Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
批准号:
10475582
负责人:
MICHAEL H ELLIOTT
金额:
$35.43万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
未结题
起止时间:
2009-12-01 至 2026-08-31
关键词:
AblationAdenovirusesAnti-Inflammatory AgentsAntiinflammatory EffectBlindnessBlood-Retinal BarrierCAV1 geneCaveolaeCell LineCellsComplexConflict (Psychology)DependovirusDevelopmentDiabetic RetinopathyDiseaseDoseEye diseasesFunctional disorderGene TransferGenesGlaucomaGoalsGrowth FactorImmuneIn VitroInfiltrationInflammationInflammatoryInflammatory ResponseInjuryLeadLinkLiteratureMaintenanceMediatingMembraneModelingMorphologyMuller&aposs cellNerve CrushNerve DegenerationNeural RetinaNeurogliaNeuronsOcular PhysiologyOptic NerveOrganPC3 cell linePharmaceutical PreparationsPlayPrimary Open Angle GlaucomaProteinsPublishingRetinaRiskRoleSignal TransductionSteroidsStressStructural ProteinSystemTestingTissuesVirusautoimmune uveitisbasebiological adaptation to stresscaveolin 1cell typechemokinecytokineexperimental studygenetic variantglial activationhuman diseasein vivoinnovationnew therapeutic targetnovelnovel therapeutic interventionprostate cancer cell lineprotein expressionprotein functionpublic health relevanceresponsereverse geneticsscaffoldside effecttherapeutic target
中文摘要
项目总结
英文摘要
Project summary
Caveolin-1 (Cav1), traditionally viewed as the signature protein of caveolae membrane domains, plays
crucial roles in blood-retinal barrier integrity and retinal inflammation. Gene variants in Cav1 are associated
with risk of primary open angle glaucoma and Cav1 protein expression is upregulated in uveitic retinas and in
models of diabetic retinopathy. We have found that Cav-1 and caveolae play important roles in blood-retinal
barrier (BRB) and inflammation-induced cytokine release. Intriguingly, ablation of Cav1 only from the
neuroretinal compartment (Müller glia and neurons) suppresses cytokine release and immune cell influx
following inflammatory and neurodegenerative insult. As Cav1 is upregulated in several retinal inflammatory
conditions, we hypothesize that local manipulation of Cav1 function presents a viable therapy to suppress
retinal inflammatory stress. Given that current steroid-based therapies for retinal inflammatory disease are not
completely effective and fraught with potentially severe side effects, we hypothesize that Cav1 represents a
novel therapeutic target to suppress retinal inflammation. Thus, it is crucial to understand the function of this
protein in the context of the retinal stress adaptation response. We have made the exciting observation that
Cav1 in Müller glial cells of the neural retina does not reside within traditional, morphologically-identifiable
caveolae. This is because differentiated Müller glia do not normally express significant levels of Cavin1 which,
via interaction with Cav1, is necessary to form caveolae. In all tissues studied to date, loss of Cavin1 results in
coincident loss of Cav1 protein stability. However, in Müller glia, Cav1 is stably expressed (outside of
caveolae) in the absence of Cavin1. This provides a unique opportunity to examine the role of non-caveolar
Cav1 in an organ in which Cav1 is associated with human disease. We hypothesize that this non-caveolar
localization is crucial to Cav1’s ability to promote secretion of cytokines, chemokines, and growth factors. In
this proposal, we will test this novel concept in Müller glia in culture and in vivo by inducing the expression of
Cavin1 to sequester Cav1 within caveolae. We will also take advantage of the unusually stable expression of
Cav1 outside of caveolae to examine the composition of the non-caveolae Cav1 domain (called herein “Cav1
scaffolds”) and to identify the mechanism by which Cav1 is stably expressed without Cavin1. These goals have
clear
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Caveolae-based mechanosensors for conventional outflow regulation
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批准号:10186755
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项目类别:
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资助金额:$47.82万
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财政年份:2018
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负责人:MICHAEL H ELLIOTT
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依托单位:
Caveolae-based mechanosensors for conventional outflow regulation
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批准号:9596193
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项目类别:
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资助金额:$49.86万
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财政年份:2018
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负责人:MICHAEL H ELLIOTT
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依托单位:
P30 Center Core Grant for Vision Research
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批准号:10272006
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项目类别:
-
资助金额:$14.51万
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财政年份:2011
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负责人:MICHAEL H ELLIOTT
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依托单位:
P30 Center Core Grant for Vision Research
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批准号:10696214
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项目类别:
-
资助金额:$14.51万
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财政年份:2011
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负责人:MICHAEL H ELLIOTT
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依托单位:
P30 Center Core Grant for Vision Research
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批准号:10477424
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项目类别:
-
资助金额:$14.51万
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财政年份:2011
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负责人:MICHAEL H ELLIOTT
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依托单位:
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
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批准号:8963726
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项目类别:
-
资助金额:$36.78万
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财政年份:2009
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负责人:MICHAEL H ELLIOTT
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依托单位:
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
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批准号:10683155
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项目类别:
-
资助金额:$36.33万
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财政年份:2009
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负责人:MICHAEL H ELLIOTT
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依托单位:
Role of caveolin-1 in the maintenance of blood-retinal barrier integrity
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批准号:9563983
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项目类别:
-
资助金额:$36.03万
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财政年份:2009
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负责人:MICHAEL H ELLIOTT
-
依托单位:
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
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批准号:8197255
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项目类别:
-
资助金额:$34.67万
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财政年份:2009
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负责人:MICHAEL H ELLIOTT
-
依托单位:
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
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批准号:7783730
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项目类别:
-
资助金额:$37.28万
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财政年份:2009
-
负责人:MICHAEL H ELLIOTT
-
依托单位:
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
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批准号:8580554
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项目类别:
-
资助金额:$31.01万
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财政年份:2009
-
负责人:MICHAEL H ELLIOTT
-
依托单位:
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
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批准号:8386605
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项目类别:
-
资助金额:$30.06万
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财政年份:2009
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负责人:MICHAEL H ELLIOTT
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依托单位:
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
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批准号:7994804
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项目类别:
-
资助金额:$34.67万
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财政年份:2009
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负责人:MICHAEL H ELLIOTT
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依托单位:
Caveolin in Mammalian Photoreceptor Outer Segements
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批准号:6525089
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项目类别:
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资助金额:$4.42万
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财政年份:2002
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负责人:MICHAEL H ELLIOTT
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依托单位:
Caveolin in Mammalian Photoreceptor Outer Segements
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批准号:6659741
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项目类别:
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资助金额:$4.81万
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财政年份:2002
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负责人:MICHAEL H ELLIOTT
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依托单位:
Caveolin in Mammalian Photoreceptor Outer Segements
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批准号:6406189
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项目类别:
-
资助金额:$3.48万
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财政年份:2001
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负责人:MICHAEL H ELLIOTT
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依托单位:
海外基金