雷帕霉素介导的Angiopoietin1对早产儿视网膜病变的视网膜血管发育和成熟的调控作用和机制研究

当前早产儿视网膜病变的治疗时机稍晚且效用不佳。我们发现雷帕霉素早期干预可上调Angiopoietin1以减轻OIR小鼠模型视网膜血管闭塞，进而减少异常新生血管，提供了早期治疗的新思路。Angiopoietin1由周细胞生成，可促进内皮细胞增殖以延长血管，并调控星形胶质细胞以指导视网膜血管生长方向，我们发现雷帕霉素可促进视网膜血管方向性生长并可能增加星形胶质细胞增殖，提示雷帕霉素可能通过上调Angiopoietin1来调控星形胶质细胞指导的血管发育。本研究拟采用OIR小鼠模型和体外周细胞与星形胶质细胞、内皮细胞共培养体系，研究雷帕霉素调控视网膜血管发育的机制，着重探索其介导的Angiopoietin1对星形胶质细胞和内皮细胞的调控作用，阐明雷帕霉素调控Angiopoietin1的分子机制，评判雷帕霉素促进血管成熟的远期效用，夯实雷帕霉素作为早产儿视网膜病变早期治疗措施的理论基础和临床前景。

The current treatment of Retinopathy of Prematurity (ROP) is relatively late and ineffective. We found that early intervention of rapamycin up-regulated Angiopoietin1 to alleviate retinal vascular occlusion in the OIR mouse model, subsequently reducing abnormal angiogenesis, which provides a new idea for ROP early management. Angiopoietin1, which is mainly generated by pericytes, can promote vascular endothelial cells’ proliferation to extend the length of vessels, and regulate astrocytes to guide the direction of retinal vessel growth. We found that rapamycin could promote the orientation growth of the retinal vessels and may increase astrocytes’ proliferation. These reminds us that rapamycin may regulate astrocytes to guide the development of blood vessels by raising Angiopoietin1. In this study, we will establish the OIR mouse model and the co-culture system between pericytes and astrocytes or endothelial cells in vitro. We will investigate the effects and mechanisms of rapamycin regulating development of retinal vessels, focusing on the regulating effects of Angiopoietin1, mediated by rapamycin, on astrocytes and endothelial cells. We will elucidate the molecular mechanisms of rapamycin regulating Angiopoietin1. Furthermore, we will evaluate the long-term effects of rapamycin on promoting vessels’ maturity. Together, we try to stabilize the theoretical basis and evaluate the clinical prospects of rapamycin as early therapy for ROP.