JAM-A mRNA 3’UTR作为ceRNA促进毛乳头细胞Versican表达及毛囊再生的机制研究

Dermal papilla cells (DPC) play an important role in the growth cycle of hair follicles and hair regeneration. The biological function abnormality of DPC is the primary factor for hair regeneration obstacle and alopecia. In the previous study,applicant discovered junction adhesion molecule A (JAM-A) gene was differentially expressed in human DPC in various hair growth cycle. But in the overexpression study, the results show that the regulation of DPC biological function independent JAM-A protein encoding region, instead, via 3’Untranslated Region of JAM-A mRNA. After bioinformatics prediction and preliminary validation, we speculate that JAM-A 3’UTR 'effect on the expression of versican by ceRNA mechanism, thereby affecting the activity and biological function of human DPC, affect hair regeneration. In order to further clarify the hypothesis, we intend to build human DPC line with JAM-A over expression and knockdown, comparative analysis of the effect of JAM-A CDS region and 3’UTR region intervention on human DPC biological function. And further through C3H/HeJ alopecia areata mice model to investigate the effect of JAM-A 3’UTR in vivo intervention on hair cycle and hair regeneration, clear the gene’s role in human hair regeneration, and also, provide a new target for the research hair loss related diseases.

毛乳头细胞在毛囊生长和周期更替中具有重要意义，其功能异常是导致毛发再生障碍和脱发性疾病的主要因素。申请者前期研究发现链接粘附分子JAM-A基因在人毛囊毛乳头细胞随毛发周期不同呈差异表达，但在过表达研究中发现，JAM-A调控毛乳头细胞的功能与其蛋白无关，而是通过其mRNA的3’UTR发挥作用。经过预测及初步验证，我们推测JAM-A 3'UTR 通过内源性竞争性RNA(ceRNA)机制影响多功能蛋白聚糖的表达，进而影响人毛乳头细胞的功能，影响毛囊再生。为进一步明确该假说，本课题拟构建不同区段JAM-A mRNA过表达及敲除的人毛乳头细胞株，对比分析JAM-A CDS区和3’UTR区对人毛乳头细胞生物学功能的影响。并进一步通过C3H/HeJ小鼠斑秃模型，探讨JAM-A 3’UTR体内干预对毛囊周期及再生的影响，明确该基因在毛发再生中的作用，并为相关疾病的研究提供新的靶点。

毛囊中的真皮乳头 (DP) 细胞是毛发生长的关键调节细胞群。斑秃的发生与人真皮乳头细胞（DCPs）的功能障碍密切相关。因此，确定DCPs的调控机制对于AA 患者的毛发再生具有重要意义。最近，越来越多的证据表明，关键基因的 3' 非翻译区 (3'UTR) 可能通过竞争性内源RNA机制参与细胞分化和疾病的调控，但在毛发再生中尚未见报道。在这里，我们证明JAM-A 的 3' UTR 可以作为一种重要的竞争性内源 RNA 来维持DCPs的功能并促进 AA 中的毛发再生。我们发现连接粘附分子A(JAM-A) 的 3'UTR 与 Versican (VCAN) mRNA 共享许多microRNAs(miRNA)反应元件，特别是miR-221-3p。并且JAM-A 3'UTR可以调控miRNA介导的DCPs自我更新过程中VCAN的表达。此外，VCAN 的上调反过来可以提高 JAM-A 的表达水平。因此，我们认为 JAM-A 3' UTR 通过miRNA-221-3p调控VCAN的表达，进而影响DCPs的凝聚样生长特性维持，诱导毛发再生能力和DCPs增殖。 JAM-A3'UTR可能是潜在的治疗脱发的新靶点。