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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：
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
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/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

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导致工作年龄失明的主要原因