miR-4687-5p通过调控EGLN2改变骨髓增生异常综合征骨髓微环境的机制研究

The pathogenesis of myelodysplastic syndrome (MDS) is not completely clear, It is currently known that the decreased degradation of hypoxia-inducibility factor 1A (HIF1A ) is a central pathobiologic mediator of inducing dysplastic and cytopenic phenotypes in MDS , but the mechanism remains to be explored. EGLN2 is a prolyl hydroxylase enzyme, which is one of the key enzymes of degrading HIF1A protein. Bioinformatics analysis revealed that miR-4687-5p may be complementary pairing with the base of the 3' non-coding end of EGLN2 mRNA to inhibit its expression or transcription. A recent study found that abnormally high expression of miR-4687-5p was detected in exosomes of peripheral blood serum from MDS patients, which may be a new target for the MDS treatment. Therefore, We propose a hypothesis: miR-4687-5p may increase the HIF1A protein by down-regulating EGLN2 to cause disease occurrence or development? Firstly, this study was to determine the relationship between IPSS-R risk category of MDS with miR-4687-5p in bone marrow supernatants. Further in vitro and in vivo experiments, it was demonstrated that miR-4687-5p altered the function of bone marrow stromal cells in the bone marrow microenvironment, by down-regulating EGLN2 to up-regulate HIF1A protein and downstream vascular endothelial growth factors, stromal cell-derived factor-1. If the study was completed, it would make us know more about the pathogenesis of MDS, and provide new targets for the treatment of MDS.

骨髓增生异常综合征（MDS）发病机制尚不完全清楚。目前已知低氧诱导因子1A（HIF1A）蛋白降解减少是导致MDS病态造血及外周血细胞减少的关键因素之一，但机制有待探索。EGLN2是一种脯氨酰羟化酶，是降解HIF1A蛋白的关键酶之一。生物信息学分析发现miR-4687-5p可能抑制EGLN2基因的表达或转录。新进研究发现miR-4687-5p在MDS外周血清外泌体中异常增高，可能作为MDS治疗的新靶点。故提出假说：miR-4687-5p可能通过下调EGLN2增高HIF1A蛋白致疾病发生或发展。本研究拟先分析骨髓上清外泌体中miR-4687-5p与MDS危险分层的相关性；然后通过体内体外实验阐明miR-4687-5p通过下调EGLN2上调HIF1A，上调下游VEGF和CXCL12改变骨髓微环境骨髓基质细胞功能的机制。项目完成后将有助于完善MDS的发病机制，可能为MDS治疗提供新的靶点。

骨髓增生异常综合征（MDS）发病机制尚不完全清楚。目前已知低氧诱导因子1A（HIF1A）蛋白降解减少是导致MDS病态造血及外周血细胞减少的关键因素之一，但机制有待探索。EGLN2是一种脯氨酰羟化酶，是降解HIF1A蛋白的关键酶之一。生物信息学分析发现miR-4687-5p可能抑制EGLN2基因的表达或转录。新进研究发现miR-4687-5p在MDS外周血清外泌体中异常增高，可能作为MDS治疗的新靶点。我们的研究证实：miR-4687-5p通过下调EGLN2增高HIF1A蛋白致疾病发生或发展。本研究先通过体内体外实验阐明miR-4687-5p通过下调EGLN2上调HIF1A，上调下游VEGF和CXCL12改变骨髓微环境骨髓间充质干细胞（MSCs）功能，损伤MSCs的造血支持力。项目完成后将有助于完善MDS的发病机制，可能为MDS治疗提供新的靶点。