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（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，还没有确定的保守治疗方法。形态学上，FECD的特征是角膜内皮细胞密度降低，细胞外基质（ECM）内皮下异常沉积持续数十年。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。在之前的一项研究中，我们首次证明了miR-29家族的表达显著降低，miR-29靶转录物COL1A1和COL4A1的相互过表达以及FECD内皮中相应蛋白的内皮下沉积。该项目将进一步研究miR-29表达降低导致ECM相关基因异常表达并导致feecd眼睛中ECM非生理性内皮下沉积的假设。将检测feecd内皮样品中其他miR-29相关ECM成分的表达。随后，我们将在体外分析miR-29变化对CECs中ECM成分的影响。最后，我们将在全球首个转基因Col8a2Q455K/Q455K突变小鼠FECD模型中研究miR-29和miR-29相关ECM成分在体内的表达。拟议的项目将有助于更好地了解miR-29家族在FED发病机制中的作用，并将作为开发新的保守疗法的基础。

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.