Investigation of ADAMTS in glaucoma pathogenesis

ADAMTS 在青光眼发病机制中的研究

• 批准号: 9902494
• 负责人: JOHN G KUCHTEY
• 金额: $ 38.72万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902494
• 关键词: ADAMTS; Affect; Age; Angiotensin II; Animal Model; Animals; Aqueous Humor; Axon; Axonal Transport; Benchmarking; Binding; Biological Assay; Blindness; Canis familiaris; Cell Death; Characteristics; Cholera Toxin; Clinical; Data; Defect; Development; Disease; Drug usage; Electron Microscopy; Electroretinography; Elements; Extracellular Matrix; Eye; Genes; Glaucoma; Human; Immunohistochemistry; Investigation; Lead; Lens dislocation; Ligands; MADH3 gene; Marfan Syndrome; Microfibrils; Modeling; Molecular; Monitor; Mus; Mutation; Optic Disk; Optic Nerve; Pathogenesis; Pathogenicity; Pathology; Patients; Pattern; Perfusion; Pharmaceutical Preparations; Phenotype; Physiologic Intraocular Pressure; Play; Primary Open Angle Glaucoma; Proteins; Protocols documentation; Reagent; Reporter; Reporting; Research; Retinal Ganglion Cells; Risk Factors; Role; Signal Transduction; Structure; Syndrome; Systemic disease; Testing; Therapeutic; Transforming Growth Factor beta; Transgenic Organisms; Visual Fields; Weill-Marchesani syndrome; Zebrafish; base; efficacy testing; extracellular; intravitreal injection; mechanotransduction; null mutation; optic nerve disorder; prevent; promoter; receptor; retinal ganglion cell degeneration; skeletal

Project Summary/Abstract Primary open angle glaucoma (POAG) is an optic neuropathy with a characteristic pattern of visual field loss and optic disc cupping due to progressive degeneration of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is an important risk factor for POAG, and artificially raising IOP is very effective at inducing glaucoma in animal models. However, the relationship between IOP and RGC death is unclear since some patients with normal IOP develop glaucoma while others with elevated IOP do not. Our group made a breakthrough discovery that a mutation in ADAMTS10 causes POAG in Beagle dogs. This finding was independently validated and expanded by identification of another mutation in ADAMTS10 causing POAG in Norwegian Elkhound dogs and 3 other mutations in a closely-related gene, ADAMTS17, in 3 other dog breeds. Relevant to human glaucoma, an ADAMTS8 locus has been identified associated with vertical cup -disc ratio. These findings suggest that mutations in ADAMTS genes cause POAG. In humans, null mutations of ADAMTS10 cause Weill-Marchesani syndrome, a disease associated with defective microfibrils and characterized by short skeletal features, lens dislocation and glaucoma. ADAMTS10 is a microfibril-associated protein that plays a role in microfibril structure and function. Microfibrils are components of the extracellular matrix that are key regulators of Transforming Growth Factor Beta (TGFβ) signaling and contribute to mechanotransduction involving ligand-independent activation of the Angiotensin II Type I Receptor (AT1R). Hyper-activation of TGFβ signaling and altered mechanotransduction are key pathogenic mechanisms for both microfibril deficiencies and POAG. Identification of a microfibril-associated gene as causative for POAG led us to formulate our central hypothesis that ADAMTS10 mutations cause glaucoma by disrupting microfibril structure and function. Establishing microfibril defects as a disease mechanism would suggest that treatments effective in other diseases caused by microfibril deficiencies may be applied to POAG. AT1R blockers (ARBs) are effective in treating diseases associated with microfibril deficiencies and they have been considered as potential glaucoma treatments owing to their IOP-lowering and neuroprotective effects. Based on our microfibril hypothesis, we will test the efficacy of ARBs in treating glaucoma caused by ADAMTS10 mutations. For this project, we will use mouse and zebrafish lines homozygous for glaucoma-causing mutations in Adamts10. In Specific Aim 1, we will test the fundamental hypothesis that microfibril deficiencies cause POAG. In Specific Aim 2, we will investigate molecular mechanisms of POAG caused by ADAMTS10 mutations. In Specific Aim 3, we will test the efficacy of ARBs in treating or preventing glaucoma phenotypes caused by ADAMTS10 mutations.

项目总结/摘要 原发性开角型青光眼（Primary open angle glaucoma，POAG）是一种具有特征性视野改变的视神经病变 由于视网膜神经节细胞（RGC）的进行性变性而导致的视神经缺失和视神经盘杯状。升高 眼内压（IOP）是POAG的一个重要危险因素，人工升高IOP对于 在动物模型中诱导青光眼。然而，IOP和RGC死亡之间的关系尚不清楚， 一些具有正常IOP的患者发展成青光眼，而其它具有升高IOP的患者则不会。我们小组做了一个 ADAMTS 10突变导致比格犬POAG的突破性发现。该结果 通过鉴定ADAMTS 10中导致POAG的另一个突变， 挪威猎鹿犬和其他3种狗品种中密切相关的基因ADAMTS 17的其他3种突变。 与人类青光眼相关，已经鉴定出ADAMTS 8基因座与垂直杯盘比相关。 这些发现表明ADAMTS基因突变导致POAG。在人类中， ADAMTS 10引起Weill-Marchesani综合征，这是一种与缺陷性微纤维和 其特征在于短骨骼特征、透镜脱位和青光眼。ADAMTS 10是一种微纤维相关的 在微纤维结构和功能中起作用的蛋白质。微纤维是细胞外基质的组成部分， 基质是转化生长因子β（TGFβ）信号传导的关键调节因子， 涉及血管紧张素II I型受体（AT 1 R）的配体非依赖性活化的机械转导。 TGFβ信号的过度激活和机械传导的改变是两者的关键致病机制 微纤维缺陷和POAG。微纤维相关基因作为POAG病因的鉴定使我们 阐明我们的核心假设，即ADAMTS 10突变通过破坏微纤维引起青光眼， 结构和功能。将微纤维缺陷作为一种疾病机制将表明， 在由微纤维缺陷引起的其它疾病中有效的药物可应用于POAG。AT 1 R阻滞剂（ARB） 有效治疗与微纤维缺乏相关的疾病， 潜在的青光眼治疗，由于其降低IOP和神经保护作用。基于我们 为了验证微纤维假说，我们将测试ARB治疗ADAMTS 10突变引起的青光眼的疗效。 在这个项目中，我们将使用小鼠和斑马鱼品系，这些品系具有引起肉瘤的突变的纯合子， 亚当斯10.在具体目标1中，我们将测试微纤维缺陷导致POAG的基本假设。 在具体目标2中，我们将研究ADAMTS 10突变引起的POAG的分子机制。在 具体目标3，我们将测试ARB在治疗或预防青光眼表型中的有效性， ADAMTS 10突变。