Molecular Regulation of Epithelial-Mesenchymal Transitions

上皮-间质转化的分子调控

基本信息

批准号：
7350756
负责人：
DOUGLAS Chase DEAN
金额：
$ 33.3万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7350756
关键词：
Affect Binding Biochemistry Boxing Brain Bromodeoxyuridine CDKN2A gene Cartilage Cell Aging Cell Culture Techniques Cell Cycle Cell Cycle Arrest Cell Proliferation Cells Complex Corneal Endothelium Corneal dystrophy Cultured Cells Defect Dependence Diagnostic Neoplasm Staging Disease E-Cadherin EP300 gene Ectoderm Cell Elements Embryo Epigenetic Process Epithelial Epithelial Cells Epithelium Equilibrium Eye Face Family Fibroblasts Foundations Gene Targeting Genes Genetic Transcription Glial Fibrillary Acidic Protein Human Knowledge Loss of E-cadherin Expression Lysine Malignant Neoplasms Mediating Mesenchymal Mesenchyme Modeling Modification Molecular Mus Mutant Strains Mice Mutation Neoplasm Metastasis Optic Nerve Palate Pathologic Pathway interactions Phenotype Pigment Epithelium Plasminogen Activator Inhibitor 1 Proliferating Regulation Repression Retina Role Series Serum Response Factor Signal Transduction Site Smooth Muscle Actin Staining Method Snails T-Lymphocyte TP53 gene Therapeutic Transcription Coactivator Transcription Repressor/Corepressor Transcriptional Regulation Transferase Up-Regulation Vimentin Zinc Fingers cancer cell design embryo tissue epithelial to mesenchymal transition falls gene repression homeodomain in vivo inhibitor/antagonist mutant outcome forecast overexpression premature promoter research study senescence skeletal subventricular zone transcription factor

项目摘要

Heterozygous mutations in the ZFHX1A zinc finger homeodomain transcriptional repressor in humans cause posterior polymorphous corneal dystrophy, a pathologic epithelization of the corneal endothelium. In mutant mice there are also epithelial vs. mesenchymal-like transition defects in the corneal endothelium, with acquisition of E cadherin expression and loss of vimentin expression. Such epithelial/ectodermal vs. mesenchymal transition defects are also evident in the embryonic retina, optic nerve, cartilage mesenchyme and subventricular zones of the brain. These defects are also characterized by expansion of the epithelial marker E-cadherin and contraction of the mescenchymal/ectodermal markers vimentin and GFAP. At these affected sites, there is also induction of cell proliferation inhibitor genes, and accordingly diminished proliferation is seen at these sites in mutant embryonic tissues in mice injected with BrdU. Similar epithelial vs. mesenchymal transition defects are recapitulated in cells cultured from mutant embryos, and the proliferative defects are also evident, thereby providing a culture model to study the biochemistry of ZFHX1A action. We propose a series of experiments to assess the mechanism of transcriptional control by ZFHX1a and thus its molecular role in defining a balance between epithelia vs. mesenchymal phenotype and control of cell proliferation in vivo and in cultured cells.

人类 ZFHX1A 锌指同源域转录抑制因子的杂合突变会导致后部多形性角膜营养不良，这是一种角膜内皮的病理性上皮化。在突变小鼠中，角膜内皮也存在上皮细胞与间质细胞样的转变缺陷，导致 E 钙粘蛋白表达的获得和波形蛋白表达的丧失。这种上皮/外胚层与间质转化缺陷在胚胎视网膜、视神经、软骨间质和脑室下区也很明显。这些缺陷的特征还在于上皮标记物 E-钙粘蛋白的扩张和上皮细胞的收缩。间充质/外胚层标记物波形蛋白和 GFAP。在这些受影响的位点，还诱导了细胞增殖抑制基因，因此在注射 BrdU 的小鼠突变胚胎组织中的这些位点处观察到增殖减少。从突变胚胎培养的细胞中重现了类似的上皮与间质转化缺陷，并且增殖缺陷也很明显，从而提供了研究 ZFHX1A 作用的生物化学的培养模型。我们提出了一系列实验来评估 ZFHX1a 的转录控制机制，及其在定义上皮与间充质表型之间的平衡以及体内和培养细胞中细胞增殖的控制中的分子作用。