Ocular surface tissue morphogenesis in normal and disease states revealed by genetically modified mice
Ocular surface tissue morphogenesis in normal and disease states revealed by genetically modified mice
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DOI：
10.1097/01.ico.0000247207.55520.a4
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发表时间：
2006-12-01
期刊：
影响因子：
2.8
通讯作者：
Kao, Winston W-Y
中科院分区：
文献类型：
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作者：
Kao, Winston W-Y
许多转基因和基因敲除小鼠表现出类似于人类眼表疾病的致病过程。因此，小鼠品系的临床表现为鉴定未知病因的遗传性人类疾病提供了依据。然而，使用传统转基因和基因靶向技术的小鼠百合通常表现出胚胎致死性和先天性缺陷，这妨碍了使用此类小鼠模型来研究获得性眼表组织疾病。这些困难可以通过制备诱导型转基因表达、组织特异性基因消融和诱导型组织特异性基因消融的小鼠系来部分克服。有条件的转基因小鼠系正常生活，直到施用强力霉素和诱导转基因表达和目的基因消融的激素。为了这个目标，我们制备了2组转基因小鼠系：（1）使用keratocan启动子转基因来创建Kera-rtTA小鼠（多西环素诱导型小鼠）和Cre-LoxP系统（即Kera-Cre小鼠；神经嵴细胞谱系和成体基质角膜细胞中的条件基因消融）和Kera-CrePR小鼠（RU-486诱导型）； (2)采用敲入策略创建Krt12-rtTA小鼠（强力霉素诱导型）、Krt12-Cre小鼠（角膜上皮条件性消融）和Krt12rtTA-tet-O-Cre小鼠（强力霉素诱导性角膜上皮特异性基因消融）。使用这些小鼠品系，我们表明转化生长因子（TGF）-β（2）对于眼睛形态发生至关重要，TGF-α是眼睑形成的形态原，lumican是一种matrikine，除了作为胶原纤维生成的调节分子外，还具有多种调节油细胞活性的功能（例如，迁移增殖和一个表达）。这些小鼠百合也可用于 Lis 模型，利用基因疗法和干细胞策略开发眼表疾病的治疗方案。
Many transgenic and knockout Mice exhibit pathogenic processes resembling human ocular surface diseases. Thus, the clinical manifestations of mouse lines call provide Cities for identifying heritable human diseases of unknown etiology. However, Mouse lilies using conventional techniques of transgenesis and gene targeting often exhibit embryonic lethality and congenital defects, which preclude the use of such mouse models to Study acquired ocular surface tissue diseases. These difficulties can be in part overcome by preparing mouse lines of inducible transgene expression, tissue-specific gene ablation, and inducible tissue-specific gene ablation. Conditional transgenic mouse lines live normally until administration of doxycycline and hormones that induce expression of the transgene and ablation of gene of interest. Toward this goal, we prepared 2 groups of genetically modified mouse lines: (1) transgenesis using keratocan promoter was used to create Kera-rtTA mice (doxycycline-inducible mice) and Cre-LoxP system (ie, Kera-Cre mice; conditional gene ablation in neural crest cell lineage and adult stromal keratocyte) and Kera-CrePR mice (RU-486 inducible); and (2) knock-in strategies were used to create Krt12-rtTA mice (doxycycline inducible), Krt12-Cre mice (conditional ablation in corneal epithelium), and Krt12rtTA-tet-O-Cre mice (doxycycline-inducible corneal epithelium-specific gene ablation). Using these mouse lines, we showed that transforming growth factor (TGF)-beta(2) is essential for eye inorphogenesis, TGF-alpha is a rnorphogen for eyelid formation, and lumican is a matrikine that has multiple regulatory functions Oil cell activities (eg, migration proliferation and,one expression) besides serving as a regulatory molecule of collagen fibrillogenesis. These mouse lilies call also be used Lis models for development of therapeutic treatment regimens of ocular Surface diseases using gene therapy and stern cell strategies.