mRNA结合蛋白HuR调控endocan影响血管新生在急性放射性皮肤损伤中的作用及机制研究

Acute radiation-induced skin injury is a common side-effect during radiotherapy and a serous concern in nuclear accidents. Acute radiation-induced skin injury is closely associated with the damage of vascular endothelial cells. HuR belongs to the embryonic lethal abnormal visual family of RNA binding protein and is ubiquitously expressed. It is known that HuR protein binds to certain mRNAs with high affinity, which regulates stability and translation of these mRNAs. However, the role of HuR in acute radiation-induced skin injury is still unknown. In our prelinary study, we found that increased HuR binding to the 3’UTR of the pro-angiogetic growth factor endocan mRNA after radiation by RNA-IP and RNA-Seq. Moreover, this binding is acompanies with an increase of the expression and secretion of endocan. This project will use mutiple molecular biology methods and HuR knock-out mice to illustrate the following issues: 1) the post-transcriptonal regulation of HuR on endocan in skin fibroblasts; 2) the effect of endocan from skin fibroblasts on vascular endotheliai cell function after radiation and on the progression of acute radiation-induced skin injury. This project aims to illustrate the mechanism of HuR by regulating endocan and angiogenesis in acute radiation-induced skin injury, which provides a novel treatment for this disease.

急性放射性皮肤损伤是肿瘤放射治疗和核事故等之后常见的并发症，严重影响患者的生活质量，其进展与血管内皮细胞的损伤密切相关。HuR可识别特定mRNA并对其进行转录后调节。 HuR是否影响放射性皮肤损伤进展尚不清楚。我们前期通过RNA-IP技术结合二代测序探索了皮肤成纤维细胞中HuR在受照射前后结合mRNA的变化，发现其在受照射后与促血管生长因子endocan的mRNA结合增加；同时endocan表达及分泌显著增高，可促进血管内皮细胞微管形成。本项目拟在前期研究基础上通过多种分子生物学手段及基因敲除小鼠进一步探索:1）皮肤成纤维细胞中HuR对endocan的转录后调控分子机制；2）皮肤成纤维细胞分泌的endocan对受照后微环境中血管内皮细胞功能及放射性皮肤损伤的影响。本项目有望揭示皮肤成纤维细胞中HuR调控endocan影响血管新生对急性放射性皮肤损伤进展的影响，为这一疾病的治疗提供新的策略。

急性放射性皮肤损伤是肿瘤放射治疗和核事故等之后常见的并发症，严重影响患者的生活质量，其进展与血管内皮细胞的损伤密切相关。HuR可识别特定mRNA并对其进行转录后调节。 HuR是否影响放射性皮肤损伤进展尚不清楚。我们前期通过RNA-IP技术结合二代测序探索了皮肤成纤维细胞中HuR在受照射前后结合mRNA的变化，发现其在受照射后与促血管生长因子endocan的mRNA结合增加；同时endocan表达及分泌显著增高，可促进血管内皮细胞微管形成。本项目拟在前期研究基础上通过多种分子生物学手段及基因敲除小鼠进一步探索了:1）皮肤成纤维细胞中HuR对endocan的转录后调控分子机制；2）皮肤成纤维细胞分泌的endocan对受照后微环境中血管内皮细胞功能及放射性皮肤损伤的影响。本项目有望揭示皮肤成纤维细胞中HuR调控endocan影响血管新生对急性放射性皮肤损伤进展的影响，为这一疾病的治疗提供新的策略。