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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：
10246536
负责人：
Nikhlesh Kumar Singh
金额：
$ 37.35万
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/10246536
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.

视网膜新生血管是糖尿病、早产儿视网膜病变和年龄相关性视网膜病变的眼部表现