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.
In this project, we will test the hypothesis that defects in microfibrillar structures in the eye cause glaucoma. We will also test the efficacy of a medication that is widely used and well tolerated by patients who suffer from other diseases in treating glaucoma. The success of this project will have direct and implementable impact on clinical treatment of glaucoma patients.
|Kuchtey, John; Kunkel, Jessica; Burgess, L Goodwin et al. (2014) Elevated transforming growth factor ?1 in plasma of primary open-angle glaucoma patients. Invest Ophthalmol Vis Sci 55:5291-7|
|Kuchtey, John; Kuchtey, Rachel W (2014) The microfibril hypothesis of glaucoma: implications for treatment of elevated intraocular pressure. J Ocul Pharmacol Ther 30:170-80|
|Kuchtey, John; Chowdhury, Uttio Roy; Uptegraft, Colby C et al. (2013) A de novo MYOC mutation detected in juvenile open angle glaucoma associated with reduced myocilin protein in aqueous humor. Eur J Med Genet 56:292-6|
|Kuchtey, John; Kunkel, Jessica; Esson, Douglas et al. (2013) Screening ADAMTS10 in dog populations supports Gly661Arg as the glaucoma-causing variant in beagles. Invest Ophthalmol Vis Sci 54:1881-6|
|Kuchtey, John; Olson, Lana M; Rinkoski, Tommy et al. (2011) Mapping of the disease locus and identification of ADAMTS10 as a candidate gene in a canine model of primary open angle glaucoma. PLoS Genet 7:e1001306|