Photoreceptor Determination of Retinal Blood Vessel Growth in Retinopathy

项目摘要/摘要 早产儿视网膜病变(ROP)是导致儿童失明和残疾的主要原因。随着技术的进步 新生儿护理，较小和更多的早产儿被挽救，他们是ROP的高危人群。因此， ROP的发生率继续增加。目前的激光消融手术破坏视网膜和抗血管内皮生长因子(血管 内皮生长因子)治疗可能导致脆弱新生儿血管生长的全身性抑制。这个 长期目标是了解ROP发生的分子机制，以制定早期预防措施 治疗。炎症介质是已知的视网膜病变的关键调节因子，但其因果联系一直难以捉摸。 而标准的抗炎药物，如类固醇或非类固醇类药物，对ROP无效。炎症通常是 被认为来自浸润性炎症细胞，包括巨噬细胞、中性粒细胞和常驻的小胶质细胞。 但在ROP发病机制中发挥重要作用的光感受器也是血管生长的信号 通过炎性蛋白。这项应用的总体目标是识别光感受器如何 确定血管生长情况。我们发现，在光感受器中，转录因子c-Fos是一种即刻早期 基因和原癌基因，以及许多炎症因子的主要调节因子，通过以下方式控制视网膜血管生成 调节视网膜病变小鼠模型中光感受器衍生的炎症信号。C-Fos位于 人类光感受器细胞在整个发育过程中。C-Fos在调控杆状基因中也起着重要作用 表达与光感受器细胞凋亡。我们的初步数据显示，c-fos在光感受器中增加。 光感受器中c-Fos的抑制抑制氧诱导的视网膜病变中的新生血管 (OIR)小鼠ROP模型。这些发现提示c-Fos可能是一条主要的信号通路。 应激光感受器传递血管的需要，是控制发育的潜在靶点 新生血管。我们假设光感受器决定ROP的病理性视网膜血管生成 通过c-Fos调节炎症信号。提出这项研究的理由是理解 ROP发生的分子机制有可能帮助开发ROP的治疗(现在 每年影响约16,000名美国婴儿)。我们建议用三个目标来检验这一假设。目标1：确定 光感受器c-Fos是否控制OIR的视网膜血管生成；目标2：确定光感受器 C-Fos通过调节炎症信号控制血管生成；目标3：确定 C-Fos的药物抑制OIR的病理性视网膜血管生成。拟议的研究 是创新的，因为它代表了对现状的实质性偏离，通过识别光感受器- 启动炎症信号控制ROP的病理性视网膜病变。这项拟议的研究具有重要意义 因为它将提供一个新的靶点(c-Fos)来开发具有广泛翻译能力的治疗策略 在预防和治疗ROP和其他一系列血管性眼病方面具有重要意义。

PROJECT SUMMARY/ABSTRACT Retinopathy of prematurity (ROP) is a major cause of blindness and disability in children. With advances in neonatal care, smaller and more premature infants are saved who are at high risk for ROP. Therefore, the incidence of ROP continues to increase. Current laser ablation surgery destroys retina and anti-VEGF (vascular endothelial growth factor) treatment may cause systemic suppression of vessel growth in fragile neonates. The long-term goal is to understand the molecular mechanisms of ROP development to devise earlier preventative therapies. Inflammatory mediators are known key regulators in retinopathy but the causal link has been elusive and standard anti-inflammatory drugs such as steroids or NSAIDS are not effective in ROP. Inflammation is often thought to come from infiltrating inflammatory cells including macrophages, neutrophils and resident microglia. But photoreceptors, which play an important role in the pathogenesis of ROP, also signal for blood vessel growth through inflammatory proteins. The overall objective in this application is to identify how photoreceptors determine blood vessel growth. We found that in photoreceptors, transcription factor c-Fos, an immediate early gene and pro-oncogene, and a master regulator of many inflammatory factors, controls retinal angiogenesis by modulating photoreceptor-derived inflammatory signals in a mouse model of retinopathy. c-Fos is found in the human photoreceptor cells throughout their development. c-Fos is also important in regulating rod-specific gene expression and photoreceptor apoptosis. Our preliminary data show that c-Fos is increased in photoreceptors and that suppression of c-Fos in photoreceptors inhibits neovascularization in an oxygen-induced retinopathy (OIR) mouse model of ROP. These findings suggest that c-Fos may be a major signaling pathway used by stressed photoreceptors to convey the need for blood vessels and is a potential target to control the development of neovascularization. We hypothesize that photoreceptors determine pathological retinal angiogenesis in ROP by modulating the inflammatory signals via c-Fos. The rationale for the proposed research is that understanding the molecular mechanisms of ROP development has the potential to help develop treatment of ROP (now affecting ~16,000 US infants per year). We propose to test this hypothesis with three Aims. Aim 1: To determine whether photoreceptor c-Fos controls retinal angiogenesis in OIR; Aim 2: To determine whether photoreceptor c-Fos controls angiogenesis through modulating inflammatory signals; and Aim 3: To determine whether pharmacological inhibitors of c-Fos suppress pathological retinal angiogenesis in OIR. The proposed research is innovative because it represents a substantive departure from the status quo by identifying a photoreceptor- initiated inflammatory signal to control pathological retinopathy in ROP. The proposed research is significant because it will provide a novel target (c-Fos) for developing therapeutic strategies that have broad translational importance in the prevention and treatment of ROP and a wide range of other vascular eye diseases.