糖尿病视网膜病变（DR）是糖尿病患者最常见的致盲眼病，抑制视网膜血管新生可有效缓解DR进展。申请人前期研究证实转甲状腺素蛋白（TTR）有抑制视网膜新生血管的作用，其机制与下调剪接复合物因子hnRNPA2/B1表达相关。而E3泛素连接酶TRIM33结合hnRNPA2/B1可调控酪氨酸磷酸酶PTPN12的可变剪切从而导致PTPN12 mRNA/circRNA表达失衡。其中，PTPN12促进β-catenin的核转位，而circPTPN12调控miR-615-5p和MEF2A。据此我们提出假说：TTR通过TRIM33促进 hnRNPA2/B1降解，进而导致PTPN12 circRNA表达升高，从而竞争性抑制miR-615-5p并上调MEF2A；而PTPN12的下调抑制了β-catenin入核和VEGF表达。本研究将通过体内外实验深入明确该假说，为揭示DR新生血管发病机制提供理论依据和新思路。

Diabetic retinopathy (DR) is one of the most significant eye diseases and often leads to blindness. Inhibition of diabetic retinal neovascularization can effectively alleviate DR progression. In our previous study, transthyretin (TTR) has been proved to repress diabetic retinal neovascularization, and the mechanism should be associated with the degradation of the splicing complex factor hnRNPA2B1. The binding of E3 ubiquitin ligase TRIM33 with hnRNPA2B1 could regulate the alternative splicing of PTPN12 and could disrupt the balance between PTPN12 mRNA/circRNA. PTPN12 has been proved to mediate the nuclear translocation of β-catenin, while cicroPTPN12 should regulate miR-615-5p and MEF2A. Therefore, a hypothesis is proposed: TTR could repress hnRNPA2B1 by TRIM33, and then cicroPTPN12 should be up-regulated with the miR-615-5p be competitively inhibited, while MEF2A should also be up-regulate; on the other hand, the down-regulation of PTPN12 should repress the nuclear translocation of β-catenin and the expression of VEGF. This study will clarify this hypothesis through in vitro and in vivo experiments, and provide theoretical basis and new ideas for revealing the pathogenesis of DR neovascularization.