Trp63 in limbal stem cell deficiency

角膜缘干细胞缺陷中的 Trp63

• 批准号: 10131482
• 负责人: Peter J. Koch
• 金额: $ 14.47万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10131482
• 关键词: Trp63; limbal; stem; cell; deficiency

Project Summary The transcription factor TP63 (human)/Trp63 (mouse), referred to as “p63” in this application, is a key regulator for the development of stratified epithelia. Mice that completely lack p63 expression fail to develop stratified epithelia, including the corneal epithelium. However, p63 is also required to maintain and repair stratified epithelia postnatally. This is underscored by the clinical phenotype of patients suffering from ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome [EEC; OMIM #604292], a disorder caused by mutations in the p63 gene. EEC patients develop limbal stem cell deficiency (LSCD), a condition that is characterized by progressive corneal erosions, corneal conjunctivalization, and ultimate loss of vision. Besides a clear causal link between p63 abnormalities and LSCD, essentially nothing is known regarding the molecular and cellular mechanisms that underlie the mutant p63-dependent pathology. Further, it is not known which cell compartment(s) in the eye are affected by EEC. We hypothesize that normal p63 function is required to maintain limbal stem cells (LSC) and to drive proper differentiation of these cells into corneal epithelial cells. To test this hypothesis, we propose to use a combination of genetically engineered mouse models and in vitro cell culture models to identify mutant p63-controlled gene regulatory pathways in the ocular epithelium. This approach will not only advance basic knowledge of cornea epithelial stem cell biology, it will also point to molecular pathways that could be targeted therapeutically in patients suffering from LSCD caused by impaired p63 function.

项目摘要 转录因子TP63（人）/TRP63（鼠标）在此应用中称为“ p63”，是关键 完全缺乏p63表达的小鼠无法 开发了分层上皮，包括角膜上皮。但是，还需要p63维护 并在产后修复上皮分层。这是由患者的临床表型强调的 患有肉眼，外胚层发育异常和唇lip/pa综合征[EEC; Omim＃604292]，a 由p63基因突变引起的障碍。 EEC患者患有边缘干细胞缺乏症（LSCD），A 以进行性角膜侵蚀，角膜结膜化和最终为特征的状况 视力丧失。除了p63异常与LSCD之间存在明确的因果关系外，本质上没有什么是 关于突变体p63依赖性的分子和细胞机制已知 病理。此外，尚不清楚眼睛中哪个细胞室受EEC的影响。我们 假设需要正常的p63功能才能维持缘干细胞（LSC）并驱动正确 这些细胞分化为角膜上皮细胞。为了检验这一假设，我们建议使用 一般工程的小鼠模型和体外细胞培养模型的组合，以识别突变体 p63控制的基因调节途径。这种方法不仅会进步 角膜上皮干细胞生物学的基础知识，它也将指向可以的分子途径 针对因p63功能受损而导致的LSCD患者进行治疗。