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

总结。 糖尿病占美国医疗保健支出的10%。这其中越来越大的一部分 费用花在糖尿病眼病的治疗上，糖尿病是最常见的缺血性视网膜病变(IR)和 这是发达国家劳动年龄成年人失明的主要原因。低氧可诱导 因子(HIF)是转录调节因子，控制高通透性和 促进黄斑水肿(ME)和视网膜发展的血管生成介质 胰岛素抵抗综合征患者的新生血管(NV)。针对一种HIF调节的血管生成的治疗 血管内皮细胞生长因子(VEGF)是治疗胰岛素抵抗时ME的金标准 最近出现了治疗糖尿病患者新城疫的有效方法。然而， 不到一半的接受治疗的患者对抗血管内皮生长因子治疗有足够的反应，这支持了其他 缺氧诱导因子调控的血管生成因子在新生血管形成中的作用HIF由一种精致的 氧敏感的亚基和普遍表达的亚基。缺氧诱导因子-1α，第一个缺氧诱导因子亚基亚型 经鉴定，已被证明在视网膜血管疾病中起重要作用。另外两个HIF 亚型HIF-2α和HIF-3α随后被报道，而HIF-2α与HIF-2密切相关。 1α还激活低氧诱导基因转录，HIF-3α与之关系更远，可以 激活或抑制HIF靶基因的表达。低氧诱导因子-1与低氧诱导因子-2对血管内皮细胞生长的相对贡献 调控新城疫病毒的启动、促进和发展的基因的表达尚不清楚。 同样，HIFs和HIF调节的基因产物在缺氧损伤后的神经保护作用 对于脆弱的神经感觉性视网膜，人们仍然知之甚少。我们假设，积累 不同细胞在低氧损伤后不同阶段的特定HIF决定了HIF- 低氧视网膜细胞的依赖基因表达特征；这种细胞特异性、时间依赖性 基因签名决定了HIF的“病理性”VS“保护性”作用(S)。要解决这个问题 假设，我们建议确定高强度因子对启动、促进和 Müler细胞在IRS(SA1)中NV的进展；确定HIFs对RGC存活的贡献 HIF-2调节PAI-1在IRS(SA2)中的作用 IRS中视网膜NV的发生(SA3)。这些研究的成功完成将提供对 缺氧诱导因子-1和缺氧诱导因子-2在不同时期不同细胞中的病理与保护作用(S) IRS患者的缺氧性损伤，并将寻找新的治疗方法来预防或 治疗患有这些威胁视力的疾病的患者。

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.