A novel rabbit model of cystic fibrosis

一种新型兔囊性纤维化模型

• 批准号: 9107635
• 负责人: JIE XU
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107635
• 关键词: Accounting; Affect; Age; Animal Model; Animals; Applications Grants; Biliary cirrhosis; Biochemical; Biocompatible Materials; Biology; Breeding; Characteristics; Complementary DNA; Cyclic AMP; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Development; Disease; Disease Progression; Epithelial Cells; Exocrine System; Exocrine pancreatic insufficiency; Exons; Family suidae; Ferrets; Fluorescence; Gallbladder; Generations; Genes; Genetic; Genotype; Growth; Housing; Human; Ileus; Infection; Inherited; Institutes; Intestinal Obstruction; Intestines; Knock-in; Knock-out; Laboratories; Life; Life Expectancy; Liver; Lung; Meconium; Mediating; Modeling; Molecular; Mutation; Neonatal; Obstruction; Oryctolagus cuniculus; Pancreas; Pathology; Patients; Phenotype; Phenylalanine; Positioning Attribute; Process; Proteins; Pulmonary Pathology; Rattus; Regimen; Regulator Genes; Research; Research Institute; Research Personnel; United States National Institutes of Health; Vas deferens structure; Work; animal model development; apical membrane; base; cost; cystic fibrosis mouse; cystic fibrosis patients; disease-causing mutation; homologous recombination; improved; intestinal fatty acid binding protein; male; mouse model; novel; nuclear transfer; offspring; promoter; public health relevance; response; skills; success; therapeutic development; therapy development

 DESCRIPTION (provided by applicant): A limitation factor in the field of cystic fibrosis (CF) has been the ineffectiveness of the CF mouse model. The recent development of the CF pig and ferret has provided additional animal models that can potentially be used to elucidate CF pathology further and to develop therapies for CF. In our preliminary work, we generated CFTR KO rabbits by using Cas9. Encouragingly CFTR null rabbits mimic human patients in several aspects including spontaneous lung infection. It is recognized that the majority of human CF patients (>70%) carry CFTR ∆F508 mutation. It is further realized that CFTRΔF508 protein from other species shows differences in its processing compared to human CFTRΔF508 (hCFTRΔF508). Thus, studies on understanding CF and developing new treatments would be further expedited with a new rabbit model expressing the hCFTR∆F508. In Aim 1, we propose to generate hCFTRΔF508 rabbits. In Aim 2, we propose to express WT rabbit CFTR (rbCFTR) in hCFTR∆F508 rabbits to increase the life expectancy of the CF rabbits which is critical to fully recapitulate CF disease progression in the animals. The success of proposed work will provide an animal model for the characterization of CF pathology and the underlying molecular mechanisms. The development of therapeutic regimens would also be greatly facilitated by a model that displayed characteristic CF pathology.

 描述(申请人提供)：囊性纤维化(CF)领域的一个限制因素是囊性纤维化小鼠模型的无效。猪和雪貂的最新发展提供了更多的动物模型，有可能被用来进一步阐明CF的病理机制和开发治疗方法。在我们的前期工作中，我们用Cas9培育了CFTRKO兔。令人鼓舞的是，cftr基因缺失的兔子在几个方面模仿了人类患者，包括自发性肺部感染。现已认识到，大多数人类CF患者(&gt；70%)携带cftr∆F508突变。进一步认识到，其他物种的cftrΔF508蛋白在加工过程中与人cftrΔF508(hCFtrΔF508)存在差异。因此，表达hCFTRF508的新的兔模型将进一步加快理解CFTRF508的研究和开发新的治疗方法。在目标1中，我们建议产生hCFTRΔF508兔。在目的2中，我们建议在hCFtR∆F508兔中表达WT兔cftr(RbCFtr)，以延长cf兔的预期寿命，这对于全面总结动物cf疾病的进展是至关重要的。这项工作的成功将为研究CF的病理特征和潜在的分子机制提供一个动物模型。一种具有特征性CF病理的模型也将极大地促进治疗方案的发展。