Study of the RPE barrier
RPE屏障的研究
基本信息
- 批准号:8534126
- 负责人:
- 金额:$ 33.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-09-01 至 2015-08-31
- 项目状态:已结题
- 来源:
- 关键词:Age related macular degenerationAlbuminsAnimal ModelBiochemicalBiochemical PathwayBiological AssayBiological MarkersBlindnessBloodBlood CirculationBlood VesselsCell Culture TechniquesCellsDataDiabetes MellitusDiabetic RetinopathyDiseaseEndothelial CellsEpithelialEpithelial CellsExperimental ModelsExtravasationFunctional disorderHumanImageryImmunoblottingIn VitroInflammationInflammatoryIntestinesIschemiaKidneyKnockout MiceKnowledgeLiteratureMeasuresMediatingMethodsMicroscopicMolecularMusNeurogliaNosePathogenesisPathologyPatientsPermeabilityPhosphorylationPhysiologicalPlayPositioning AttributeProtein IsoformsProtein Kinase CProteinsPublic HealthRegulationRetinaRetinalRetinal DetachmentRetinal NeovascularizationRetinal PigmentsRetinopathy of PrematurityRoleSeveritiesSignal TransductionStructure of retinal pigment epitheliumSystemTNF geneTestingTherapeuticTight JunctionsUveitisVascular DiseasesVascular Endothelial Growth Factor ReceptorVascular Endothelial Growth Factor Receptor-2Vascular Endothelial Growth FactorsVascular Permeabilitiesautocrineautoimmune uveitisbasebevacizumabcellular targetingdesigndiabeticinhibitor/antagonistknockout genemacular edemamonolayeroccludinreceptorresearch studysuccesstherapeutic target
项目摘要
The inner and outer blood-retina barriers (BRBs) are formed by tight junctions
between adjacent endothelial or retinal pigment epithelial (RPE) cells. Breakdown of
BRBs is a major pathological change in age-related macular degeneration, diabetic
retinopathy, retinopathy of prematurity, and uveitis. While previous studies have yielded
a better understanding about the roles of the inner BRB under physiological and
pathological conditions, surprisingly little is known about the regulation and
pathophysiology of the outer BRB. Since the outer BRB is responsible for ~85% of blood
circulation to the retina, it is unimaginable that ischemia-induced pathological change in
the outer BRB plays an insignificant role in the overall pathology of retinochoroidal
vascular diseases. To investigate the mechanisms of outer BRB breakdown and to test
the concept of inhibiting outer BRB permeability as a therapeutic strategy for
retinochoroidal vascular diseases, we have prepared gene knockout systems for the
mouse RPE and M¿ller glia, cells that regulate the function of both inner and outer BRBs
through vascular endothelial growth factor (VEGF-A). Using these conditional gene
knockout systems, we have disrupted VEGF and its receptor (VEGFR2) in the mouse
RPE and have generated mice with VEGF disruption in the M¿ller cells.
In Specific Aim 1, we will test our hypothesis that outer BRB breakdown is a
significant contributor to diabetes/ischemia-induced overall retinal "vascular leakage"
through autocrine VEGF/VEGF-R2 signaling in the RPE by measuring the total retinal
vascular leakage, the number of significant breakpoints in the outer BRB, and the
quantity of outer BRB-specific leakage in the RPE-specific VEGF and VEGFR2 knockout
mice after inducing ischemia or diabetes. In Specific Aim 2, we will test the concept of
inhibiting outer BRB permeability as a therapeutic strategy for uveitis by examining the
total retinal vascular leakage, the number and severity of retinal detachment, the
quantity of outer BRB-specific leakage, and the expression of inflammatory biomarkers
in the RPE-specific VEGFR2 knockout mice after inducing uveitis. As a control for inner
BRB breakdown, we will also measure the same parameters in uveitic M¿ller cell-
specific VEGF knockout mice. In Specific Aim 3, we will determine the molecular
mechanism of diabetes/ischemia-induced outer BRB breakdown by investigating the
biochemical pathway governing the regulation of tight-junction proteins.
内部和外部血视网膜屏障(BRB)由紧密连接形成
相邻内皮细胞或视网膜色素上皮 (RPE) 细胞之间。细分
BRBs是年龄相关性黄斑变性、糖尿病性黄斑变性的主要病理变化
视网膜病变、早产儿视网膜病变和葡萄膜炎。虽然之前的研究已经取得了
更好地了解内部 BRB 在生理和心理条件下的作用
令人惊讶的是,人们对病理条件的调节和了解知之甚少。
外部 BRB 的病理生理学。由于外部 BRB 负责约 85% 的血液
血液循环到视网膜,缺血引起的病理变化是难以想象的
外部 BRB 在视网膜脉络膜的整体病理学中起着微不足道的作用
血管疾病。研究外部 BRB 击穿机制并进行测试
抑制外部 BRB 通透性作为治疗策略的概念
视网膜脉络膜血管疾病,我们准备了基因敲除系统
小鼠 RPE 和米勒神经胶质细胞,调节内部和外部 BRB 的功能
通过血管内皮生长因子(VEGF-A)。使用这些条件基因
敲除系统,我们破坏了小鼠体内的 VEGF 及其受体 (VEGFR2)
RPE 并已培育出 M¿ller 细胞中 VEGF 受到破坏的小鼠。
在具体目标 1 中,我们将检验我们的假设,即外部 BRB 故障是
是糖尿病/缺血引起的整体视网膜“血管渗漏”的重要促成因素
通过测量视网膜总面积,通过 RPE 中自分泌 VEGF/VEGF-R2 信号传导
血管渗漏、外部 BRB 中显着断点的数量以及
RPE 特异性 VEGF 和 VEGFR2 敲除中外部 BRB 特异性渗漏的数量
诱导缺血或糖尿病后的小鼠。在具体目标 2 中,我们将测试以下概念:
通过检查抑制外部 BRB 通透性作为葡萄膜炎的治疗策略
视网膜血管渗漏总量、视网膜脱离的数量和严重程度、
外部 BRB 特异性渗漏量以及炎症生物标志物的表达
在诱导葡萄膜炎后 RPE 特异性 VEGFR2 敲除小鼠中。作为内在的控制
BRB 分解,我们还将测量葡萄膜 M¿ller 细胞中的相同参数 -
特异性 VEGF 基因敲除小鼠。在具体目标 3 中,我们将确定分子
通过研究糖尿病/缺血引起的外部 BRB 破坏的机制
控制紧密连接蛋白调节的生化途径。
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Expression of netrin-1 receptors in retina of oxygen-induced retinopathy in mice.
- DOI:10.1186/1471-2415-14-102
- 发表时间:2014-08-22
- 期刊:
- 影响因子:2
- 作者:Liu D;Xiong SQ;Shang L;Tian XF;Yang J;Xia XB
- 通讯作者:Xia XB
Efficient induction of productive Cre-mediated recombination in retinal pigment epithelium.
有效诱导视网膜色素上皮细胞中生产性 Cre 介导的重组。
- DOI:
- 发表时间:2014
- 期刊:
- 影响因子:2.2
- 作者:Fu,Shuhua;Zhu,Meili;Wang,Changyun;Le,Yun-Zheng
- 通讯作者:Le,Yun-Zheng
VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases.
- DOI:10.1016/j.visres.2017.05.005
- 发表时间:2017-10
- 期刊:
- 影响因子:1.8
- 作者:Le YZ
- 通讯作者:Le YZ
Intravitreous high expression level of netrin-1 in patients with proliferative diabetic retinopathy.
- DOI:10.3969/j.issn.1000-4432.2011.02.017
- 发表时间:2011-06
- 期刊:
- 影响因子:0
- 作者:Liu J;Xia X;Xiong S;Le Y;Xu H
- 通讯作者:Xu H
G protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases.
- DOI:10.1016/j.visres.2017.05.001
- 发表时间:2017-10
- 期刊:
- 影响因子:1.8
- 作者:Hu J;Li T;Du X;Wu Q;Le YZ
- 通讯作者:Le YZ
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YUN Zheng LE其他文献
YUN Zheng LE的其他文献
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{{ truncateString('YUN Zheng LE', 18)}}的其他基金
ROLE OF VEGF SIGNALING IN CONE AND ROD PHOTORECEPTOR SURVIVAL
VEGF 信号传导在视锥细胞和视杆细胞存活中的作用
- 批准号:
8360284 - 财政年份:2011
- 资助金额:
$ 33.74万 - 项目类别:
COBRE: PI 3-KINASE & ITS DOWNSTREAM TARGET BCL-XL IN RPE
COBRE:PI 3-激酶
- 批准号:
7610499 - 财政年份:2007
- 资助金额:
$ 33.74万 - 项目类别:
COBRE: PI 3-KINASE & ITS DOWNSTREAM TARGET BCL-XL IN RPE
COBRE:PI 3-激酶
- 批准号:
7381938 - 财政年份:2006
- 资助金额:
$ 33.74万 - 项目类别:
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