Bile Acids and Complications of Prematurity

本文介绍的研究与早产儿视网膜病变(ROP)的治疗有关，ROP是早产儿的主要原因 婴儿失明。ROP是一种以视网膜血液异常生长为特征的发育性血管疾病 极低胎龄(1250克，28周)未完全血管化的视网膜血管 怀孕)。由于氧疗的毒性，围产期护理导致早产儿ROP 在发育中的视网膜血管系统。到目前为止，ROP的治疗方法应用于最晚期和 本质上涉及潜在的有害副作用，包括严重的视野丧失、青光眼和其他。 在这里，我们提出了一种新的策略，通过系统地给药治疗活性物质来改善ROP 次级胆汁酸、熊去氧胆酸(UDCA)及其衍生物牛磺酸-UDCA(TUDCA)和甘氨酸-UDCA (GUDCA)在扎实的初步结果的基础上，这项建议将对深度给药进行评估 UDCA、TUDCA和GUDCA降低ROP的策略及作用机理 氧源性视网膜病变(OIR)。在这个小鼠模型中，我们将概括ROP的两个主要阶段 评估这三种胆汁酸的最佳治疗窗口/应用，并评估它们的作用模式。我们的 研究目的：1)探讨UDCA、TUDCA和GUDCA对病理性视网膜的影响 2)评价UDCA、TUDCA和GUDCA对视网膜内皮细胞的影响 血管生成和屏障功能。拟议中的研究的潜在结果可能立即产生临床效果。 申请，因为含有美国FDA批准的配方的UDCA已经在市场上出售，并可能 被迅速地重新用于这一新的重要和迫切需要的治疗应用。

The studies here presented are relevant to the treatment of retinopathy of prematurity (ROP) a leading cause of blindness in infants. ROP is a developmental vascular disorder characterized by abnormal growth of retinal blood vessels in the incompletely vascularized retina of extremely low gestational age neonates (<1250 g, <28 weeks gestation). ROP occurs in premature babies as consequence of perinatal care due to toxicity of oxygen therapy on the developing retinal vasculature. To date, therapies for ROP are applied in the most advanced stages and essentially involve potentially harmful side effects, including significant loss of visual field, glaucoma and others. Herein we present a novel strategy to ameliorate ROP by systemic administration of a therapeutically active secondary bile acid, ursodeoxycholic acid (UDCA) and its derivative taurine-UDCA (TUDCA) and glycine-UDCA (GUDCA). Based on the foundation of solid preliminary results, this proposal will evaluate in-depth dosing strategy and mechanism of action for UDCA, TUDCA and GUDCA to reduce ROP in an experimental model of oxygen-induced retinopathy (OIR). In this mouse model recapitulating the two main phases of ROP we will assess the best therapeutic window/application of the three bile acids and evaluate their mode of action. Our study aims are: 1)) To investigate the effects of UDCA, TUDCA and GUDCA on pathological retinal neovascularization; 2)) To assess the effects of UDCA, TUDCA and GUDCA on retinal endothelial cells angiogenic and barrier function. The potential outcomes of the proposed studies could have immediate clinical application, as UDCA containing US-FDA approved formulations are already available in the market and could be rapidly re-purposed for this new important and much needed therapeutic application.