Microfibril deficiency in glaucoma pathogenesis

描述(申请人提供)：在美国，原发性开角型青光眼(POAG)是视网膜神经节细胞(RGC)死亡导致的第二大致盲原因。我们的长期目标是识别疾病基因，并研究它们在POAG发病机制中的作用。POAG的危险因素很多，包括高龄、角膜薄和眼压升高。高眼压是由于小梁网对房水流出的阻力增加所致。薄角膜与青光眼之间的联系机制尚不完全清楚，但它可能导致RGC死亡的易感性，而不依赖于眼压。目前，唯一可改变的风险因素是眼压，可以通过药物、激光或手术降低眼压。然而，眼压和RGC死亡之间的关系尚不清楚，因为一些眼压在正常范围的患者会发生青光眼视神经损害，而另一些眼压升高的患者则不会。尽管如此，降低眼压会减缓疾病的进展，即使是对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，我们确定ADAMTS10是遗传性POAG犬群体中的疾病基因。ADAMTS10蛋白参与了微纤维的形成，微纤维是主要由纤维蛋白-1聚合物组成的细胞外基质结构。除了提供可伸展的支撑之外 在血管和皮肤等组织中，微纤维是转化生长因子β(TGFbeta)的主要储存库。在与微纤维缺陷相关的疾病中，如马凡综合征，血浆中TGFbeta升高，TGFbeta信号在受影响的器官中过度激活。有缺陷的微纤维可能首次提供了一种机制解释 在人类POAG患者的AH中，已经证实了TGFbeta的升高，这被认为与青光眼的发病机制有关。ADAMTS10作为POAG基因的发现使我们形成了假设，并在这一建议中进行了验证，即微纤维缺陷导致青光眼。使用两个具有公认的微纤维缺陷的独立小鼠系，我们将：1.测试微纤维缺陷影响AH动力学的假设，2.测试微纤维缺陷小鼠在正常和高眼压时容易发生RGC死亡的假设，3.测试一种药物在预防或逆转青光眼表型方面的有效性，该药物抑制结构性TGFbeta信号并对治疗马凡综合征有效，Marfan综合征是一种已知的微纤维缺陷。该项目的预期重大成果是：1.检验微纤维缺乏导致青光眼的基本假设。2.建立非高眼压青光眼模型。3.研究与高眼压无关的青光眼RGC病理改变。4.基于微纤维假说，测试青光眼的治疗方法。

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.