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

• 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
• 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

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.

建议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 儿童中可预防的失明。早产儿暴露于ROP是ROP发生的重要触发因素 出生后吸氧。这会延迟正常的视网膜血管生长，而这种生长仍然发生在早产儿的视网膜上。什么时候 婴儿被带到室内空气中，这会导致组织缺血，异常的视网膜新生血管，以及， 可能是视网膜脱离和失明。可用的干预措施适用于最高级的 这种疾病包括视网膜新生血管束的消融或玻璃体内注射抗血管生成因子 (即，血管内皮生长因子)。所有这些程序和治疗都与严重的副作用有关，包括显著的 视野丧失和晚期复发。我们最近发现核受体激动剂 法尼醇-X受体(FXR)在氧诱导ROP模型中的保护作用 视网膜病变；OIR)。有趣的是，我们还发现FXR的表达和FXR内源性配体的水平 在OIR中下调，进一步支持了利用/恢复FXR依赖的信号的假设 可在ROP/OIR中发挥关键保护作用。为了证实这一点，我们发现FXR存在于视网膜星形胶质细胞中 以及主要受OIR影响的内皮细胞。FXR刺激可诱导血管内皮细胞的抗凋亡反应 星形胶质细胞和视网膜内皮细胞的抗血管生成作用，从而靶向参与 OIR的诱导和发展。我们的工作假设是视网膜FXR信号的改变起到了关键作用 在ROP发病机制中的作用及对这些通路的药理调节代表了一种新的治疗方法 限制ROP病理的工具。我们设计了在活体内进行的实验，使用OIR模型 体外实验1)研究FXR受体信号在OIR中的作用；2) 研究OIR时视网膜星形胶质细胞和内皮细胞中的FXR信号。这一政策的潜在后果 拟议的研究可能会填补对ROP新的更好治疗方法的需求。