Bile Acids and Complications of Prematurity

胆汁酸和早产并发症

基本信息

批准号：
9789681
负责人：
Menaka Chanu Thounaojam
金额：
$ 7.64万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789681
关键词：
Affect Bile Acids Bilirubin Biological Markers Blindness Blood Vessels Cessation of life Child Childhood Chronic Comorbidity Complication Development Disease Dose Drug Formulations Endothelial Cells Experimental Models Exposure to FDA approved Formulation Foundations Future Gestational Age Glaucoma Glycine Goals Growth Human Icterus Infant Inflammation Life Molecular Molecular Analysis Myopia Ophthalmologist Organ Outcome Oxidative Stress Oxygen Oxygen Therapy Care Pathologic Pathologic Neovascularization Pathology Patients Perinatal Care Personal Satisfaction Phase Pregnancy Premature Infant Prevention strategy Protocols documentation Retina Retinal Retinal Diseases Retinal Neovascularization Retinopathy of Prematurity Risk Factors Solid Stimulus Taurine Testing Therapeutic Tissues Toxic effect United States Ursodeoxycholic Acid Vascular Diseases Vascular Endothelial Growth Factors Visual Fields Visual impairment base brain endothelial cell clinical application design experimental study legally blind mouse model neonate neovascular neurotoxic neurovascular novel strategies novel therapeutics oxygen toxicity perinatal complications premature protective effect retina blood vessel structure side effect tauroursodeoxycholic acid

项目摘要

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.

这里提出的研究与治疗预性早产（ROP）有关的主要原因是婴儿的失明。 ROP是一种发育性血管疾病，其特征是视网膜血液异常生长极低的胎龄新生儿的不完全血管化视网膜中的血管（<1250 g，<28周妊娠）。由于氧疗法的毒性，由于围产期护理而导致ROP发生在早产婴儿中在发育中的视网膜脉管系统上。迄今为止，在最高级的阶段应用ROP的疗法本质上涉及潜在的有害副作用，包括视野的重大丧失，青光眼等。在此，我们提出了一种通过系统地给药的新型策略来改善ROP 次生胆汁酸，ursdexycycholic（UDCA）及其衍生牛磺酸-UDCA（TUDCA）和甘氨酸-UDCA （gudca）。基于固体初步结果的基础，该提案将评估深入的剂量 UDCA，Tudca和Gudca在实验模型中降低ROP的策略和作用机理氧诱导的视网膜病变（OIR）。在此鼠标模型中，概括了ROP的两个主要阶段，我们将评估三种胆汁酸的最佳治疗窗口/应用，并评估其作用方式。我们的研究目的是：1））研究UDCA，Tudca和Gudca对病理视网膜的影响新血管化； 2））评估UDCA，TUDCA和GUDCA对视网膜内皮细胞的影响血管生成和屏障功能。拟议研究的潜在结果可能立即进行临床应用，因为包含UDCA包含US-FDA批准的配方已在市场上可用，可以为这一新的重要且急需的治疗应用程序快速重新使用。