National Ferret Resource and Research Center on Lung Disease

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性研究至关重要。小鼠在这一努力中发挥了无价的作用，但对于许多疾病来说，这个物种无法模拟人类的表型。这在囊性纤维化(CF)、α-1抗胰蛋白酶(AAT)缺乏和原发性纤毛运动障碍(PCD)等人类肺部疾病中尤为明显。这种疾病易感性的物种特异性的基础与这两种差异有关。 在肺解剖学和细胞生物学以及小鼠和人类的遗传分化方面。动物模型领域的最新进展使家雪貂在模拟人类疾病的新的遗传柔韧物种中处于领先地位。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，雪貂的基因组最近被测序，现在可以向公众开放，提供了必要的信息，以询问雪貂的遗传适宜性，以建立特定疾病的模型，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。作为概念的证明，囊性纤维化跨膜传导调节因子(CFTR)基因敲除雪貂已经被产生并被发现模拟了在CF患者中所见的多器官疾病(包括自发性肺部感染)的各个方面。此外，已经产生了在肠道(在FABPI启动子的指导下)特异性表达fCFTR的转基因雪貂，并显示出纠正了新生的CF雪貂的胎粪肠梗阻表型。这份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，重点关注CF雪貂资源的分布和创建新的肺病和NHLBI感兴趣的其他疾病的雪貂模型。这项提议的其他重点将是提供雪貂用于研究的培训，为替代的体外和体外呼吸道模型提供服务，并通过一个网站促进与社区的信息交流，该网站编目和分发雪貂研究常用的“工具箱”资源(抗体、DNA、病毒载体、初级呼吸道细胞、改进的基因组注释文件，用于组学研究)。这项申请的战略目标将是扩大研究界可用的雪貂疾病模型的数量，允许广泛且具有成本效益的CF雪貂模型的使用，并在本提案的五年内为该中心的持续运作建立一个自我维持的商业模式。

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.