National Ferret Resource and Research Center on Lung Disease

国家雪貂资源与肺部疾病研究中心

基本信息

批准号：
8751112
负责人：
JOHN F ENGELHARDT
金额：
$ 83.26万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8751112
关键词：
Affect Age Alternative Therapies Anatomy Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Birth Blood Boxing Bronchiectasis Businesses Cataloging Catalogs Caucasians Caucasoid Race Cell Therapy Cells Cellular biology Chromosomes Chronic Communities Complementary DNA Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Databases Deposition Disease Disease Progression Disease model Disease susceptibility Effectiveness Enzyme-Linked Immunosorbent Assay Ferrets Functional disorder Funding Gene Proteins Gene Targeting Generations Genetic Genetic Drift Genetic Engineering Genetic Models Genome Genomics Goals Heart Diseases Home environment Human Ileus Immunoprecipitation In Vitro Infection Information Distribution Inherited Institution Iowa Knock-in Mouse Knock-out Laboratories Lead Lung Lung diseases Mass Spectrum Analysis Meconium Methodology Methods Mission Modeling Monoclonal Antibody R24 Mus National Heart, Lung, and Blood Institute Neonatal Newborn Infant Organ Other Genetics Outcome Pathogenesis Patients Peer Review Pharmaceutical Preparations Phenotype Pliability Preparation Primary Ciliary Dyskinesias Process Proteins Proteomics Protocols documentation Pulmonary Emphysema Reagent Research Research Personnel Resources Respiratory Tract Infections Sampling Services Source Species Specificity Specimen Staging Stem cells Technology Testing Tissue Model Tissue Sample Tissues Training Transgenic Organisms Translational Research Universities VX-770 Viral Vector Western Blotting Withdrawal Work Xenograft procedure abstracting alpha 1-Antitrypsin alpha 1-Antitrypsin Deficiency base clinical care cost cost effective cystic fibrosis patients gene therapy genome annotation human disease improved information gathering interest meetings mouse model mutant pregnant promoter public health relevance recombinant virus repository research study sample collection somatic cell nuclear transfer therapy development tool web site

项目摘要

DESCRIPTION (provided by applicant): Animal models of human disease are critical for translational research aimed at dissecting disease mechanisms and for developing new therapies. The mouse has been invaluable in this effort, but for many diseases this species fails to model the human phenotype. This is particularly evident in the cases of human lung diseases such as cystic fibrosis (CF), alpha-1 antitrypsin (AAT) deficiency, and primary ciliary dyskinesia (PCD). The basis for this species-specificity in disease susceptibility relates to both differences in lung anatomy and cell biology, and the genetic divergence of mice and humans. Recent advances in the field of animal modeling have placed the domestic ferret at the forefront of new genetically pliable species for modeling human diseases. First, we have developed methods for generating knockout, knock-in, and transgenic ferrets that utilize somatic cell nuclear transfer (SCNT). Second, the ferret genome was recently sequenced and is now publically accessible, providing the information needed to interrogate the genetic suitability of the ferret to model a particular disease, generate gene-targeting constructs, and rapidly generate research tools for studies in this species. As proof of concept, cystic fibrosis transmembrane conductance regulator (CFTR) knockout ferrets have been generated and found to model aspects of multi-organ disease (including spontaneous lung infections) seen in CF patients. Additionally, transgenic ferrets that express fCFTR specifically in the gut (under the direction of the FABPi promoter) have been generated and shown to correct the meconium ileus phenotype in newborn CF ferrets. This R24 resource proposal seeks to create a Center that provides services for ferret disease modeling, with a focus on the distribution of CF ferret resources and the creation of new ferret models of lung disease and of other diseases of NHLBI interest. Other focuses of this proposal will be to provide training in the use of ferrets for research, provide services for alternative in vitro and ex vivo airway models, and promote information exchange with the community through a web site that catalogs and distributes "tool-box" resources of general use for research in the ferret (antibodies, cDNAs, viral vectors, primary airway cells, improved genome annotation files for omics research). Strategic goals of this application will be to expand the number of ferret disease models available to the research community, allow for broad and cost-effective usage of CF ferret models, and build a self-sustaining business model for ongoing function of the Center past the five years of this proposal.

描述（由申请人提供）：人类疾病的动物模型对于旨在解剖疾病机制和开发新疗法的转化研究至关重要。在这项工作中，小鼠是无价的，但是对于许多疾病，该物种无法对人类表型进行建模。在人类肺部疾病（例如囊性纤维化（CF），α-1抗胰蛋白酶（AAT）缺乏和原发性纤毛性运动障碍（PCD）等人类肺部疾病中，这一点尤其明显。这种物种特异性在疾病敏感性中的基础与这两种差异有关在肺解剖学和细胞生物学中，以及小鼠和人类的遗传差异。动物建模领域的最新进展使家庭雪貂处于建模人类疾病的新遗传柔韧物种的最前沿。首先，我们开发了利用体细胞核转移（SCNT）的敲除，敲除和转基因雪貂的方法。其次，最近对雪貂基因组进行了测序，现在可以公开访问，提供了询问雪貂以建模特定疾病，生成基因靶向构建体并迅速生成该物种研究的研究工具所需的信息。作为概念证明，已经产生了囊性纤维化跨膜电导调节剂（CFTR）敲除雪貂，并发现在CF患者中看到多器官疾病（包括自发性肺部感染）的方面。此外，已经产生了在肠道（在FABPI启动子的指导下）中特异性表达FCFTR的转基因雪貂，并显示出可以纠正新生儿CF雪貂中的幼虫的幼虫表型。该R24资源提案旨在创建一个为雪貂疾病建模提供服务的中心，重点是CF雪貂资源的分布以及创建新的肺部疾病雪貂模型和其他NHLBI兴趣的疾病。 Other focuses of this proposal will be to provide training in the use of ferrets for research, provide services for alternative in vitro and ex vivo airway models, and promote information exchange with the community through a web site that catalogs and distributes "tool-box" resources of general use for research in the ferret (antibodies, cDNAs, viral vectors, primary airway cells, improved genome annotation files for omics research).该应用程序的战略目标将是扩大研究界可用的雪貂疾病模型的数量，允许对CF雪貂模型的广泛和成本效益的使用，并建立一个自我维持的业务模型，以实现该提案五年的中心的持续功能。