Exploring the angiogenesis-to-fibrosis transition in ischemic retinopathies

探索缺血性视网膜病中血管生成到纤维化的转变

• 批准号: 10091447
• 负责人: Amani A Fawzi
• 金额: $ 37.57万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091447
• 关键词: Address; Adult; Affect; Age; Anatomy; Animal Model; Birth; Blindness; Blood Vessels; Blood capillaries; Blood flow; Cells; Childhood; Cicatrix; Clinical; Complication; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Endothelial Cells; Endothelin; Endothelin A Receptor; Endothelin Receptor; Endothelin-1; Endothelin-2; Endothelium; Exhibits; Fibronectins; Fibrosis; Gene Expression; Gene Expression Profile; Goals; Green Fluorescent Proteins; Human; Hyperoxia; Immunohistochemistry; Inflammation; Intervention; Ischemia; Knock-out; Knockout Mice; Knowledge; Mediating; Membrane; Mesenchymal; Modeling; Molecular; Mus; Neuroglia; Neurons; Nutrient; Operative Surgical Procedures; Outcome; Oxidative Stress; Oxygen; Pathogenesis; Pathologic; Pathologic Neovascularization; Pathology; Pathway interactions; Pericytes; Pharmaceutical Preparations; Pharmacology; Play; Population; Process; Reporter; Research Personnel; Retina; Retinal Diseases; Role; Scientist; Series; Signal Transduction; Source; Streptozocin; Surgeon; System; Tamoxifen; Testing; Tissues; Traction; Transgenic Mice; Transgenic Organisms; Translating; Universities; Validation; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vision; Visual; angiogenesis; bench to bedside; bevacizumab; comparative efficacy; design; druggable target; experimental study; human disease; improved; in vivo; molecular marker; mouse model; novel; novel imaging technology; novel therapeutics; postnatal; prevent; receptor; retina blood vessel structure; retinal imaging; retinal ischemia; success; therapeutic target; transcriptome sequencing

Diabetic retinopathy (DR) and other forms of retinal ischemia are a leading cause of blindness in working age adults. There is a need to identify the mechanisms that control the transition from angiogenesis to fibrosis in these conditions. This would be a first step towards new therapies to address progressive vascular endothelial damage that ultimately leads to pre-retinal fibrosis and traction detachment with poor visual and anatomic outcomes. To address this gap in our knowledge, we have designed a series of experiments that build logically on our preliminary data, which shows evidence for endothelin-1 (ET-1) involvement in fibrovascular human surgical membranes. We hypothesize that dysregulated endothelial ET-1 is particularly important in the pathogenesis of ischemia-induced retinopathy and its complications. To examine this hypothesis, we will study animal models that span the entire spectrum of retinal ischemia, including streptozotocin (STZ)-induced diabetes and models of developmental ischemia- the oxygen induced retinopathy (OIR, to replicate angiogenesis in ischemia) and the limited hyperoxia-induced proliferative retinopathy (l-HIPR), which replicates the angiofibrotic end-stages of severe ischemia. We will use these models to test the hypothesis that dysregulation of vascular endothelial cell-derived ET-1 is critically involved in the promotion of vascular pathology, using an inducible, targeted vascular endothelial ET-1 knockout transgenic mouse (ET-1Eko). In aim 1, we subject this ET-1Eko mouse to the STZ-induced diabetes and the developmental models of ischemia to study the role of endothelial ET-1 dysregulation in angiogenesis and fibrosis. In aim 2, we will cross the ET-1Eko with a transgenic reporter mouse model to focus on the endothelial- to-mesenchymal transition in the retinal vessels and the surrounding pericytes, glia and neurons. Finally, in aim 3, we will focus on developing pharmacologic interventions geared towards ET-1 receptors to improve retinal pathology in models of DR, ischemia- induced angiogenesis and fibrosis (OIR and l-HIPR), as a first step towards translating our findings to the bedside. The mechanistic experiments proposed herein will capitalize on the interdisciplinary expertise of the clinician- scientist PI and her collaborators. Dr. Fawzi is a clinician-scientist retina surgeon with special expertise in non- invasive retinal imaging, animal models of ischemia and retinal vascular diseases. Her co-investigator, Dr. Schnaper is a clinician-scientist, pediatric nephrologist, who is a world expert in fibrogenic signaling. Finally, the group also capitalizes on novel imaging technologies in Dr. Zhang’s lab at Northwestern University, another collaborator.

糖尿病视网膜病变（DR）和其他形式的视网膜缺血是工作年龄失明的主要原因 成年人了有必要确定控制从血管生成到纤维化的转变的机制， 了以下条件这将是迈向新疗法的第一步， 最终导致视网膜前纤维化和牵引性脱离的损伤， 结果。 为了解决我们知识中的这一差距，我们设计了一系列实验，这些实验在逻辑上建立在我们的 初步数据显示内皮素-1（ET-1）参与纤维血管人类外科手术的证据， 膜。我们推测内皮细胞ET-1的失调在糖尿病的发病机制中特别重要。 缺血性视网膜病变及其并发症。 为了验证这一假设，我们将研究跨越整个视网膜缺血谱的动物模型， 包括链脲佐菌素（STZ）诱导的糖尿病和发育性缺血模型-氧诱导的 视网膜病变（OIR，复制缺血中的血管生成）和有限的高氧诱导的增殖 视网膜病变（l-HIPR），其复制严重缺血的血管纤维化终末期。我们将会用这些 模型来检验血管内皮细胞衍生的ET-1的失调与 使用可诱导的靶向血管内皮ET-1敲除促进血管病理学 转基因小鼠（ET-1 Eko）。在目的1中，我们将这种ET-1 Eko小鼠置于STZ诱导的糖尿病中， 缺血的发育模型，以研究内皮ET-1失调在血管生成中的作用， 纤维化在目标2中，我们将ET-1 Eko与转基因报告小鼠模型杂交，以集中于内皮细胞- 在视网膜血管和周围的周细胞，神经胶质细胞和神经元中向间充质转化。最后，在aim 3，我们将专注于开发针对ET-1受体的药物干预措施，以改善视网膜病变。 作为第一步，在DR、缺血诱导的血管生成和纤维化（OIR和l-HIPR）模型中的病理学 将我们的发现应用于临床 本文提出的机制实验将利用临床医生的跨学科专业知识- 科学家PI和她的合作者。Fawzi博士是一位临床科学家视网膜外科医生，在非视网膜疾病方面具有特殊专长。 侵入性视网膜成像、缺血和视网膜血管疾病的动物模型。她的合作研究员，博士。 Schnaper是一位临床科学家，儿科肾病学家，是纤维化信号传导方面的世界专家。最后， 该小组还利用了西北大学张博士实验室的新成像技术， 合作者