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研究至关重要。小鼠在这方面的努力是无价的，但对于许多疾病，这个物种未能模仿人类的表型。这在人类肺部疾病如囊性纤维化（CF）、α-1抗胰蛋白酶（AAT）缺乏和原发性纤毛运动障碍（PCD）的情况下尤其明显。疾病易感性的这种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成为人类疾病模型的新的遗传可塑性物种的前沿。首先，我们已经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。第二，雪貂基因组最近被测序，现在可以通过计算机访问，提供了询问雪貂遗传适合性所需的信息，以模拟特定疾病，生成基因靶向构建体，并快速生成用于该物种研究的研究工具。作为概念的证明，已经产生了囊性纤维化跨膜传导调节因子（CFTR）敲除雪貂，并且发现其对CF患者中所见的多器官疾病（包括自发性肺部感染）的方面进行建模。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，并显示其纠正新生CF雪貂中的胎粪肠梗阻表型。这个R24资源提案旨在创建一个中心，为雪貂疾病建模提供服务，重点是CF雪貂资源的分布和肺部疾病和NHLBI感兴趣的其他疾病的新雪貂模型的创建。该提案的其他重点将是提供使用雪貂进行研究的培训，提供替代性体外和离体气道模型的服务，并通过一个网站促进与社区的信息交流，该网站对雪貂研究中常用的“工具箱”资源（抗体、cDNA、病毒载体、初级气道细胞、组学研究的改进基因组注释文件）进行编目和分发。该申请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雪貂模型的广泛和具有成本效益的使用，并建立一个自我维持的商业模式，以实现该中心在本提案五年后的持续功能。

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.