The role of transcription factor 4 repeat expansion in Fuchs endothelial corneal dystrophy

转录因子4重复扩增在Fuchs内皮性角膜营养不良中的作用

• 批准号: 8966770
• 负责人: Keith H Baratz
• 金额: $ 24.87万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8966770
• 关键词: 3' Untranslated Regions; Accounting; Address; Affect; Architecture; Binding; Biochemical Pathway; Biological Markers; CAG repeat; Caucasians; Cell physiology; Characteristics; Clinical; Collaborations; Corneal Endothelium; Corneal dystrophy; Corneal edema; Critical Pathways; Data; Development; Disease; Disease Progression; Endothelial Cells; Epithelial; European; Extracellular Matrix; Eye diseases; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Goals; Homologous Transplantation; Human; Investigation; Keratoplasty; Late-Onset Disorder; Lead; Link; Medical; Mesenchymal; Messenger RNA; Molecular; Molecular Profiling; Mutation; Myotonic Dystrophy; Nuclear RNA; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pattern; Platelet Factor 4; Play; Point Mutation; Population; Predictive Value; Process; Protein Kinase; Proteins; RNA; RNA Splicing; Research Institute; Role; Single Nucleotide Polymorphism; Solid; Testing; Tissues; Toxic effect; Transcript; Trinucleotide Repeat Expansion; United States; Untranslated RNA; Vision; Work; base; clinical phenotype; genetic variant; genome wide association study; insight; mRNA Expression; novel; novel strategies; public health relevance; research study; role model; therapeutic target; transcription factor

 DESCRIPTION (provided by applicant): This is a multiple PI R21 application to test the hypothesis that trinucleotide repeat (TNR) expansion plays a role in the pathogenesis of Fuchs endothelial corneal dystrophy (FECD), a common, autosomal dominant, late-onset eye disease. Corneal edema due to FECD is the most common indication for corneal transplantation in the United States. There are no known medical therapies to halt disease progression, and the pathogenesis is not well understood. Our previous work has identified a TGC TNR expansion in the transcription factor 4 (TCF4) gene as the most robust biomarker for the disease, being present in ~80% of cases and in 3% of controls. We now have preliminary data suggesting that transcripts from the TCF4 repeat expansion form RNA foci in corneal endothelial cells from FECD patients. This finding is analogous to myotonic dystrophy, type 1 (DM1) in which an identical trinucleotide expansion in the 3' untranslated region of a protein kinase gene leads to aggregation of the transcribed repeat sequence into characteristic nuclear RNA foci, which sequester the critical splicing factor muscleblind-like 1 (MBNL1). In DM1 the reduction in effective MBNL1 levels alters the patterns of mRNA splicing of numerous transcripts, contributing to the spectrum of clinical findings in the disease. We propose to test the hypothesis that expansion of CTG repeats in TCF4 similarly alters splicing patterns in the corneal endothelium from FECD patients. Secondary objectives will include analysis of the effect of TCF4 repeat expansion on gene expression profiles and the relationship between such widespread changes in the genomic architecture of corneal endothelial cells and disease progression in FECD. Our unifying hypothesis is that FECD is a TNR expansion disease. Mechanistically, we hypothesize that the disease results from both qualitative and quantitative effects of TNR expansion on gene expression in the corneal endothelium (CE). To address this issue, we will analyze mRNA expression patterns in diseased and normal human CE to determine how gene expression patterns are altered in FECD patients. Relevance Preliminary experiments suggest the hypothesis that FECD is the most common TNR expansion disease described to date. If the proposed experiments support this hypothesis, it will provide insight int pathogenic mechanisms and suggest novel approaches for treating FECD. There is no plausible way to reverse TNR expansion, so our hope for novel therapies depends upon detailing the molecular basis of FECD pathogenesis. We hope to eventually identify therapeutic targets to mitigate disease progression and reduce the need for corneal transplants.

 描述（通过应用程序证明）：这是一种多个PI R21应用于三核苷酸（TNR）膨胀在Fuchs Hothotherathialial Corneal Dromtrophy（FECD）的发病机理中，这是一种常见的，常染色体主导，晚期，晚期眼科病没有已知的医疗疗法，并且没有转录因子4（TCF4）基因是该疾病的最大生物标志物数据表明来自TCF4重复膨胀的转录本在FECD患者的角膜内皮细胞中形成RNA焦点。在DM1中，临界的肌肉盲型1（MBNL1）中的核RNA焦点。假设CTG在FECD专利性中的TCF4剪接模式中的剪接模式对TCF4的Fe效应对TCF4的Fe效应。在角膜内皮中的基因表达（CE）。 。