Novel Therapeutic Strategies for Retinal Vascular Inflammation and Angiogenesis in Diabetic Retinopathy.

项目总结/摘要 作为一名儿科眼科医生，他担心肥胖、代谢综合征、 和糖尿病在儿科人群中，特别是在西班牙裔患者中，我选择把我的研究重点放在 糖尿病视网膜病变炎症和血管生成预示着视力威胁的发展 糖尿病视网膜病变（DR）的并发症包括视网膜水肿、视网膜脱离、青光眼和视网膜脱离。 血管内皮生长因子（VEGF）抑制剂是治疗视力的标准药物 威胁DR并发症;然而，其有效性仅限于某些患者人群， 替代疗法已经出现在临床实践中。趋化因子CXCL 8，已知影响 与DR相关的病理机制，在糖尿病患者的眼睛中积累，其水平与 DR进展。然而，我们并不完全理解其归纳的功能含义， 随后的积累。我们发现多种促炎和促血管生成分子 与DR相关的CXCL 8在人视网膜细胞中诱导，并且CXCL 8可以影响人视网膜内皮细胞， 与DR发病和进展相关的细胞反应。我相信CXCL 8是一个关键的中介， 调节和促进DR病理学中早期和晚期事件的多个信号通路的接合点， 包括VEGF信号传导。因此，CXCL 8受体可能是新型DR治疗的理想靶点。几 CXCL 8受体的抑制剂正在进行非眼部疾病的临床试验，但它们干扰 视网膜中DR的机制尚未被探索。我相信，测试这些抑制剂是有价值的， 临床试验和重新利用它们来治疗DR患者。然而，在追求这一目标之前， CXCL 8在眼睛中诱导与DR病理学机制相关的意义（目的1）以及 这些抑制剂干扰这些机制（目标2）必须严格评估。我打算这么做 使用补充基于人原代细胞培养的体外测定的逐步方法（Müller glia和 血管内皮细胞，Aim 1）与DR相关病理事件的体内小鼠模型 （链脲霉素诱导的糖尿病和氧诱导的视网膜病变模型，目的2）。证明了 阻断DR相关致病过程的市售CXCL 8受体抑制剂将证实其 治疗DR的治疗潜力，并为未来临床前和临床试验的设计提供信息。这一指导 我的经验将使我能够生成试点数据，成功地竞争R级资金， 了解DR病理生理学，并加速新DR疗法的开发，因此 促进我作为临床研究者的独立性技能、协作关系和数据 通过执行本建议书及其培训计划，沿着我的眼科培训， 最佳定位我的职业生涯，成功的长期资金和对病人护理的重大影响。

PROJECT SUMMARY/ABSTRACT As a pediatric ophthalmologist concerned by the growing incidence of obesity, metabolic syndrome, and diabetes in the pediatric population, especially in Hispanic patients, I have chosen to focus my research on diabetic retinopathy. Inflammation and angiogenesis herald the development of vision-threatening complications of diabetic retinopathy (DR), including retinal edema, hemorrhages, glaucoma and detachments. Vascular endothelial growth factor (VEGF) inhibitors are the standard of care drugs used to treat vision threatening DR complications; however, their effectiveness is limited to certain patient populations and no alternative therapies have emerged into clinical practice. The chemokine CXCL8, which is known to affect pathologic mechanisms associated with DR, accumulates in the eyes of diabetics and its levels correlate with DR progression. However, we do not fully understand the functional implications of its induction and subsequent accumulation. We have found that multiple pro-inflammatory and pro-angiogenic molecules associated with DR induce CXCL8 in human retinal cells, and that CXCL8 can affect human retinal endothelial cell responses associated with DR onset and progression. I believe that CXCL8 is a key intermediary at the juncture of multiple signaling pathways that regulate and promote both early and late events in DR pathology, including VEGF signaling. Therefore, CXCL8 receptors may be ideal targets for novel DR therapies. Several inhibitors of CXCL8 receptors are in clinical trials for non-ocular conditions, yet their potential to interfere with mechanisms of DR in the retina has not been explored. I believe that there is value in testing these inhibitors in clinical trials and repurposing them to treat patients with DR. However, before pursuing that goal, the significance of CXCL8 induction in the eye in relation to mechanisms of DR pathology (Aim 1) and the value of these inhibitors to interfere with those mechanisms (Aim 2) must be rigorously evaluated. I intend to do this using a stepwise approach complimenting human primary cell culture-based in vitro assays (Müller glia and vascular endothelial cells, Aim1), with in vivo mouse models of DR-associated pathologic events (Streptozotocin-induced diabetes and oxygen-induced retinopathy models, Aim 2). Confirming the ability of commercially-available CXCL8 receptor inhibitors to block DR-relevant pathogenic processes would affirm their therapeutic potential to treat DR, and inform the design of future pre-clinical and clinical trials. This mentored experience will allow me to generate pilot data to successfully compete for R-level funding, to advance the understanding of DR pathophysiology, and to accelerate the development of new DR therapies, therefore promoting my independence as a clinician investigator. The skills, collaborative relationships, and data acquired by the execution of this proposal and its training plan, along with my ophthalmology training, should optimally position my career for successful long term funding and significant impact on patient care.