Diabetic retinopathy (DR) affects approximately one-third of diabetic patients and, if left untreated, progresses to proliferative DR (PDR) with associated vitreous hemorrhage, retinal detachment, iris neovascularization, glaucoma and irreversible blindness. In vitreous samples of human patients with PDR, we found elevated levels of hypoxia inducible factor 1 alpha (HIF1α). HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases. To recreate the human PDR phenotype for a preclinical animal model, we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein, a protein that targets HIF1α for ubiquitination. We found that the neuroretinal cells in these mice overexpressed HIF1α and developed severe, irreversible ischemic retinopathy that has features of human PDR. Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders. In addition, this model system can be used to manipulate the modulation of the hypoxia signaling pathways, for the treatment of non-ocular ischemic and inflammatory disorders.

中文翻译：

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神经视网膜缺氧信号在增生性糖尿病视网膜病变的新的临床前鼠模型中。

糖尿病性视网膜病（DR）会影响大约三分之一的糖尿病患者，如果不加以治疗，则会发展为增殖性DR（PDR），伴有玻璃体出血，视网膜脱离，虹膜新生血管形成，青光眼和不可逆性失明。在人类PDR患者的玻璃体样本中，我们发现缺氧诱导因子1α（HIF1α）水平升高。HIF是促进缺氧适应的转录因子，在多种缺血性和炎性疾病中具有重要的功能作用。为了为临床前动物模型重建人类PDR表型，我们产生了神经视网膜特异性丧失von Hippel Lindau肿瘤抑制蛋白的小鼠，该蛋白靶向HIF1α进行泛素化。我们发现这些小鼠的神经视网膜细胞过表达HIF1α并发展为严重的，具有人类PDR功能的不可逆性缺血性视网膜病。在这些突变小鼠中，视网膜病变的快速发展应有助于评估缺血性和炎性致盲疾病的治疗剂。另外，该模型系统可用于操纵缺氧信号通路的调节，用于治疗非眼部缺血性和炎症性疾病。