重要， 将产生转基因小鼠，其中PDGF-B在转基因小鼠中表达。 细支气管上皮可以通过给予强力霉素来诱导。 如上所述，将检查这些动物的lng的组织学变化 类似于BO。 两种潜在机制同时存在的动物 积极的也将得到评价。 确定同种异体免疫应答是否足以诱导 BO的发展将特别重要，因为此时 增强的免疫抑制是BO患者的主要疗法。 如果PDGF的过度表达在BO的病因学中起重要作用， 将表明，针对生长因子的治疗可能是 benfefetion. 这些动物将提供一个模型系统， 可以测试各种治疗方法。 博士斯威特预计将加入儿科系 1996年7月，在支助期间， 遗传学系的泰德汉森教授。 提供的资金 这个奖项将促进斯维斯博士的发展成为一个独立的 科学家