Department of Respiratory and Sleep Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
Department of Respiratory and Sleep Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
Am J Pathol. 2020 May;190(5):977-993. doi: 10.1016/j.ajpath.2020.01.009. Epub 2020 Feb 18.
Animal models of cystic fibrosis (CF) are essential for investigating disease mechanisms and trialing potential therapeutics. This study generated two CF rat models using clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 gene editing. One rat model carries the common human Phe508del (ΔF508) CF transmembrane conductance regulator (CFTR) mutation, whereas the second is a CFTR knockout model. Phenotype was characterized using a range of functional and histologic assessments, including nasal potential difference to measure electrophysiological function in the upper airways, RNAscope in situ hybridization and quantitative PCR to assess CFTR mRNA expression in the lungs, immunohistochemistry to localize CFTR protein in the airways, and histopathologic assessments in a range of tissues. Both rat models revealed a range of CF manifestations, including reduced survival, intestinal obstruction, bioelectric defects in the nasal epithelium, histopathologic changes in the trachea, large intestine, and pancreas, and abnormalities in the development of the male reproductive tract. The CF rat models presented herein will prove useful for longitudinal assessments of pathophysiology and therapeutics.
囊性纤维化（CF）动物模型对于研究疾病机制和试验潜在治疗方法至关重要。本研究使用成簇规律间隔短回文重复/成簇规律间隔短回文重复相关蛋白 9 基因编辑技术生成了两种 CF 大鼠模型。一种大鼠模型携带常见的人类 Phe508del（ΔF508）CF 跨膜电导调节剂（CFTR）突变，而第二种是 CFTR 敲除模型。表型特征采用了一系列功能和组织学评估，包括测量上呼吸道电生理功能的鼻电位差、RNAscope 原位杂交和定量 PCR 评估肺中 CFTR mRNA 表达、免疫组织化学定位气道中的 CFTR 蛋白，以及一系列组织的组织病理学评估。两种大鼠模型均表现出多种 CF 表现，包括存活率降低、肠梗阻、鼻上皮的生物电缺陷、气管、大肠和胰腺的组织病理学变化以及男性生殖道发育异常。本文介绍的 CF 大鼠模型将有助于对病理生理学和治疗方法进行纵向评估。
