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Investigation of endomucin as a novel regulator of angiogenesis

内粘蛋白作为血管生成的新型调节剂的研究

基本信息

批准号：
9238401
负责人：
Patricia Ann D'Amore
金额：
$ 49.25万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
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：
2017-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9238401
关键词：
Address Adult Age related macular degeneration Binding Biological Assay Birth Blindness Blood Vessels Blood capillaries Cell Communication Cell physiology Cell surface Cells Choroidal Neovascularization Cytoplasmic Tail Development Diabetic Retinopathy Disease Endothelial Cells Equilibrium Event Extracellular Domain Eye Glycoproteins Growth Growth Factor Histology Human ICAM2 gene Impairment In Vitro Investigation KDR gene Lasers Lead Legal Blindness Life Light Macular degeneration Measures Mediating Messenger RNA Modeling Molecular Mucins Mus Mutation Ocular Pathology Oxygen Pathologic Pathologic Neovascularization Pathology Permeability Persons Phosphoric Monoester Hydrolases Phosphorylation Play Process Proteins Regulation Reporting Reproduction Retinal Retinal Diseases Retinal Neovascularization Retinopathy of Prematurity Role Signal Transduction Small Interfering RNA Subfamily lentivirinae Surface System Testing Therapeutic Tube Tyrosine Phosphorylation Site Vascular Endothelial Growth Factor Receptor-1 Vascular Permeabilities Vascularization Veins Wound Healing angiogenesis antiangiogenesis therapy capillary crosslink density design endothelial-specific sialomucin in vivo inhibitor/antagonist intravitreal injection knock-down loss of function migration mutant new growth novel novel therapeutics ocular neovascularization overexpression postnatal proliferative diabetic retinopathy promoter retina blood vessel structure retinal angiogenesis small hairpin RNA

项目摘要

ABSTRACT Angiogenesis, the growth of new blood vessels, is an important component of development, wound healing, and reproduction as well as a number of pathologies. Abnormal retinal angiogenesis leads to vision loss in a range of ocular pathologies including diabetic retinopathy, wet macular degeneration, and the retinopathy of prematurity. Endomucin (EMCN) is a mucin-like glycoprotein specifically expressed by endothelial cells of veins and capillaries. Our preliminary studies reveal a role for EMCN in the regulation of VEGF-induced endothelial functions in vitro and in normal angiogenesis in vivo. Reduction of EMCN expression using siRNA led to decreased VEGF-stimulated endothelial proliferation, migration and tube formation in vitro, and impaired retinal vascularization in vivo. This application proposes to test the hypothesis that EMCN plays a role in VEGF-induced pathologic neovascularization and that EMCN influences VEGF-stimulated functions by modulating its signaling. Studies are outlined to examine the role of EMCN in pathological angiogenesis using models of abnormal retinal and choroidal blood vessel growth as well as to understand the molecular mechanism that underlies EMCN's effects on VEGF-induced endothelial cell functions using in vitro systems. Studies in Aim 1 will examine the role of EMCN in the development of pathologic ocular neovascularization in vivo. The oxygen-induced model of retinal neovascularization and the laser-induced model of choroidal neovascularization will be utilized in conjunction with both gain and loss of function studies, using both siRNA and lentivirally-delivered shEMCN under the control of ICAM2, an endothelial-specific promoter, as well as adEMCN under the control of ICAM2. The effect of EMCN knockdown and overexpression on pathologic vessel growth will be quantified. Aim 2 proposes to elucidate the molecular mechanism of EMCN's role in the regulation of VEGF-induced endothelial functions. Studies using EMCN deletion mutants will be employed to determine if the effects of EMCN are mediated at the cell surface. The role of EMCN at the cell surface will be further investigated by examining its effect on VEGF binding and VEGFR2 stabilization/internalization. Intracellular effects will focus on a possible role of EMCN phosphorylation, the effect of EMCN on VEGFR2 phosphatase activity as well as the identification of potential EMCN intracellular binding partners. Results of these proposed studies will provide a better understanding of the role of EMCN in normal and pathologic angiogenesis and may lead to the development of novel endothelial cell-specific therapies for the suppression of vessel growth. !

摘要