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

• 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
• 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

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变视力丧失的原因 (IR)，一组临床明确定义的慢性眼血管并发症，导致视力受损， 失明 在所有年龄组。 阐明血管生成细胞功能和行为的分子基础， 生理和病理条件将在IR的治疗中具有重要的治疗意义， 人类在此，我们的目标是获得新的见解的功能和机制， 组织生长因子（CTGF aka CCN 2），血管细胞外基质（ECM）的特定组分， 在视网膜血管发育过程中协调血管生成和屏障形成程序的执行 和病理CTGF是一种主要在内皮细胞中表达的发育调控的胎儿基因 (ECs)和视网膜脉管系统的周细胞。CTGF表达在血管内皮生长中被快速诱导 在培养的内皮细胞中，VEGF刺激的内皮细胞在VEGF诱导的视网膜新生血管中显著增加， 尽管CTGF信号传导的功能后果是未知的，但在体内模型中。从结构上讲， 蛋白质含有直接结合整联蛋白受体和/或细胞周膜中的部分的模块结构域 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有关， 发展视网膜血管细胞中细胞骨架改变的形态学和分子学证据， 也与CTGF缺乏有关。我们的假设是CTGF通过其相互作用调节， 网络，肌动蛋白细胞骨架动力学，在血管生成和屏障形成的各个步骤中至关重要。我们 进一步假设在缺血条件下CTGF相互作用网络的失调改变了 血管生成因子的活性、可用性和结构，最终导致异常的血管生成和渗透性 应答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和驱动视网膜血管生长的变化， 形态发生目的2将确定EC和周细胞来源的CTGF对细胞增殖的相对贡献。 屏障形成，并阐明CTGF信号有助于形成和 稳定EC-EC连接复合物以确保细胞内聚和屏障功能。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 已建立的血管疾病体内模型中的异常血管生成和血管高渗透性 眼睛在这些研究中，更多的重点将放在CTGF如何相互作用和降解网络 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的治疗提供了具有相当科学和治疗意义的新信息。