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：
BELA ANAND-APTE
金额：
$ 39.63万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
https://reporter.nih.gov/project-details/9900004
关键词：
Age related macular degeneration Angiogenesis Inhibition Angiogenesis Inhibitors Angiogenic Factor Bilateral Binding Blindness C-terminal CD44 gene Cells Choroid Choroidal Neovascularization Clinical Code Comparative Study Data Degenerative Disorder Development Disease Endothelial Cells Exons Exposure to Extracellular Matrix Exudative age-related macular degeneration FGF2 gene Fibroblast Growth Factor Receptors Functional disorder Genes Growth Factor Hyaluronan In Vitro Inherited KDR gene Knock-in Mouse Knowledge Laboratories Lasers Lead MMP9 gene Matrix Metalloproteinases Mediating Mitogen-Activated Protein Kinases Modeling Molecular Mus Mutant Strains Mice Mutation Pathologic Pathway interactions Patients Peptides Phenotype Phosphorylation Play Protein Region Proteins Rare Diseases Regulation Reporting Retina Role STAT3 gene Signal Transduction Sorsby&apos s fundus dystrophy TIMP3 gene Testing Transgenic Mice Tumor Cell Migration Variant Vascular Endothelial Growth Factors Vision angiogenesis base experimental study genetic association macula mutant neovascularization new therapeutic target novel novel 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.

项目摘要索斯比眼底营养不良（SFD）是一种主要遗传的黄斑的退化性疾病由于脉络膜新生血管形成（CNV），其特征是双边丧失中央视力。涉及外显子5或内含子4-EXON5边界的TIMP-3基因中的特定突变已显示为要为病因。今年年初，AMD财团确定了Timp3基因中的稀有编码变体分析16,144例患者和17,832例对照。此外，他们确定了第一个遗传关联信号特定于MMP9附近的湿AMD。 AMD和SFD之间的临床和组织病理学相似性 AMD中基质金属蛋白酶途径中变体的鉴定表明类似下游效应子在两种情况下都可能发挥作用。更好地了解病理生理学在SFD中促成CNV的机制将提供可能在 AMD。在使用TIMP-3缺乏小鼠的比较研究中，S156CTIMP-3转基因小鼠和体外培养实验我们已经确定TIMP-3通过阻断结合部分抑制了血管生成 VEGF至VEGR-2的of。 S156C TIMP-3突变蛋白通过VEGF和BFGF诱导血管生成。我们有还表明，缺乏功能性TIMP-3会导致调节透明质酸的积累脉络膜脉管系统。基于这些结果，我们假设需要timp3来控制和本地化 RPE/脉络膜中的矩阵降解，并且在此方面的timp3功能损失导致异常生长因子/血管生成因子，HA信号传导增加和新血管形成。