A novel rabbit model of cystic fibrosis

一种新型兔囊性纤维化模型

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：囊性纤维化（CF）领域的限制因素一直是CF小鼠模型的无效性。 CF猪和雪貂的最新发展提供了其他动物模型，这些模型有可能用于进一步阐明CF病理并开发CF的疗法。在我们的初步工作中，我们使用Cas9生成了CFTR KO兔子。令人鼓舞的是，CFTR无效的兔子模仿了包括赞助肺部感染在内的多个方面的人类患者。人们认识到，大多数人CF患者（> 70％）携带CFTR ∆F508突变。进一步意识到，与人CFTRΔF508（HCFTRΔF508）相比，来自其他物种的CFTRΔF508蛋白在加工方面显示出差异。这是关于理解CF和开发新疗法的研究，将通过表达HCFTRΔF508的新兔子模型进一步加快。在AIM 1中，我们建议生成HCFTRΔF508兔子。在AIM 2中，我们建议在HCFTRΔF508兔子中表达WT兔CFTR（RBCFTR），以提高CF兔子的预期寿命，这对于完全概括动物中CF疾病进展至关重要。拟议工作的成功将为CF病理学和潜在的分子机制的表征提供动物模型。表现出特征性CF病理学的模型也将大力准备治疗方案的开发。