CELLULAR MECHANISMS OF PATHOLOGICAL RETINAL NEOVASCULARIZATION

病理性视网膜新生血管化的细胞机制

基本信息

批准号：
10225726
负责人：
Nikhlesh Kumar Singh
金额：
$ 17.92万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225726
关键词：
Abbreviations Adult Affect Age related macular degeneration Angiogenic Factor Angiogenic Proteins Apoptosis Blindness Blood Vessels CASP1 gene CASP3 gene Caspase Cells Child Consequentialism Data Developed Countries Development Diabetes Mellitus Diabetic Retinopathy Disease Disintegrins Down-Regulation Elderly Endothelial Cells Endothelium Exudative age-related macular degeneration Fibrosis Functional disorder Gene Silencing Genetic Growth Hematopoietic stem cells Hypoxia Impairment Inflammasome Inflammation Mediators Inflammatory Injections Interleukins Knowledge Lasers Lead Mediating Metalloproteases Microglia Modeling Mus Myelogenous Oxygen Pathologic Pathologic Neovascularization Patients Pattern Pharmacology Phase Phenotype Production Proteins Publishing RNA Interference Reporting Research Retina Retinal Detachment Retinal Diseases Retinal Neovascularization Retinopathy of Prematurity Role Signal Transduction Small Interfering RNA Surface Testing Therapeutic Thrombospondins Traction Tumorigenicity Vascular Permeabilities Visual impairment Vitreous humor age group angiogenesis base bevacizumab cadherin 5 conditional knockout connective tissue growth factor design improved light transmission macrophage migration mouse model neovascularization novel novel therapeutic intervention proliferative diabetic retinopathy receptor recruit response retinal angiogenesis retinal damage tissue regeneration wound healing

项目摘要

Retinal neovascularization is an ocular manifestation of diabetes, retinopathy of prematurity and age-related macular degeneration, which leads to vision loss. Despite the use of anti-VEGF and laser treatments, progression of retinal neovascularization continues to cause blindness. The development of new therapeutic approaches against retinal neovascularization is limited, because of lack of knowledge about its pathophysiology. Retinal neovascularization is characterized by production of several angiogenic factors, with consequential growth of aberrant new blood vessels on retinal surface that interferes with light transmission and results in vision loss. An elevated levels of inflammation and inflammatory mediators have been observed in retinas or vitreous isolated from patients with pathological retinal neovascularization. Therefore, the ability to modulate inflammation and inflammatory mediators and thereby selectively modulating aberrant retinal neovascularization, would be a great strategy in the treatment of pathological retinal neovascularization. To understand the functional significance of inflammation and inflammatory mediators in retinal neovascularization, we performed preliminary studies using mouse model of oxygen-induced retinopathy. Our preliminary studies suggest a predominant role caspase-3 and inflammatory caspase (caspase-1) in retinal neovascularization. Our primary hypothesis to be tested is novel and fills some voids in our understanding about pathological neoangiogenesis. The specific aims of our proposed studies are to test the hypotheses that (1) IL-33 and caspases mediates hypoxia-induced pathological retinal neovascularization, (2) IL-33/ST2L mediated ADAMTS10 or VE-cadherin activation regulates sprouting angiogenesis and vessel branching, and (3) IL-33/ST2L signaling regulates the functional polarization of inflammatory cells to M2-like macrophages in hypoxic retina. Achieving these specific aims will elucidate the mechanisms through which various inflammatory molecules affect retinal neovascularization and open up a new line of understanding about the pathophysiology of various proliferative retinopathies. In addition, the proposed research will certainly contribute to the development of new therapeutic strategies against proliferative diabetic retinopathy and retinopathy of prematurity.

视网膜新生血管形成是糖尿病、早产儿和年龄相关性视网膜病变的眼部表现黄斑变性，导致视力丧失。尽管使用抗 VEGF 和激光治疗，视网膜新生血管的进展继续导致失明。新疗法的开发由于缺乏对其的了解，对抗视网膜新生血管形成的方法有限。病理生理学。视网膜新生血管形成的特点是产生多种血管生成因子，视网膜表面异常新血管的生长，干扰光传输并导致视力丧失。观察到炎症和炎症介质水平升高从患有病理性视网膜新生血管的患者分离出视网膜或玻璃体。因此，有能力调节炎症和炎症介质，从而选择性调节异常视网膜新生血管形成，将是治疗病理性视网膜新生血管形成的一个很好的策略。到了解视网膜炎症和炎症介质的功能意义新生血管形成，我们使用氧诱导视网膜病变的小鼠模型进行了初步研究。我们的初步研究表明 caspase-3 和炎性 caspase (caspase-1) 在视网膜中起主导作用新血管形成。我们要测试的主要假设是新颖的，填补了我们理解中的一些空白关于病理性新生血管生成。我们提出的研究的具体目的是检验以下假设： (1) IL-33 和半胱天冬酶介导缺氧诱导的病理性视网膜新生血管形成，(2) IL-33/ST2L 介导的 ADAMTS10 或 VE-钙粘蛋白激活调节萌芽血管生成和血管分支，以及 (3) IL-33/ST2L信号调节炎症细胞向M2样巨噬细胞的功能极化视网膜缺氧。实现这些具体目标将阐明各种机制炎症分子影响视网膜新生血管形成并开辟了关于视网膜新生血管的新认识各种增殖性视网膜病的病理生理学。此外，拟议的研究肯定会有助于开发针对增殖性糖尿病视网膜病变的新治疗策略，早产儿视网膜病变。