Zeb1 and epithelial-mesenchymal balance in the eye

Zeb1 和眼睛上皮间质平衡

• 批准号: 7663058
• 负责人: DOUGLAS Chase DEAN
• 金额: $ 22.2万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663058
• 关键词: Back; Binding; Boxing; Cells; Characteristics; Complication; Corneal Endothelium; Corneal dystrophy; Development; E-Cadherin; Ectopic Expression; Embryonic Development; Epithelial; Equilibrium; Exhibits; Eye; Eye diseases; Gene Expression; Genes; Genetic Transcription; Human; Knockout Mice; Link; Mesenchymal; Molecular; Morphology; Mus; Mutant Strains Mice; Mutation; Normal tissue morphology; Pathologic; Patients; Phenotype; Pigments; Principal Investigator; Proliferative Vitreoretinopathy; Repression; Retinal Detachment; Retinal Pigments; Role; Series; Specific qualifier value; Structure of retinal pigment epithelium; Zinc Fingers; base; epithelial to mesenchymal transition; homeodomain; in vivo; overexpression; prevent; programs; public health relevance; research study; transcription factor

DESCRIPTION (provided by applicant): Overexpression of zinc finger homeodomain 1 (Zeb1) triggers epithelial-mesenchymal transition (EMT) by repressing key epithelial specialization genes, including E-cadherin. By contrast, mutation of Zeb1 leads to mesenchymal-epithelial transition with ectopic expression of epithelial genes. Mutation of Zeb1 in patients is linked to epithelization of corneal endothelium and posterior polymorphous corneal dystrophy (PPCD). Mice null for Zeb1 exhibit PPCD characteristics late in embryogenesis, whereas such pathologic changes are delayed until adulthood in heterozygous mice. Overexpression of Zeb1 occurs in dedifferentiation of retinal pigment epithelial (RPE) cells, an EMT characterized by ectopic proliferation, loss of pigment and transition to fibroblastic morphology. Such RPE dedifferentiation contributes to proliferative vitreoretinopathy, the major complication in retinal detachment. Heterozygous mutation of Zeb1 prevents RPE dedifferentiation. We propose a series of experiments to begin examining the molecular basis for Zeb1 function in regulating epithelial-mesenchymal balance in eye cells. PUBLIC HEALTH RELEVANCE: Epithelial vs. mesenchymal balance is crucial for normal tissue formation in development, and this balance is disrupted in eye diseases such as posterior corneal dystrophies and proliferative vitreoretinopathy. We provide evidence that the zinc finger E-box binding homeodomain1 (Zeb1) is important in regulating epithelial-mesenchymal balance in corneal endothelium and retinal pigmented epithelium.

描述（由申请人提供）：锌指同源结构域 1 (Zeb1) 的过度表达通过抑制关键的上皮特化基因（包括 E-钙粘蛋白）来触发上皮间质转化 (EMT)。相比之下，Zeb1 的突变导致间充质-上皮转变，并导致上皮基因异位表达。患者中 Zeb1 的突变与角膜内皮上皮化和后部多形性角膜营养不良 (PPCD) 有关。 Zeb1缺失的小鼠在胚胎发生后期表现出PPCD特征，而这种病理变化在杂合小鼠中则延迟到成年。 Zeb1 的过度表达发生在视网膜色素上皮 (RPE) 细胞的去分化过程中，这是一种 EMT，其特征是异位增殖、色素丧失和向成纤维细胞形态的转变。这种 RPE 去分化会导致增殖性玻璃体视网膜病变，这是视网膜脱离的主要并发症。 Zeb1 的杂合突变可阻止 RPE 去分化。我们提出了一系列实验来开始研究 Zeb1 调节眼细胞上皮间质平衡功能的分子基础。公共卫生相关性：上皮与间质的平衡对于发育过程中正常组织的形成至关重要，而这种平衡在后角膜营养不良和增殖性玻璃体视网膜病变等眼部疾病中被破坏。我们提供的证据表明，锌指 E-box 结合同源域 1 (Zeb1) 对于调节角膜内皮和视网膜色素上皮的上皮间质平衡非常重要。

项目成果

Mouse fibroblasts lacking RB1 function form spheres and undergo reprogramming to a cancer stem cell phenotype.

• DOI: 10.1016/j.stem.2009.02.015
• 发表时间: 2009-04-03
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Liu Y;Clem B;Zuba-Surma EK;El-Naggar S;Telang S;Jenson AB;Wang Y;Shao H;Ratajczak MZ;Chesney J;Dean DC
• 通讯作者: Dean DC