Divergent Roles for Hypoxia-Inducible Factor-1 and -2 in Ischemic Retinal Disease

摘要 糖尿病占美国医疗保健支出的10%。其中越来越多的 糖尿病眼病的治疗费用，最常见的缺血性视网膜病变（IR）， 这是发达国家工作年龄成年人失明的主要原因。缺氧诱导 HIF-1 α因子（HIF-1 α）是转录调节因子，其控制高渗透性的表达， 血管生成介质，促进黄斑水肿（ME）和视网膜病变的发展 IR患者的新生血管形成（NV）。靶向一种HIF调节的血管生成的疗法 介质血管内皮生长因子（VEGF）是治疗IR中ME的金标准 患者，并且最近已经成为糖尿病患者中NV的有效治疗方法。然而，在这方面， 不到一半的治疗患者对抗VEGF治疗有充分反应，支持了其他治疗方法的作用。 在NV的发展中HIF调节的血管生成因子。HIF是由一种精致的 氧敏感性β亚基和普遍表达的β亚基。HIF-1α，第一个HIF β亚基亚型 已显示在视网膜血管疾病中发挥重要作用。两个HIF 随后报道了HIF-2α和HIF-3α的亚型;而HIF-2α与HIF-3 α密切相关。 HIF-1α也激活缺氧诱导基因转录，HIF-3α的亲缘关系更远， 激活或抑制HIF靶基因的表达。HIF-1与HIF-2对肿瘤细胞增殖的相对贡献 调控NV的起始、促进和进展的基因的表达是未知的。 类似地，缺氧损伤后HIF-和HIF-调节的基因产物的神经保护作用 对脆弱的神经视网膜的影响仍然知之甚少。我们假设， 低氧损伤后不同细胞中特定HIF的精确阶段决定了HIF-1 α的表达。 缺氧视网膜细胞中的依赖性基因表达特征;这种细胞特异性，时间依赖性 基因标记决定了HIF的“病理”作用与“保护”作用。为了解决这个 假设，我们建议确定HIF的启动，促进， IR中Müller细胞的NV进展（SA 1）;确定HIF对RGC存活的贡献 在IR（SA 2）中的缺氧损伤之后;并确定HIF-2调节派-1对IR（SA 2）的作用。 IR中视网膜NV的发展（SA 3）。这些研究的成功完成将提供深入了解 HIF-1和HIF-2在不同细胞中的病理作用与保护作用 缺氧损伤的IR患者，并将确定新的治疗方法，用于预防或 治疗这些威胁视力的疾病。

SUMMARY. Diabetes accounts for 10% of healthcare spending in the United States. A growing portion of this cost is spent on treatments for diabetic eye disease, the most common ischemic retinopathy (IR) and the leading cause of blindness among working-age adults in the developed world. Hypoxia-inducible factors (HIFs) are transcriptional regulators that control the expression of the hyperpermeabilty and angiogenic mediators that promote the development of macular edema (ME) and retinal neovascularization (NV) in patients with IRs. Therapies targeting one HIF-regulated angiogenic mediator, vascular endothelial growth factor (VEGF), are the gold standard for treating ME in IR patients, and have more recently emerged as effective treatments for NV in diabetic patients. However, less than half of treated patients respond adequately to anti-VEGF therapies, supporting a role for other HIF-regulated angiogenic factors in the development of NV. HIFs are composed of an exquisitely oxygen-sensitive  subunit and a ubiquitously-expressed  subunit. HIF-1α, first HIF  subunit isoform to be identified, has been shown to play an important role in retinal vascular disease. Two other HIF isoforms, HIF-2α and HIF-3α, have subsequently been reported; while HIF-2α is closely related to HIF- 1α and also activates hypoxia-inducible gene transcription, HIF-3α is more distantly related and can either activate or repress expression of HIF target genes. The relative contribution of HIF-1 vs HIF-2 to the expression of genes that regulate the initiation, promotion, and progression of NV is not known. Similarly, the neuroprotective role of HIFs – and HIF-regulated gene products – following hypoxic injury to the vulnerable neurosensory retina remains poorly understood. We hypothesize that accumulation of specific HIFs in different cells at precise stages following hypoxic injury determines the HIF- dependent gene expression signature in hypoxic retinal cells; this cell-specific, time-dependent gene signature determines the “pathologic” vs “protective” role(s) of HIFs. To address this hypothesis, we propose to determine the contribution of HIFs to the initiation, promotion, and progression of NV by Müller cells in IRs (SA1); determine the contribution of HIFs to RGC survival following hypoxic injury in IRs (SA2); and determine the contribution of HIF-2 regulation of PAI-1 to the development of retinal NV in IRs (SA3). Successful completion of these studies will provide insight into the pathologic vs protective role(s) of HIF-1 and HIF-2 in different cells at different stages following hypoxic injury in patients with IRs, and will identify novel therapeutic approaches for preventing or treating patients with these vision threatening disease.