LncRNA-DIO3OS编码的新型小分子功能肽调控JAM2治疗盆底功能障碍性疾病的作用和机制研究

盆底功能障碍性疾病（PFD）是中老年女性常见疾病。盆底组织中胶原蛋白等细胞外基质成分改变是PFD发生的重要原因。课题组前期研究发现，PFD患者成纤维细胞膜上连接粘连分子2（JAM2）低表达，是导致FGF2无法激活下游通路和胶原蛋白分泌减少的关键因素；而LncRNA-DIO3OS sORF编码的功能肽段可能是挽回JAM2低表达和修复PFD患者盆底组织的重要靶点。由此，本项目将进一步阐明LncRNA-DIO3OS sORF编码的功能肽段对JAM2表达的调控作用，并阐述其在PFD发病机制中的作用。在此基础上，用富血小板血浆（PRP）混合包裹该功能肽段的控释微囊，注射至PFD大鼠盆底薄弱位置，且原位凝胶化，以验证该功能肽段的体内活性，并实现其在体内长期、稳定释放。本项目旨在证实该PRP-功能肽段控释微囊系统能有效改善盆底组织中成纤维细胞分泌胶原蛋白的能力，为临床微创治疗PFD提供新方法和理论依据。

Pelvic floor dysfunction (PFD) is a group of clinical conditions, including stress urinary incontinence (SUI), pelvic organ prolapse (POP), overactive bladder syndrome, and fecal incontinence. The prevalence of PFD is high in women and increases with age. Treatments for these conditions are conservative and symptom-based and surgeries are only considered for those who decline or fail in conservative treatments. However, current treatment options are suboptimal. A weakening of pelvic connective tissues is considered a contributing factor in PFD. Since they are critical components of the extracellular matrix (ECM) of pelvic floor connective tissues, the abnormality of collagen and elastin molecules due to abnormal synthesis, interruption in homeostasis and increased degradation, has been shown to be obvious in patients with PFD. Fibroblast growth factor 2(FGF2), a member of the fibroblast growth factor family, could improve the ability of fibroblasts to secrete collagen and elastin into connective tissues. Previously, we discovered that the expression of FGF2 was up-regulated in PFD, while the expression of JAM2 was decreased significantly in patients with PFD. In a recent study, JAM2 is an immunoglobulin superfamily (IgSF) member, which is key to FGF2-induced MAPK activation. Taken together, these suggest that blockage of JAM2 could inhibit FGF2-induced MAPK/Erk signaling. Furthermore, we found that the functional peptide segment encoded by LncRNA-DIO3OS sORF was related to the expression of JAM2 in fibroblasts. Therefore, we propose to further verify the regulatory effect of the functional peptide encoded by LncRNA-DIO3OS sORF on the expression of JAM2 in this study. Moreover, peptides as complex macromolecules, are prone to chemical and physical degradation during storage and usage, which causes undesired side-effects after their administration. To maintain the stabilization and biological active conformation of peptides, we plan to synthesize the controlled-release microcapsules with LncRNA-DIO3OS sORF peptide to induce the expression of JAM2 in fibroblasts in this study. And then, we will use PRP as the delivery system of the functional peptide controlled-release microcapsule, and inject into the weak spot of the pelvic floor of rats PFD model, which will help the generated fibroblast to secrete collagen and elastin and then ultimately enhance the pelvic floor tissue regeneration and repair. The results of this project will provide a new method for early and minimally invasive treatment of PFD in clinic.