Microfibril deficiency in glaucoma pathogenesis

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）死亡导致的第二大致盲原因。我们的长期目标是确定疾病基因并研究它们在POAG发病机制中的功能。POAG的许多危险因素已被确定，包括高龄、角膜薄和眼压升高。IOP升高是由于房水（AH）通过小梁网流出的阻力增加引起的。薄角膜与青光眼之间的联系机制尚不完全清楚，但它可能导致独立于IOP的RGC死亡易感性。目前，唯一可改变的危险因素是IOP，它可以通过药物、激光或手术来降低。然而，IOP与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会发生青光眼视神经损伤，而其他IOP升高的患者则不会。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张力型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的狗身上发现了ADAMTS10作为疾病基因。ADAMTS10蛋白参与微原纤维的形成，微原纤维是主要由纤维蛋白-1聚合物组成的细胞外基质结构。除了提供可伸缩的支撑

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.