Trangenic Approaches to understanding the biology of airways gene tranfer

了解气道基因转移生物学的转基因方法

基本信息

批准号：
7741479
负责人：
MICHAEL J. WELSH
金额：
$ 28.86万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7741479
关键词：
Accounting Address Affect Alleles Animal Model Animals Anions Area Benchmarking Biliary cirrhosis Biology Birth Characteristics Clinical Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Development Disease Disease Progression Distal Epithelial Epithelium Exhibits Family suidae Gallbladder Gene Transfer Genes Genetic Goals Hereditary Disease Human Ileus Intestinal Obstruction Intestines Light Liver Lung Lung diseases Male Genital Organs Meconium Mediating Modeling Morbidity - disease rate Mus Mutate Mutation Newborn Animals Newborn Infant Obstruction Operative Surgical Procedures Organ Pancreas Pathogenesis Pathway interactions Patients Phenotype Phosphorylation Play Proteins Pulmonary Cystic Fibrosis Regulator Genes Research Role Severities Sweat Glands Syndrome Testing Therapeutic Transgenes clinical phenotype gene therapy in utero mortality mutant new therapeutic target novel prevent programs promoter therapeutic gene

项目摘要

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.

囊性纤维化（CF）是一种由囊性纤维化跨膜电导丧失引起的遗传性疾病调节器（CFTR）。该病涉及多个器官，其中肺部疾病是目前导致该病的主要原因发病率和死亡率。基因转移提供了在患者肺部表达 CFTR 的潜力从而减缓或预防疾病进展。然而，尽管研究取得了显着的进展，但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复制人类常见的疾病。为了规避当前动物模型的局限性，我们生产了 CFTR-/- 和 CFTRAF/- 猪。新生动物表现出 CI' 运输缺陷复制新生儿的异常现象。我们的初步数据表明 CFTR-/- 猪也可能像人类一样患呼吸道疾病。我们将使用这个新颖的模型来解决 CF 的关键问题。目的 1.CFTR的肠道表达能否预防CFTRAF508/-猪的胎便性肠梗阻？为了回答这个问题问题，我们将产生CFTRAF508/-猪，其携带在肠道中表达CFTR的转基因。这由此产生的动物可能对该计划中的其他项目有价值，并且结果可能有助于阐明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. 进行遗传修饰剂影响 CFTRAF508/AF508 猪的临床表型？我们将把我们的猪杂交到猪的遗传多样性品系，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饰 AF508 突变蛋白或影响 AF508 表现的途径疾病，从而揭示新的治疗靶点。目标 3. CFTR 表达何时需要改变 CF表型？我们将产生 CFTRAF508 猪，其在诱导型的控制下表达 CFTR 发起人回答关键问题。 CFTR 在子宫内的表达会预防新生儿疾病吗？将要出生后开始的上皮 CFTR 表达可以预防肺部疾病吗？ CFTR表达会治疗还是减缓已确定的 ainway 疾病的进展？答案将作为指导治疗的基准策略包括基因转移。