Glaucoma is a leading cause of blindness, afflicting more than 60 million people worldwide. Vision loss in glaucoma is due to progressive loss of retinal ganglion cells, supporting glial cells and microvasculature, leading to deformation of the optic nerve. While the pathogenic events triggering the various forms of glaucoma remain obscure, increased intraocular pressure (IOP) due to impaired aqueous humor drainage has been identified as a major risk factor. Accordingly, current medical and surgical therapies are designed to promote fluid drainage from the anterior chamber to reduce ocular hypertension. While these therapies show some benefit, none are curative. The greatest obstacle to finding a cure has been a poor understanding of the molecular events leading to decreased aqueous humor drainage and retinal ganglion loss, preventing the development of therapies based on underlying disease mechanisms. We have shown that genetic disruption of the Angiopoietin-Tie2 signaling pathway in mice results in high IOP, bupthalmos and classic features of glaucoma including retinal ganglion degeneration and blindness due to loss of lymphatic-like Schlemm’s canal and corneal limbal lymphatics. Furthermore, we have identified mutations in the TIE2 and Angiopoietin 1 genes in children with pediatric congenital glaucoma, a devastating form of the disease associated with early loss of vision and high IOP. In this proposal we will test the hypotheses that 1) The size and function of Schlemm’s canal and limbal lymphatics required for drainage of the anterior chamber of the eye are dependent on the level of activity of the TIE2 receptor and reduced size and/or function of these vessels is sufficient to cause full-blown glaucoma. 2) The TIE2 and Angiopoietin-1 mutations observed in children with PCG reduce signaling function of the TIE2 receptor 3) Activation of the TIE2 receptor through inhibition of the phosphatase VE-PTP will reduce IOP and rescue PCG phenotypes in mice and ultimately patients. To test these hypotheses we have assembled a multidisciplinary team of opthalmologists, vision scientists, geneticists, proteomics experts and chemists and a number of unique reagents permitting us to determine: 1) the impact of a range of reductions in Angpt-Tie2 signaling on anterior chamber angle development, IOP and features of glaucoma in genetically engineered mice 2) how the TIE2 and Angiopietin-1 mutations in children with PCG affect activity of the receptor 3) whether activation of TIE2 using genetic or small molecule approaches rescues the glaucoma phenotype. Our studies provide an unprecedented opportunity to determine novel molecular mechanisms of glaucoma and ocular hypertension and an innovative approach to treat glaucoma and ocular hypertension through development of the first biologically-targeted therapy.
|Effective start/end date||5/1/16 → 4/30/20|
- National Eye Institute (5R01EY025799-04)
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