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: 9886577
• 负责人: Amani A Fawzi
• 金额: $ 39.5万
• 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/9886577
• 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导致工作年龄失明的主要原因 成年人。有必要确定控制血管生成向纤维化转变的机制。 这些条件。这将是朝着解决进行性血管内皮细胞疾病的新疗法迈出的第一步 最终导致视网膜前纤维化和牵引性脱离的损害，视觉和解剖能力差 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，这些实验建立在我们的 初步数据显示，内皮素-1(ET-1)参与了纤维血管人类外科手术 膜。我们推测，内皮ET-1调节失调在高血压的发病机制中起着特别重要的作用 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范围的动物模型， 包括链脲佐菌素(STZ)诱导的糖尿病和发育性缺血-氧诱导的模型 视网膜病变(OIR，复制缺血时的血管生成)与有限的高氧诱导的增殖 视网膜病变(L-HIPR)，复制严重缺血的血管纤维化终末期。我们将使用这些 模型检验血管内皮细胞来源的ET-1调节失调在 使用可诱导的、靶向的血管内皮细胞ET-1敲除促进血管病理 转基因小鼠(ET-1Eko)。在目标1中，我们使这只ET-1Eko小鼠遭受STZ诱导的糖尿病和 研究内皮ET-1异常在血管生成和血管生成中作用的脑缺血动物模型 纤维化症。在目标2中，我们将ET-1Eko与转基因报告鼠模型杂交，以专注于内皮细胞- 视网膜血管及其周围的周细胞、神经胶质细胞和神经元向间充质转化。最后，在AIM中 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 作为第一步的DR、缺血诱导的血管生成和纤维化(OIR和L-HIPR)模型的病理学 将我们的发现转化到床边。 这里提出的机械实验将利用临床医生的跨学科专业知识- 科学家派和她的合作者。Fawzi博士是一位临床科学家兼视网膜外科医生，在非 侵入性视网膜成像，缺血和视网膜血管疾病的动物模型。她的合作调查员Dr。 施纳珀是一位临床科学家、儿科肾病学家，也是纤维化信号方面的世界专家。最后， 该小组还利用了张博士在西北大学的实验室中的新成像技术，这是另一所 合作者。