COBRE: HIF-1 AS THERAPEUTIC TARGET IN DIABETIC RETINOPATHY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。糖尿病视网膜病变是糖尿病的主要并发症，也是导致失明的主要原因。在其后期阶段，这种疾病的特点是视网膜血管的过度增生，或血管生成。缺氧诱导因子-1 （Hypoxia inducible factor -1, HIF-1）是一种在缺氧条件下被快速诱导的转录因子，可调节几种对血管生成和葡萄糖调节至关重要的基因的表达。HIF-1已被证明在视网膜中对缺氧和晚期糖基化产物（AGEs）的反应显著增加，与糖尿病相关的大分子改变。推动这些研究的总体假设是，通过特异性破坏HIF-1抑制血管生成是潜在控制增殖性视网膜病变的一个新的早期靶点。特异性靶标之一的目标是通过使用核酶或RNA的催化片段，在信使RNA水平上靶向hif - α， HIF-1的一个关键亚基。特异性目的二的目标是利用噬菌体肽展示找到hif - α和hif -1 β (ARNT)亚基相互作用的特异性肽抑制剂。核酶和多肽都将通过腺病毒被引入视网膜局部。这些药物对血管生成和HIF-1下游靶点（VEGF, pal -1）的影响将通过氧诱导小鼠缺血模型进行检测。利用这些分子方法，我们试图确定HIF-1在增生性糖尿病视网膜病变中的作用，并确定这种转录因子是否代表了这种疾病状态下治疗的有效靶标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetic retinopathy is a major complication of diabetes and a leading cause of blindness. In its later stages this disease is characterized by a hyperproliferation of retinal blood vessels, or angiogenesis. Hypoxia inducible factor -1 (HIF-1) is a transcription factor that is rapidly induced in response to hypoxia and regulates the expression of several genes critical to angiogenesis and glucose regulation. HIF-1 has been shown to be significantly increased in the retina in response to hypoxia and to advanced glycation products (AGEs), altered macromolecules associated with diabetes. The overall hypothesis driving these studies is that inhibition of angiogenesis through the specific disruption of HIF-1 is a novel, early target for potentially controlling proliferative retinopathy. The goal of specific aim one is to target HIF-lalpha, a critical subunit of HIF-1, at the messenger RNA level through the use of ribozymes, or catalytic pieces of RNA. The goal of specific aim two is to find specific peptide inhibitors of the interaction between the HIF-lalpha and the HIF-1beta (ARNT) subunit using phage peptide display. Both the ribozymes and the peptides will be introduced locally into the retina using adenovirus. The effect of these agents on angiogenesis and on downstream targets of HIF-1 (VEGF, PAl-l) will be examined using an oxygen-induced mouse ischemia model. Using these molecular approaches we seek to define a role for HIF-1 in proliferative diabetic retinopathy and to determine whether this transcription factor represents a valid target for therapy in this disease state.