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

基本信息

批准号：
10589138
负责人：
Amani A Fawzi
金额：
$ 38.39万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10589138
关键词：
Ablation Address Adult Affect Age Anatomy Animal Model Birth Blindness Blood Vessels Blood capillaries Blood flow Breeding 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 LoxP-flanked allele 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 Play Population Process Proliferating Reporter Reporter Genes 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 antagonist 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 pharmacologic postnatal prevent receptor retina blood vessel structure retinal imaging retinal ischemia success therapeutic target transcriptome sequencing

项目摘要

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段失明的主要原因需要确定控制成人从血管生成到纤维化转变的机制。这将是解决进展性血管内皮细胞新疗法的第一步。最终导致视网膜前纤维化和牵引性脱离，并导致视觉和解剖结构不良的损伤结果。为了弥补我们知识上的差距，我们设计了一系列实验，这些实验逻辑上建立在我们的知识基础上。初步数据，显示内皮素-1 (ET-1) 参与人类纤维血管手术的证据我们认为内皮细胞 ET-1 失调在发病机制中尤为重要。缺血引起的视网膜病变及其并发症。为了验证这一假设，我们将研究涵盖整个视网膜缺血范围的动物模型，包括链脲佐菌素 (STZ) 诱发的糖尿病和发育性缺血模型（氧诱发）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），它复制了严重缺血的血管纤维化末期。模型检验血管内皮细胞来源的 ET-1 失调在使用诱导型、靶向血管内皮 ET-1 敲除技术促进血管病理学的发展转基因小鼠 (ET-1Eko) 在目标 1 中，我们让 ET-1Eko 小鼠遭受 STZ 诱导的糖尿病和糖尿病。缺血发育模型研究内皮 ET-1 失调在血管生成和血管生成中的作用在目标 2 中，我们将 ET-1Eko 与转基因报告小鼠模型杂交，重点关注内皮细胞。最后，目标是视网膜血管和周围周细胞、神经胶质细胞和神经元的间质转化。 3、我们将重点开发针对 ET-1 受体的药物干预措施，以改善视网膜 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，作为第一步将我们的发现转化为临床。本文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 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拥有特殊的专业知识。她的合作研究员，博士，侵入性视网膜成像，缺血和视网膜血管疾病的动物模型。 Schnaper 是一位临床科学家、儿科肾病专家，也是纤维发生信号传导方面的世界专家。该小组还利用了西北大学张博士实验室的新型成像技术，该实验室是另一所合作者。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Superficial capillary perfusion on optical coherence tomography angiography differentiates moderate and severe nonproliferative diabetic retinopathy.

DOI：
10.1371/journal.pone.0240064
发表时间：
2020
期刊：
PloS one
影响因子：
3.7
作者：
Ong JX;Kwan CC;Cicinelli MV;Fawzi AA
通讯作者：
Fawzi AA

Limited Hyperoxia-Induced Proliferative Retinopathy (LHIPR) as a Model of Retinal Fibrosis, Angiogenesis, and Inflammation.

DOI：
10.3390/cells12202468
发表时间：
2023-10-17
期刊：
Cells
影响因子：
6
作者：
通讯作者：

Limited hyperoxia-induced proliferative retinopathy: A model of persistent retinal vascular dysfunction, preretinal fibrosis and hyaloidal vascular reprogramming for retinal rescue.

DOI：
10.1371/journal.pone.0267576
发表时间：
2022
期刊：
PloS one
影响因子：
3.7
作者：
通讯作者：

Rationale for American Society of Retina Specialists Best Practice Recommendations for Conducting Vitreoretinal Surgery during the COVID-19 Era.

DOI：
10.1177/2474126420941707
发表时间：
2020-10-01
期刊：
Journal of vitreoretinal diseases
影响因子：
0
作者：
Chao DL;Sridhar J;Kuriyan AE;Leng T;Barnett BP;Carlin AF;Wykoff CC;Gayer S;Mruthyunjaya P;Yonekawa Y;Fawzi AA;Berrocal AM;Yeh S;Ting D;Modi Y;Zacks DN;Yannuzzi N;Afshari NA;Murray T
通讯作者：
Murray T