CTGF Function in Retinal Vessel Development and Pathology

CTGF 在视网膜血管发育和病理学中的功能

基本信息

批准号：
9381475
负责人：
BRAHIM CHAQOUR
金额：
$ 40.38万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9381475
关键词：
Actins Adherens Junction Adverse effects Affect Angiogenesis Inhibitors Animal Model Antibodies Automobile Driving Binding Binding Proteins Blindness Blood Vessels Blood-Retinal Barrier Cell physiology Cells Choroidal Neovascularization Chronic Clinical Complex Connective Tissue Coupled Cytoskeletal Proteins Cytoskeleton Data Defect Development Diabetic Retinopathy Disease Edema Endothelial Cells Environment Extracellular Matrix Extracellular Matrix Proteins Extravasation Eye diseases Fibrosis Functional disorder Gelatinase A Gene Targeting Genes Growth Heart Heparin Human Immediate-Early Genes In Vitro Inflammation Integrin Binding Integrins Intercellular Junctions Ischemia Kidney Knowledge Link Liver Maintenance Modeling Molecular Morphogenesis Morphology Mus Natural regeneration Neovascular Glaucoma Organ Outcome Oxygen Pathogenesis Pathologic Pathologic Neovascularization Pathology Pericytes Permeability Pharmacology Pharmacotherapy Physiological Prevention Prevention strategy Property Proteins Proteolysis Reaction Regulation Reperfusion Therapy Retina Retinal Retinal Detachment Retinal Diseases Retinal Neovascularization Retinal Vascular Occlusion Retinal Vein Occlusion Retinopathy of Prematurity Role Signal Transduction Site Structure Testing Therapeutic Thinness Tight Junctions Tissues Transgenes Vascular Diseases Vascular Endothelial Growth Factors Visual impairment World Health Organization afadin age group angiogenesis base cell behavior cell type cohesion connective tissue growth factor diagnostic biomarker fetal improved in vivo in vivo Model insight interest macular edema mouse model neovascular novel novel therapeutic intervention overexpression pandemic disease preclinical study programs protein expression receptor response retina blood vessel structure therapeutic target vascular abnormality

项目摘要

Disorders of retinal vessel growth and barrier dysfunction are responsible for vision loss in ischemic retinopathy (IR), a set of clinically well-defined chronic ocular vascular complications causing vision impairment and blindness in all age groups. Elucidation of the molecular bases of angiogenic cell function and behavior in physiological and pathological conditions will have important therapeutic implications in the treatment of IR in humans. Herein, our objectives are to gain new insights into the function and mechanisms whereby connective tissue growth factor (CTGF aka CCN2), a specific component of the vascular extracellular matrix (ECM), orchestrates the execution of angiogenesis and barriergenesis programs during retinal vascular development and pathology. CTGF is a developmentally-regulated fetal gene predominantly expressed in endothelial cells (ECs) and pericytes of the retinal vasculature. CTGF expression is rapidly induced in vascular endothelial growth factor (VEGF)-stimulated ECs in culture and substantially increased in VEGF-induced retinal neovascularization models in vivo although the functional consequences of CTGF signaling are unknown. Structurally, the CTGF protein contains modular domains that bind directly to integrin receptors and/or moieties in the pericellular environment including VEGF and matrix metalloproteinase (MMP)-2. Our data showed that CTGF-deficiency was coupled to severe vascular abnormalities and a breach of vascular barrier function in the retina during development. Morphological and molecular evidence of cytoskeletal alterations in retinal vascular cells was associated with CTGF-deficiency as well. It is our hypothesis that CTGF, regulates, through its interactomic network, actin cytoskeleton dynamics that are critical in various steps of angiogenesis and barriergenesis. We further postulate that dysregulation of the CTGF interactomic networks under ischemic conditions alters vasogenic factor activity, availability and structure, ultimately leading to aberrant angiogenic and permeability responses. We will test these hypotheses in the following specific Aims: Aim 1 will define the cell type-specific CTGF signals, the associated cytoskeletal remodeling and the changes driving retinal vessel growth and morphogenesis. Aim 2 will determine the relative contribution of EC- and pericyte-derived CTGF to barriergenesis, and elucidate the mechanisms whereby CTGF signals contribute to the formation and stabilization of EC-EC junctional complexes to insure cellular cohesion and barrier function. Aim 3 will determine how CTGF-induced cytoskeletal changes, or lack thereof, contribute to development and/or progression of aberrant angiogenesis and vascular hyperpermeability in established in vivo models of vascular diseases of the eye. In these studies, greater emphasis will be placed on how CTGF interactomic and degradomic networks determine the angiogenic outcome and barrier function or dysfunction under ischemic conditions. Our studies will provide new information of considerable scientific and therapeutic interest in the treatment of IR.

视网膜血管生长障碍和屏障功能障碍是导致缺血性视网膜病视力丧失的原因（IR），一组临床明确的慢性眼血管并发症，导致视力障碍和失明在所有年龄段。阐明血管生成细胞功能和行为的分子基础生理和病理条件对于 IR 的治疗具有重要的治疗意义人类。在这里，我们的目标是获得对连接的功能和机制的新见解组织生长因子（CTGF 又名 CCN2），血管细胞外基质 (ECM) 的特定成分，在视网膜血管发育过程中协调血管生成和屏障生成程序的执行和病理学。 CTGF 是一种发育调节的胎儿基因，主要在内皮细胞中表达（EC）和视网膜血管系统的周细胞。 CTGF 表达在血管内皮生长中被快速诱导培养物中因子 (VEGF) 刺激的 EC 并在 VEGF 诱导的视网膜新生血管中显着增加尽管 CTGF 信号传导的功能后果尚不清楚，但我们已经在体内建立了模型。从结构上看，CTGF 蛋白质含有直接与细胞周围的整联蛋白受体和/或部分结合的模块结构域环境包括 VEGF 和基质金属蛋白酶 (MMP)-2。我们的数据显示，CTGF 缺乏与严重的血管异常和视网膜血管屏障功能的破坏相结合发展。视网膜血管细胞细胞骨架改变的形态学和分子证据也与 CTGF 缺乏有关。我们的假设是 CTGF 通过其相互作用组学进行调节网络、肌动蛋白细胞骨架动力学在血管生成和屏障生成的各个步骤中至关重要。我们进一步假设缺血条件下 CTGF 相互作用网络的失调会改变血管生成因子的活性、可用性和结构，最终导致血管生成和渗透性异常回应。我们将在以下具体目标中测试这些假设：目标 1 将定义细胞类型特异性 CTGF 信号、相关的细胞骨架重塑以及驱动视网膜血管生长和生长的变化形态发生。目标 2 将确定 EC 和周细胞衍生的 CTGF 对屏障形成，并阐明 CTGF 信号有助于形成和形成的机制 EC-EC 连接复合物的稳定性，以确保细胞凝聚力和屏障功能。目标 3 将决定 CTGF 诱导的细胞骨架变化或缺乏细胞骨架变化如何促进细胞骨架的发育和/或进展已建立的血管疾病体内模型中的异常血管生成和血管通透性过高眼睛。在这些研究中，将更加重视 CTGF 如何相互作用组学和退化组学网络确定缺血条件下的血管生成结果和屏障功能或功能障碍。我们的研究将为 IR 的治疗提供具有重大科学和治疗意义的新信息。