Bile acid receptor signaling in retinopathy of prematurity

拟议的研究与早产儿视网膜病变（ROP）的治疗有关，ROP是早产儿视网膜病变的主要原因。 可预防的儿童失明。ROP发展的一个重要触发因素是早产儿的暴露 出生后的氧气这延迟了正常的视网膜血管生长，仍然发生在未成熟的视网膜中。当 将婴儿带回室内空气中，这导致组织缺血、异常视网膜新生血管形成，并且， 可能导致视网膜脱落和失明现有的干预措施适用于最先进的阶段， 该疾病包括视网膜新生血管丛的切除或抗血管生成因子的玻璃体内注射 (i.e., VEGF）。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ROP（氧诱导）实验模型中发挥保护作用 视网膜病; OIR）。有趣的是，我们还发现FXR表达和FXR内源性配体水平 在OIR中下调，进一步支持了利用/恢复FXR依赖性信号传导的假设， 在ROP/OIR中发挥关键的保护作用。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， FXR刺激可引起OIR中主要受影响的内皮细胞的抗凋亡反应。 星形胶质细胞和视网膜内皮细胞中的抗血管生成作用，从而靶向参与视网膜血管生成的两个关键事件。 我们的工作假设是视网膜FXR信号的改变在OIR的诱导和进展中起关键作用。 在ROP发病机制中的作用和这些途径的药理学调节代表了一种新的治疗方法， 限制ROP病理的工具。我们设计了在体内进行的实验，使用OIR模型 和体外实验设置，以1）研究调节FXR受体信号传导在OIR中的作用; 2） 研究OIR中视网膜星形胶质细胞和内皮细胞中的FXR信号。 提出的研究可以满足对ROP的新的和更好的治疗的需要。

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.