Photoreceptor Determination of Retinal Blood Vessel Growth in Retinopathy

视网膜病变中视网膜血管生长的光感受器测定

• 批准号: 9817106
• 负责人: YE SUN
• 金额: $ 44.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9817106
• 关键词: Ablation; Affect; Agonist; Anti-inflammatory; Apoptosis; Apoptotic; Biological Assay; Birth; Blindness; Blood Vessels; Blood-Retinal Barrier; Cell Death; Cells; Child; Complex; Darkness; Data; Development; Disease; Electroretinography; Extravasation; Eye diseases; FOS gene; Family; Fetus; Functional disorder; Gene Expression; Gestational Age; Goals; Growth; Human; Hypoxia; IL6 gene; Immediate-Early Genes; Incidence; Infant; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Interleukin-1 beta; Knock-out; Laser Surgery; Lasers; Lead; Light; Link; Luciferases; Microglia; Modeling; Molecular; Morphology; Mus; Mutant Strains Mice; Non-Steroidal Anti-Inflammatory Agents; Nuclear; Oncogenes; Operative Surgical Procedures; Optical Coherence Tomography; Oxygen; Pathogenesis; Pathologic; Pathologic Neovascularization; Pharmaceutical Preparations; Pharmacology; Phosphoproteins; Photoreceptors; Physiological; Play; Premature Infant; Prevention; Preventive therapy; Proteins; Public Health; Reporter; Research; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Neovascularization; Retinal Photoreceptors; Retinopathy of Prematurity; Rod Outer Segments; Role; Signal Pathway; Signal Transduction; Steroids; Stimulus; Stress; TNF gene; Testing; Therapeutic; Transcription Factor AP-1; Transforming Growth Factor beta; Treatment Factor; VLDL receptor; Vascular Endothelial Growth Factors; Vascularization; Visual; Wild Type Mouse; Work; activator 1 protein; angiogenesis; chromatin immunoprecipitation; disability; high risk; improved; in vivo; inhibitor/antagonist; innovation; macrophage; mouse model; neonatal care; neonate; neovascular; neovascularization; neutrophil; novel; novel strategies; novel therapeutics; prevent; response; retina blood vessel structure; retinal angiogenesis; retinal rods; transcription factor

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.

项目总结/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。的进步 新生儿护理，挽救了更小和更多的早产儿，他们处于ROP的高风险中。因此 ROP的发病率持续增加。目前的激光消融手术破坏视网膜和抗VEGF（血管内皮生长因子）， 内皮生长因子）治疗可能导致脆弱新生儿血管生长的系统性抑制。的 长期目标是了解ROP发展的分子机制，以制定早期预防措施， 治疗炎症介质是视网膜病变的关键调节因子，但其因果关系尚不清楚 并且标准的抗炎药如类固醇或NSAIDS对ROP无效。炎症通常 被认为来自于浸润的炎性细胞，包括巨噬细胞、嗜中性粒细胞和常驻的小胶质细胞。 但是光感受器在ROP的发病机制中起着重要作用，也为血管生长提供信号 通过炎症蛋白质。本申请的总体目标是确定光感受器如何 确定血管生长。我们发现，在光感受器中，转录因子c-Fos， 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： 在视网膜病小鼠模型中调节光感受器衍生的炎症信号。c-Fos存在于 人类感光细胞在其发育过程中。c-Fos在调节视杆细胞特异性基因中也起重要作用 表达和感光细胞凋亡。我们的初步数据表明，c-Fos在光感受器中增加， 抑制光感受器中的c-Fos抑制氧诱导的视网膜病变中的新血管形成 (OIR)ROP小鼠模型。这些结果表明，c-Fos可能是一个主要的信号通路， 强调光感受器传达对血管的需求，是控制发展的潜在目标 新血管形成的可能性我们假设视网膜色素变性中光感受器决定病理性视网膜血管生成 通过c-Fos调节炎症信号。拟议研究的基本原理是， ROP发展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视网膜血管生成;目的2：确定光感受器c-Fos是否控制OIR视网膜血管生成 c-Fos通过调节炎症信号控制血管生成;目的3：确定是否 c-Fos的药理学抑制剂抑制OIR中的病理性视网膜血管生成。 是创新的，因为它代表了一个实质性的偏离现状，确定一个感光器- 启动炎症信号以控制ROP中的病理性视网膜病变。所提出的研究是有意义的 因为它将为开发具有广泛翻译活性的治疗策略提供新的靶点（c-Fos）， 在预防和治疗ROP和广泛的其他血管性眼病中具有重要意义。