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 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 primary congenital glaucoma (PCG), a particularly devastating form of the disease in children that accounts for 5% of childhood blindness and 18% of blind-school registry. The primary defect in our mice is loss of Schlemm's canal and corneal limbal lymphatics resulting in defects of aqueous humor drainage. In 174 children with PCG, we have identified 10 mutations in the TIE2 gene and its ligand, Angiopoietin 1 (ANGPT1), suggesting this pathway plays a major role in human disease. In this proposal we will test the hypotheses that: 1) The development of the anterior angle of the eye including the outflow tract is dependent on the level of activity of the Tie2 receptor and reduced size and/or function of the draining vessels is sufficient to cause ocular hypertension, resulting in retinal ganglion cell los and glaucoma. 2) The TIE2 and ANGPT1 mutations observed in children with PCG reduce signaling function of the TIE2 receptor leading to alterations in Schlemm's canal and outflow of the anterior chamber. 3) Activation of TIE2 signaling within the corneal limbal region will enhance the size and function of Schlemm's canal, promoting aqueous humor drainage, reducing IOP and preventing retinal ganglion and vision loss. To test these hypotheses we have assembled a multidisciplinary team of ophthalmologists, vision scientists, geneticists, proteomics experts, vascular biologists and a number of unique reagents permitting us to determine: 1) the impact of a range of reductions in Angpt-Tie2 signaling on development of the irido-corneal angle, IOP and features of glaucoma in genetically engineered mice 2) how the TIE2 and ANGPT1 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.
Glaucoma is a leading cause of blindness afflicting more than 60 million people worldwide and is linked to increased pressure within the eye. We have discovered the molecular `building blocks' (known as the Angiopoietin-Tie2 pathway) needed to drain fluid from the eye and maintain a healthy, low pressure. We have shown that genetic mutations in this pathway cause severe glaucoma and blindness in mice and children. In this application, we will determine how genetic defects in this pathway lead to eye disease and test a new drug treatment targeting this pathway, to lower eye pressure, cure glaucoma and prevent blindness.
|Daly, Christopher; Qian, Xiaozhong; Castanaro, Carla et al. (2018) Angiopoietins bind thrombomodulin and inhibit its function as a thrombin cofactor. Sci Rep 8:505|
|Laursen, Sidsel B; Finsen, Stine; Marcussen, Niels et al. (2018) Endothelial mineralocorticoid receptor ablation does not alter blood pressure, kidney function or renal vessel contractility. PLoS One 13:e0193032|
|Liu, Pan; Thomson, Benjamin R; Khalatyan, Natalia et al. (2018) Selective permeability of mouse blood-aqueous barrier as determined by 15N-heavy isotope tracing and mass spectrometry. Proc Natl Acad Sci U S A 115:9032-9037|
|Loganathan, Krishnapriya; Salem Said, Ebtisam; Winterrowd, Emily et al. (2018) Angiopoietin-1 deficiency increases renal capillary rarefaction and tubulointerstitial fibrosis in mice. PLoS One 13:e0189433|
|Kenig-Kozlovsky, Yael; Scott, Rizaldy P; Onay, Tuncer et al. (2018) Ascending Vasa Recta Are Angiopoietin/Tie2-Dependent Lymphatic-Like Vessels. J Am Soc Nephrol 29:1097-1107|
|Ide, Shintaro; Finer, Gal; Maezawa, Yoshiro et al. (2018) Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the Gdnf-Axis in Kidney Development. J Am Soc Nephrol 29:2795-2808|
|Souma, Tomokazu; Thomson, Benjamin R; Heinen, Stefan et al. (2018) Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. Proc Natl Acad Sci U S A 115:1298-1303|
|Thomson, Benjamin R; Souma, Tomokazu; Tompson, Stuart W et al. (2017) Angiopoietin-1 is required for Schlemm's canal development in mice and humans. J Clin Invest 127:4421-4436|
|Michael, Iacovos P; Orebrand, Martina; Lima, Marta et al. (2017) Angiopoietin-1 deficiency increases tumor metastasis in mice. BMC Cancer 17:539|
|Bartlett, Christina S; Scott, Rizaldy P; Carota, Isabel Anna et al. (2017) Glomerular mesangial cell recruitment and function require the co-receptor neuropilin-1. Am J Physiol Renal Physiol 313:F1232-F1242|