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：
9283593
负责人：
JOHN F ENGELHARDT
金额：
$ 80.96万
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/9283593
关键词：
Affect Age Alternative Therapies Anatomy Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Birth Blood Bronchiectasis Businesses Catalogs Caucasians 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 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 Pharmacology 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 Stem cells Testing Tissue Model Tissue Sample Tissues Training Transgenic Organisms Translational Research Universities VX-770 Viral Vector Western Blotting Withdrawal Work Xenograft procedure alpha 1-Antitrypsin alpha 1-Antitrypsin Deficiency base clinical care cost cost effective cystic fibrosis patients experimental study gene therapy genetic resource genetic technology genome annotation human disease improved interest mouse model mutant novel therapeutics pregnant promoter public health relevance recombinant virus repository 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剖析疾病机制和开发新疗法的转化研究至关重要。小鼠在这项工作中发挥了不可估量的作用，但对于许多疾病，该物种无法模拟人类表型。这在人类肺部疾病中尤其明显，例如囊性纤维化 (CF)、α-1 抗胰蛋白酶 (AAT) 缺乏和原发性纤毛运动障碍 (PCD)。这种疾病易感性的物种特异性的基础与这两种差异有关肺解剖学和细胞生物学，以及小鼠和人类的遗传差异。动物模型领域的最新进展使家养雪貂处于用于模拟人类疾病的新遗传柔韧物种的前沿。首先，我们开发了利用体细胞核移植（SCNT）产生敲除、敲入和转基因雪貂的方法。其次，雪貂基因组最近已完成测序，现已可供公众访问，提供了询问雪貂遗传适用性所需的信息，以模拟特定疾病，生成基因靶向结构，并快速生成用于该物种研究的研究工具。作为概念证明，囊性纤维化跨膜电导调节器 (CFTR) 敲除雪貂已被培育出来，并被发现可以模拟 CF 患者中出现的多器官疾病（包括自发性肺部感染）的各个方面。此外，已经产生了在肠道中特异性表达 fCFTR（在 FABPi 启动子的指导下）的转基因雪貂，并显示可以纠正新生 CF 雪貂的胎粪性肠梗阻表型。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 雪貂资源的分配以及创建肺病和 NHLBI 感兴趣的其他疾病的新雪貂模型。该提案的其他重点是提供使用雪貂进行研究的培训，为替代体外和离体气道模型提供服务，并通过编目和分发“工具箱”的网站促进与社区的信息交流用于雪貂研究的通用资源（抗体、cDNA、病毒载体、初级气道细胞、用于组学研究的改进基因组注释文件）。该应用程序的战略目标是扩大研究界可用的雪貂疾病模型的数量，允许 CF 雪貂模型的广泛且具有成本效益的使用，并为中心过去的持续运作建立一个自我维持的业务模型。该提案实施五年了。