The role of heme in retinal vascular development and disease

血红素在视网膜血管发育和疾病中的作用

基本信息

批准号：
10568168
负责人：
David Antonetti
金额：
$ 53.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10568168
关键词：
Age related macular degeneration Alleles Area Back Blindness Blocking Antibodies Blood Vessels Blood capillaries Brain Cell Culture Techniques Cells Central Nervous System Choroidal Neovascularization Collaborations Coupled Data Defect Development Diabetic Retinopathy Disease Down-Regulation Endothelial Cells Endothelium Family Feline Leukemia Virus Gene Deletion Gene Expression Regulation Genes Genetic Genetic Transcription Goals Growth Heme Hemin Human Hypoxia Impairment In Vitro Knock-in Knock-out Knockout Mice Laboratories Lasers Link Mediating Medical Membrane Metabolism Modeling Mus Mutate Mutation Natural regeneration Norrie&apos s disease Oxygen Patients Perfusion Phenocopy Phenotype Primary Cell Cultures Production Proliferating Publications Publishing Regulation Research Retina Retinal Diseases Retinal Neovascularization Retinal Vein Occlusion Retinopathy of Prematurity Role Signal Pathway Signal Transduction Syndrome System Testing Tissues Transgenic Organisms Treatment Factor United States Vascular Diseases Vascular Endothelial Growth Factors Vascularization Vision angiogenesis beta catenin cofactor experimental study genetic approach genetic manipulation in vivo inhibitor knock-down mouse model neovascularization notch protein novel novel therapeutic intervention overexpression oxygen transport pharmacologic prenatal receptor retina blood vessel structure retinal angiogenesis tool trafficking uptake

项目摘要

PROJECT ABSTRACT Retinal vascular diseases are major causes of vision loss in the United States and around the world. To better treat these disorders, we need to understand the signaling pathways that control the growth and integrity of retinal blood vessels. Our recent publications and preliminary data detail a novel angiogenic signaling system centered around heme, a co-factor critical for oxygen transport, metabolism, and gene transcription. We found that heme promotes angiogenic growth in the retina by regulating tip/stalk selection, and that reduced heme production or import leads to reduced retinal vascularization and tissue hypoxia, similar to other retinal vasculopathies including retinopathy of prematurity, choroidal neovascularization, and the rare but important exudative vitreoretinopathies. Furthermore, we found that VEGF suppresses, while Norrin-bCatenin promotes, the expression of the obligate endothelial heme importer, Flvcr2. Based on these data, we hypothesize that heme, is involved in retinal angiogenesis and retinal vasculopathies. The Specific Aims of this proposal are to (1) determine how heme intersects with Notch signaling to control angiogenic tip/stalk selection, (2) determine whether induction of Flvcr2/heme signaling is sufficient and necessary to reverse the vascular defects and downstream vision changes observed in mouse models of exudative vitreoretinopathy, and (3) characterize the role for Flvcr2/heme in VEGF-induced angiogenic proliferation and neo-vascularization. To accomplish these aims, we developed new tools to directly manipulate heme in cultured retinal endothelial cells and assess heme transport and intracellular trafficking in vitro. We also generated new conditional knock-in and knock-out alleles to manipulate endothelial heme transport in vivo. Our studies will fundamentally impact our understanding of how endothelial heme levels are controlled, and the role of heme in retinal angiogenesis and vascular disease.

项目摘要视网膜血管疾病是美国和世界各地视力丧失的主要原因。更好治疗这些疾病，我们需要了解控制控制生长和完整性的信号传导途径视网膜血管。我们最近的出版物和初步数据详细介绍了一种新型的血管生成信号系统围绕血红素，这是一种对氧运输，代谢和基因转录至关重要的共同因素。我们发现血红素通过调节尖端/茎的选择来促进视网膜的血管生长，并降低血红素生产或进口导致视网膜血管和组织缺氧减少，类似于其他视网膜血管疾病包括早产，脉络膜新生血管形成和罕见但很重要的血管病变渗出性玻璃体病。此外，我们发现VEGF抑制了，而诺林 - 巴特宁促进了，强制内皮血红素进口商FLVCR2的表达。基于这些数据，我们假设血红素参与视网膜血管生成和视网膜血管病。该提议的具体目的是（1）确定血红素如何与Notch信号相交以控制血管生成尖端/茎的选择，（2）确定 FLVCR2/血红素信号的诱导是否足够且必要以逆转血管缺陷和在渗出性玻璃体肾上腺病的小鼠模型中观察到的下游视力变化，（3）表征 FLVCR2/血红素在VEGF诱导的血管生成增殖和新血管形成中的作用。完成这些目的，我们开发了新的工具来直接操纵培养的视网膜内皮细胞中的血红素并评估血红素体外运输和细胞内贩运。我们还产生了新的有条件敲门和淘汰等位基因操纵体内内皮血红素的运输。我们的研究将从根本上影响我们对如何控制内皮血红素水平，以及血红素在视网膜血管生成和血管疾病中的作用。