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

缺氧诱导因子-1 和-2 在缺血性视网膜疾病中的不同作用

基本信息

批准号：
10589944
负责人：
Akrit Singh Sodhi
金额：
$ 53.03万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589944
关键词：
3-Dimensional Address Adult Age American Angiogenic Factor Blindness CRISPR/Cas technology Cell Survival Cells Data Development Diabetes Mellitus Disease Distant Endothelial Cell Inhibitor Endothelial Cells Exposure to Eye diseases Gene Expression Gene Expression Profile Genes Genetic Transcription Healthcare Hypoxia Hypoxia Inducible Factor In Vitro Injury Ischemia Link Literature Mediator Molecular Molecular Target Muller&apos s cell Nuclear Oxygen Pathologic Pathologic Neovascularization Pathway interactions Patients Plasminogen Activator Inhibitor 1 Play Protein Isoforms Publishing Regulation Reporting Repression Retina Retinal Diseases Retinal Ganglion Cells Retinal Neovascularization Role Time Tissues United States Vascular Diseases Vascular Endothelial Growth Factors Vision autocrine bHLH-PAS factor HLF cell motility cell type clinical phenotype cost diabetic diabetic patient droplet sequencing effective therapy gene product genetic signature human pluripotent stem cell hypoxia inducible factor 1 in vivo insight ischemic injury macular edema mouse model neovascular neovascularization neuroprotection neurosensory new therapeutic target novel novel therapeutic intervention paracrine postnatal prevent response retinal ischemia rho GTP-Binding Proteins targeted treatment transcription factor transcriptome sequencing

项目摘要

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.

概括。糖尿病占美国医疗保健支出的 10%，而且这一比例还在不断增长。费用用于治疗糖尿病眼病、最常见的缺血性视网膜病 (IR) 和是发达国家工作年龄成年人失明的主要原因。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针对 IR 患者的新生血管形成 (NV) 的治疗。血管内皮生长因子 (VEGF) 是治疗 IR 中 ME 的金标准近来已成为糖尿病患者 NV 的有效治疗方法。不到一半的治疗患者对抗 VEGF 疗法有充分反应，这支持了其他疗法的作用 HIF 形成过程中受 HIF 调节的血管生成因子由一系列精细的成分组成。氧敏感 α 亚基和普遍表达的 β 亚基，第一个 HIF α 亚基异构体。待确定，已被证明在视网膜血管疾病中发挥重要作用的另外两种HIF。随后报道了 HIF-2α 和 HIF-3α 亚型，而 HIF-2α 与 HIF- 密切相关； HIF-3α 与 HIF-1α 的关系更远，并且还可以激活缺氧诱导基因转录。激活或抑制 HIF 靶基因的表达 HIF-1 与 HIF-2 对 HIF 靶基因的相对贡献。调节 NV 起始、促进和进展的基因表达尚不清楚。同样，HIF 和 HIF 调节的基因产物在缺氧损伤后的神经保护作用我们对脆弱的神经感觉视网膜的积累仍知之甚少。缺氧损伤后不同细胞中特定 HIF 的数量决定了 HIF- 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、时间依赖性基因特征决定了 HIF 的“病理性”与“保护性”作用。假设，我们建议确定 HIF 对启动、促进和 IR 中 Müller 细胞的 NV 进展（SA1）；确定 HIF 对 RGC 存活的贡献； IR 缺氧损伤后 (SA2)；并确定 HIF-2 对 PAI-1 的调节对 IR 中视网膜 NV 的发展 (SA3) 的成功完成将提供对 IR 视网膜 NV 的深入了解。 HIF-1和HIF-2在不同阶段的不同细胞中的病理作用与保护作用如下 IR 患者缺氧损伤，并将确定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。