Bile acid receptor signaling in retinopathy of prematurity

早产儿视网膜病变中胆汁酸受体信号传导

基本信息

批准号：
10568100
负责人：
Menaka Chanu Thounaojam
金额：
$ 38.5万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10568100
关键词：
Ablation Acids Adult Affect Agonist Air Angiogenesis Inhibitors Angiogenic Factor Apoptotic Astrocytes Back Bile Acid Biosynthesis Pathway Bile Acids Birth Blindness Blood Vessels Blood-Retinal Barrier Cataract Cell Death Cells Child Data Development Diabetic Retinopathy Disease Endothelial Cells Endothelium Environment Event Experimental Designs Experimental Models Failure GPBAR1 gene Goals Growth Hyperoxia Hypoxia In Vitro Infant Inflammation Intervention Ischemia Knockout Mice Knowledge Ligands Liver diseases Modeling Molecular Mus Nature Nuclear Receptors Ocular Pathology Outcome Oxidative Stress Oxygen Pathogenesis Pathogenicity Pathology Pathway interactions Pattern Peripheral Phase Play Premature Birth Premature Infant Procedures Publishing Receptor Activation Receptor Signaling Recurrence Reporting Retina Retinal Degeneration Retinal Detachment Retinal Diseases Retinal Neovascularization Retinopathy of Prematurity Role Signal Transduction Sterols Therapeutic Therapeutic Effect Tissues Ursodeoxycholic Acid Uterus Vascular Endothelial Growth Factors Visual Fields angiogenesis cell type clinically relevant design effective therapy farnesoid X-activated receptor ganglion cell improved in vivo intravitreal injection neovascular neovascularization neuronal survival new therapeutic target novel therapeutic intervention novel therapeutics pharmacologic photoreceptor degeneration postnatal premature prevent protective effect receptor receptor expression response retina blood vessel structure retinal ischemia side effect tauroursodeoxycholic acid tool treatment strategy

项目摘要

The proposed studies are relevant to the treatment of retinopathy of prematurity (ROP), the leading cause of preventable blindness in children. An important trigger for ROP development is the exposure of premature infants to oxygen after birth. This delays normal retinal vascular growth, still taking place in the premature retina. When the infant is brought back to room air, this leads to tissue ischemia, abnormal retinal neovascularization, and, possibly, retinal detachment and blindness. Available interventions are applied in the most advanced stages of the disease and consist of ablation of retinal neovascular tufts or intravitreal injections of anti-angiogenic factors (i.e., VEGF). All these procedures and treatments are associated with severe side effects, including significant loss of visual field and late recurrences. We have recently found that agonists of the nuclear receptor farnesoid-X-receptor (FXR) exert protective effects in an experimental model of ROP (oxygen-induced retinopathy; OIR). Interestingly, we have also found that FXR expression and levels of FXR endogenous ligands are downregulated in OIR, further supporting the hypothesis that leveraging/restoring FXR-dependent signaling could exert key protective effects in ROP/OIR. To confirm this, we found that FXR is present in retinal astrocytes and endothelial cells that are primarily affected in OIR. FXR stimulation may elicit anti-apoptotic responses in astrocytes and anti-angiogenic effects in retinal endothelial cells, thus targeting two key events involved in the induction and progression of OIR. Our working hypothesis is that alterations in retinal FXR signaling play a key role in ROP pathogenesis and the pharmacological modulation of these pathways represents a new therapeutic tool in limiting ROP pathology. We have designed experiments to be conducted in vivo, using the OIR model and in vitro experimental settings to 1) investigate the effects of modulating FXR receptor signaling in OIR; 2) investigate FXR signaling in retinal astrocytes and endothelial cells in OIR. The potential outcomes of the proposed studies could fill the need for new and better therapies for ROP.

拟议的研究与治疗预性早产（ROP）有关，这是儿童可预防的失明。 ROP开发的一个重要触发因素是暴露早产儿出生后氧气。这延迟了正常的视网膜血管生长，仍在预视网膜过早发生。什么时候婴儿被带回房间空气，这导致组织缺血，视网膜新血管形成异常，以及可能是视网膜脱离和失明。可用的干预措施是在最高级的阶段应用的该疾病由视网膜新血管簇或玻璃体内注射抗血管生成因子的消融（即VEGF）。所有这些程序和治疗都与严重的副作用有关，包括重要视野和后期复发的丧失。我们最近发现核受体的激动剂在ROP的实验模型（氧诱导的视网膜病； OIR）。有趣的是，我们还发现FXR表达和FXR内源配体的水平在OIR中被下调，进一步支持了利用/恢复FXR依赖性信号的假设可以在ROP/OIR中发挥关键保护作用。为了确认这一点，我们发现FXR存在于视网膜星形胶质细胞中和主要在OIR中受影响的内皮细胞。 FXR刺激可能会引起抗凋亡反应星形胶质细胞和视网膜内皮细胞中的抗血管生成作用，因此针对了涉及的两个关键事件 OIR的诱导和进展。我们的工作假设是，视网膜FXR信号的变化播放钥匙在ROP发病机理和这些途径的药理调制中的作用代表了一种新的治疗性限制ROP病理学的工具。我们设计了使用OIR模型在体内进行的实验并在体外实验环境1）研究OIR中调节FXR受体信号传导的影响； 2）研究OIR视网膜星形胶质细胞和内皮细胞中的FXR信号传导。潜在的结果拟议的研究可以满足对ROP的新疗法的需求。