Regulation of Choroidal Neovascularization in Sorsby's Fundus Dystrophy
索尔斯比眼底营养不良中脉络膜新生血管的调节
基本信息
- 批准号:9900004
- 负责人:
- 金额:$ 39.63万
- 依托单位:
- 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:2017-04-01 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:Age related macular degenerationAngiogenesis InhibitionAngiogenesis InhibitorsAngiogenic FactorBilateralBindingBlindnessC-terminalCD44 geneCellsChoroidChoroidal NeovascularizationClinicalCodeComparative StudyDataDegenerative DisorderDevelopmentDiseaseEndothelial CellsExonsExposure toExtracellular MatrixExudative age-related macular degenerationFGF2 geneFibroblast Growth Factor ReceptorsFunctional disorderGenesGrowth FactorHyaluronanIn VitroInheritedKDR geneKnock-in MouseKnowledgeLaboratoriesLasersLeadMMP9 geneMatrix MetalloproteinasesMediatingMitogen-Activated Protein KinasesModelingMolecularMusMutant Strains MiceMutationPathologicPathway interactionsPatientsPeptidesPhenotypePhosphorylationPlayProtein RegionProteinsRare DiseasesRegulationReportingRetinaRoleSTAT3 geneSignal TransductionSorsby&aposs fundus dystrophyTIMP3 geneTestingTransgenic MiceTumor Cell MigrationVariantVascular Endothelial Growth FactorsVisionangiogenesisbaseexperimental studygenetic associationmaculamutantneovascularizationnew therapeutic targetnovelnovel therapeutic intervention
项目摘要
PROJECT SUMMARY
Sorsby fundus dystrophy (SFD) is a dominantly inherited, degenerative disease of the macula that is
characterized by bilateral loss of central vision as a consequence of choroidal neovascularization (CNV).
Specific mutations in the TIMP-3 gene involving exon 5 or the intron4-exon5 boundary have been shown to
be causative. Early this year, the AMD consortium identified rare coding variants in the TIMP3 gene when
analyzing 16,144 patients and 17,832 controls. In addition, they identified the first genetic association signal
specific to wet AMD near MMP9. The clinical and histopathological similarities between AMD and SFD
and the identification of variants in the matrix metalloproteinase pathway in AMD suggest that similar
downstream effectors might be in play in both conditions. A better understanding of the pathophysiological
mechanisms contributing to the CNV in SFD will provide information that could be potentially useful in
AMD. In comparative studies using TIMP-3 deficient mice, S156CTIMP-3 transgenic mice and in vitro
culture experiments we have determined that TIMP-3 partially inhibits angiogenesis by blocking the binding
of VEGF to VEGR-2. S156C TIMP-3 mutant protein induces angiogenesis via VEGF and bFGF. We have
also shown that the absence of functional TIMP-3 results in an accumulation of hyaluronan that regulates
choroidal vasculature. Based on these results, we hypothesize that TIMP3 is required to control and localize
matrix degradation in the RPE/choroid, and loss of TIMP3 function in this regards leads to an abnormality in
growth factor/angiogenesis factor, increased HA signaling and neovascularization.
项目总结
索尔斯比眼底营养不良(SFD)是一种主要遗传的黄斑退行性疾病,即
以脉络膜新生血管(CNV)所致的双眼中央视力丧失为特征。
涉及外显子5或内含子4-外显子5边界的TIMP-3基因的特定突变已被证明
要有因果性。今年早些时候,AMD联盟在TIMP3基因中发现了罕见的编码变体,当时
分析了16,144名患者和17,832名对照。此外,他们还识别出了第一个基因关联信号
特定于MMP9附近的湿性AMD。AMD和SFD的临床和组织病理学相似性
对AMD中基质金属蛋白酶途径变异的鉴定表明,类似的
下游效应器可能在这两种情况下发挥作用。对病理生理学有更深入的了解
在SFD中有助于CNV的机制将提供可能在以下方面有用的信息
AMD。利用TIMP-3基因缺陷小鼠、S156 CTIMP-3转基因小鼠和体外实验进行比较研究
培养实验我们已经确定TIMP-3通过阻断结合部分抑制血管生成
血管内皮生长因子对VEGR-2的作用。S156C TIMP-3突变蛋白通过血管内皮生长因子和碱性成纤维细胞生长因子诱导血管生成。我们有
研究还表明,缺乏功能性TIMP-3会导致透明质酸蓄积,从而调节
脉络膜血管系统。基于这些结果,我们假设需要TIMP3来控制和定位
RPE/脉络膜基质降解和TIMP3功能丧失导致
生长因子/血管生成因子,增加HA信号和新生血管。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('BELA ANAND-APTE', 18)}}的其他基金
FGF and hyaluronan-mediated alterations in epithelial-mesenchymal transition and metabolism of RPE cells in Sorsby Fundus Dystrophy.
FGF 和透明质酸介导的索斯比眼底营养不良中 RPE 细胞上皮-间质转化和代谢的改变。
- 批准号:
10408757 - 财政年份:2017
- 资助金额:
$ 39.63万 - 项目类别:
FGF and hyaluronan-mediated alterations in epithelial-mesenchymal transition and metabolism of RPE cells in Sorsby Fundus Dystrophy.
FGF 和透明质酸介导的索斯比眼底营养不良中 RPE 细胞上皮-间质转化和代谢的改变。
- 批准号:
10636830 - 财政年份:2017
- 资助金额:
$ 39.63万 - 项目类别:
Role of Retinoic Acid in the Regulation of the Blood-Retinal Barrier.
视黄酸在血视网膜屏障调节中的作用。
- 批准号:
9769753 - 财政年份:2016
- 资助金额:
$ 39.63万 - 项目类别:
Role of Retinoic Acid in the Regulation of the Blood-Retinal Barrier.
视黄酸在血视网膜屏障调节中的作用。
- 批准号:
9334214 - 财政年份:2016
- 资助金额:
$ 39.63万 - 项目类别:
Role of Retinoic Acid in the Regulation of the Blood-Retinal Barrier.
视黄酸在血视网膜屏障调节中的作用。
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10011815 - 财政年份:2016
- 资助金额:
$ 39.63万 - 项目类别:
Cole Eye Institute Vision Science Training Program
科尔眼科研究所视觉科学培训计划
- 批准号:
10407662 - 财政年份:2015
- 资助金额:
$ 39.63万 - 项目类别:
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