Trangenic Approaches to understanding the biology of airways gene tranfer

囊性纤维化是一种遗传性疾病，由囊性纤维化跨膜传导性丧失引起。 调整器(CFTR)。该病累及多个器官，而肺部疾病是目前 发病率和死亡率。基因转移提供了在患者和患者的肺中表达CFTR的潜力 从而延缓或防止疾病进展。然而，尽管取得了显著的研究进展，我们仍然缺乏 许多关键问题的答案。进展的一个主要障碍是缺乏动物模型 这复制了通常在人类中发现的疾病。为了绕过当前动物模型的局限性， 我们已经生产了CFTR-/-和CFTRAF/-猪。新生动物表现出CI运输缺陷和 在新生儿身上复制异常。我们的初步数据表明，CFTR-/-猪也可能 会像人类一样患上呼吸道疾病。我们将使用这个新的模型来解决关键的CF问题。目标 1.CFTRAF508/-猪在肠道表达CFTRAF508能预防胎粪肠梗阻吗？要回答这个问题 问题，我们将产生CFTRAF508/-在肠道中携带表达CFTR的转基因猪。这个 由此产生的动物可能对该计划中的其他项目有价值，结果可能会对 胎粪性肠梗阻和远端肠梗阻综合征的潜在发病机制。目标2.做基因 改良剂对CFTRAF508/AF508猪临床表型的影响？我们将把我们的猪交叉到 并询问CF表型是如何改变的。发现表型 变化可能有助于识别修改AF508突变蛋白或影响AF508突变蛋白的表现的途径 疾病，从而揭示新的治疗目标。目标3.何时需要更改CFTR表达 Cf表型？我们将产生CFTRAF508头猪，在可诱导的控制下表达CFTR 发起人回答关键问题。CFTR在子宫中的表达能预防新生儿的疾病吗？将要 出生后开始的上皮CFTR表达可以预防肺部疾病吗？Cftr基因的表达是治疗还是减缓 已建立的大路疾病的进展情况？这些答案将作为指导治疗的基准 策略包括基因转移。

Cystic fibrosis (CF) is a genetic disease caused by loss of cystic fibrosis transmembrane conductance regulator (CFTR). The disease involves many organs, and lung disease is the current major cause of morbidity and mortality. Gene transfer offers the potential to express CFTR in the lungs of patients and thereby slow or prevent disease progression. Yet despite outstanding research progress, we still lack answers to many crucial questions. A major impediment to progress has been the lack of an animal model that replicates disease typically found in humans. To circumvent limitations of current animal models, we have produced CFTR-/- and CFTRAF/- pigs. Newborn animals exhibit defective CI' transport and replicate abnormalities in newborn humans. Our preliminary data suggest that CFTR-/- pigs may also develop respiratory disease like humans. We will use this novel model to address questions key to CF. Aim 1. Will intestinal expression of CFTR prevent meconium ileus in CFTRAF508/- pigs? To answer this question, we will generate CFTRAF508/- pigs carrying a transgene expressing CFTR in the intestine. The resulting animals may be of value to other projects in the program, and the results may shed light on the underlying pathogenesis of meconium ileus and distal intestinal obstruction syndrome. Aim 2. Do genetic modifiers influence the clinical phenotype of CFTRAF508/AF508 pigs? We will cross our pigs to genetically diverse strains of pigs and ask how the CF phenotypes are altered. Discovering phenotypic changes could help identify pathways that modify the AF508 mutant protein or affect manifestations of the disease, thereby revealing novel therapeutic targets. Aim 3. When is CFTR expression required to alter the CF phenotype? We will generate CFTRAF508 pigs that express CFTR under control of an inducible promoter to answer key questions. Will CFTR expression in utero prevent disease in newborns? Will epithelial CFTR expression that begins after birth prevent lung disease? Will CFTR expression treat or slow the progression of established ainway disease? The answers will serve as a benchmark to guide therapeutic strategies including gene transfer.