Molecular studies of miR-29 associated deposition of extracellular matrix in Fuchs endothelial corneal dystrophy

Fuchs 内皮性角膜营养不良中 miR-29 相关细胞外基质沉积的分子研究

• 批准号: 324044200
• 负责人: Professor Dr. Mario Magnus Goswin Matthaei
• 金额: --
• 依托单位: Klinik und Poliklinik für allgemeine Augenheilkunde
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/324044200?language=en
• 关键词: Molecular; studies; miR; 29; associated

Fuchs endothelial corneal dystrophy (FECD) is a bilateral disorder of the corneal endothelium and among the most common reasons for corneal transplant surgery in the Western world. So far, there are no established conservative treatments available. Morphologically, FECD is characterized by a decrease in corneal endothelial cell density with abnormal subendothelial deposition of extracellular matrix (ECM) progressing over several decades.MicroRNAs (miRNAs) are short non-coding RNAs and regulate gene expression at the post-transcriptional level. The miR-29 family is an important modulator of ECM homeostasis. In a previous study we have demonstrated for the first time significantly reduced expression of the miR-29 family with reciprocal overexpression of miR-29 target transcripts COL1A1 and COL4A1 and subendothelial deposition of the corresponding proteins in FECD endothelium.The proposed project will further investigate the hypothesis that reduced miR-29 expression leads to abnormal expression of ECM-related genes with unphysiological subendothelial deposition of ECM in FECD eyes.FECD endothelial samples will be assayed for expression of additional miR-29 associated ECM components. Subsequently, the effect of changes in miR-29 on ECM components in CECs will be analyzed in vitro. Finally, the expression of miR-29 and miR-29 associated ECM components in vivo will be studied in the worldwide first transgenic Col8a2Q455K/Q455K mutant mouse model of FECD.The proposed project will contribute to an improved understanding of the role of the miR-29 family in FED pathogenesis and will serve as a basis for the development of new conservative therapies.

富克斯角膜内皮营养不良（FECD）是一种双侧角膜内皮疾病，是西方世界角膜移植手术最常见的原因之一。到目前为止，还没有成熟的保守治疗方法。FECD的形态学特征是角膜内皮细胞密度降低，内皮下细胞外基质（extracellular matrix，ECM）异常沉积。microRNAs（miRNAs）是一种短的非编码RNA，在转录后水平调控基因表达。miR-29家族是ECM稳态的重要调节剂。在先前的研究中，我们首次证明了miR-29家族的表达显著降低，miR-29靶转录物COL 1A 1和COL 4A 1的反向过表达以及相应蛋白在FECD内皮中的内皮下沉积。将测定FECD内皮样品中另外的miR-29相关ECM组分的表达。随后，将在体外分析miR-29的变化对CEC中ECM组分的影响。最后，我们将在全球首个转基因Col 8a 2 Q455 K/Q455 K突变小鼠FECD模型中研究miR-29及其相关ECM成分的体内表达，为进一步了解miR-29家族在FED发病机制中的作用提供理论依据，并为开发新的保守疗法奠定基础。