Microfibril deficiency in glaucoma pathogenesis

青光眼发病机制中的微纤维缺陷

• 批准号: 9313254
• 负责人: Rachel W Kuchtey
• 金额: $ 65.82万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313254
• 关键词: Address; Affect; Age; Animal Model; Aqueous Humor; Axon; Blindness; Blood Vessels; Canis familiaris; Cell Death; Cessation of life; Clinical Treatment; Complex; Cornea; Data; Defect; Disease; Disease Progression; Drug usage; Elastic Fiber; Elderly; Equilibrium; Extracellular Matrix; Eye; FBN1; Funding; Genes; Glaucoma; Goals; Human; Inherited; Knowledge; Lasers; Link; Marfan Syndrome; Matrix Metalloproteinases; Mediating; Microfibrils; Modeling; Mus; Mutation; Normal Range; Operative Surgical Procedures; Optic Nerve; Organ; Pathogenesis; Pathogenicity; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Physiologic Intraocular Pressure; Plasma; Play; Polymers; Predisposition; Primary Open Angle Glaucoma; Process; Proteins; Resistance; Retinal Ganglion Cells; Risk Factors; Role; Signal Transduction; Skin; Stretching; Structure; Testing; Therapeutic; Thinness; Time; Tissues; Trabecular meshwork structure; Transforming Growth Factor beta; United States; Wild Type Mouse; animal model development; anterior chamber; aqueous humor flow; base; cell injury; efficacy testing; eye chamber; ganglion cell; modifiable risk; neuronal cell body; prevent; public health relevance; success; therapeutic evaluation

DESCRIPTION (provided by applicant): In the United States, Primary Open Angle Glaucoma (POAG) is the second leading cause of blindness due to death of retinal ganglion cells (RGC). Our long term goals are to identify disease genes and investigate their function in the pathogenesis of POAG. Many risk factors for POAG have been identified, including advanced age, thin cornea and elevated intraocular pressure (IOP). Elevated IOP is caused by increased resistance to outflow of aqueous humor (AH) through the trabecular meshwork. The mechanisms linking thin cornea to glaucoma are not fully known, but it may cause susceptibility to RGC death independent of IOP. Currently, the only modifiable risk factor is IOP, which can be lowered by drugs, laser or surgery. However, the relationship between IOP and RGC death is unclear since some patients with IOP in the normal range develop glaucomatous optic nerve damage while others with elevated IOP do not. Nonetheless, lowering IOP slows progression of the disease, even for patients with so-called normal tension glaucoma. During our previous funding period, we identified ADAMTS10 as the disease gene in a colony of dogs with inherited POAG. ADAMTS10 protein is involved in formation of microfibrils which are extracellular matrix structures primarily composed of fibrillin-1 polymers. In addition to providing stretchable support in tissues such as blood vessels and skin, microfibrils are the primary reservoir of transforming growth factor beta (TGFbeta). TGFbeta is elevated in plasma and TGFbeta signaling is hyper-activated in affected organs in diseases associated with microfibril defects, such as Marfan syndrome. Defective microfibrils could for the first time provide a mechanistic explanation for the well-established elevation of TGFbeta in the AH of human POAG patients, which is thought to contribute to glaucoma pathogenesis. Discovery of ADAMTS10 as a POAG gene led us to form the hypothesis to be tested in this proposal that microfibril defects cause glaucoma. Using two independent mouse lines with well-established microfibril deficiencies, we will: 1. Test the hypothesis that microfibril deficiencies affect AH dynamics, 2. Test the hypothesis that microfibri deficient mice are susceptible to RGC death at normal and elevated IOP and 3. Test efficacy in preventing or reversing glaucoma phenotypes of a drug that inhibits constitutive TGFbeta signaling and is effective in treating Marfan syndrome, a known microfibril deficiency. The anticipated significant accomplishments of this project are: 1. Test a fundamental hypothesis that microfibril deficiencies cause glaucoma. 2. Establish a new model of glaucoma independent of elevated IOP. 3. Investigate glaucomatous RGC pathology independent of elevated IOP. 4. Test therapeutic approach to treat glaucoma based on the microfibril hypothesis.

描述（由申请人提供）：在美国，原发性开角型青光眼（POAG）是由于视网膜神经节细胞（RGC）死亡导致失明的第二大原因。我们的长期目标是鉴定疾病基因并研究它们在POAG发病机制中的作用。POAG的许多危险因素已被确定，包括高龄、角膜薄和眼内压（IOP）升高。眼压升高是由于对通过小梁网流出的房水（AH）的阻力增加所致。薄角膜与青光眼的联系机制尚不完全清楚，但它可能导致RGC死亡的易感性，而与IOP无关。目前，唯一可改变的风险因素是IOP，可以通过药物、激光或手术降低。然而，IOP和RGC死亡之间的关系尚不清楚，因为一些IOP在正常范围内的患者发展为青光眼性视神经损伤，而其他IOP升高的患者则没有。尽管如此，降低IOP可以减缓疾病的进展，即使对于所谓的正常眼压性青光眼患者也是如此。在我们之前的资助期间，我们在一群患有遗传性POAG的狗中确定了ADAMTS 10作为疾病基因。ADAMTS 10蛋白参与微纤维的形成，所述微纤维是主要由微管蛋白-1聚合物组成的细胞外基质结构。除了提供可伸展的支撑外， 在诸如血管和皮肤的组织中，微纤维是转化生长因子β（TGF β）的主要储存库。在与微纤维缺陷相关的疾病（例如马凡氏综合征）中，TGF β在血浆中升高，并且TGF β信号传导在受影响的器官中被过度激活。有缺陷的微纤维可能首次为细胞的生长提供了一个机制性的解释。 在人POAG患者的AH中，TGF β的明确升高被认为有助于青光眼发病机制。ADAMTS 10作为POAG基因的发现使我们形成了微纤维缺陷导致青光眼的假设。使用两个独立的小鼠系，具有良好的微纤维缺陷，我们将：1。检验微纤维缺陷影响AH动力学的假设，2。检验以下假设：在正常和升高的IOP和3.测试抑制组成性TGF β信号传导并有效治疗马凡氏综合征（一种已知的微纤维缺乏症）的药物预防或逆转青光眼表型的功效。本项目预期的主要成果是：1。测试微纤维缺乏导致青光眼的基本假设。2.建立一种不依赖于高眼压的新型青光眼模型。3.研究与IOP升高无关的青光眼RGC病理学。4.测试基于微纤维假说的青光眼治疗方法。