- Glaucoma is a leading cause of blindness affecting more than 60 million people worldwide. Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of glaucoma and results from increased resistance to aqueous humor outflow. IOP reduction has been shown to reduce the risk of conversion to glaucoma in eyes with ocular hypertension and reduce the risk of disease worsening in eyes with existing glaucoma damage. While IOP-lowering therapies capable of restoring structure and function of the diseased tissues that increase outflow resistance are particularly desirable, few such therapies currently exist. These diseased tissues reside in the conventional outflow tract that is comprised of the trabecular meshwork (TM) and Schlemm?s canal (SC). In 2013, our group discovered that reduced activity of the Angiopoietin (Angpt)- TEK vascular signaling pathway results in a severe form of primary congenital glaucoma (PCG) in mice due to failure of the SC to form. During the last grant cycle, we showed that the Angiopoietin1 ligand is expressed in the TM and is required to activate the Tie2/TEK receptor in the SC and that severity of glaucoma disease phenotype correlates tightly with the dose of Angpt/TEK signal strength. We were able to rescue the PCG disease phenotype in mice, by inhibiting the vascular-specific phosphatase PTPRB, thereby boosting TEK signal strength in a ligand-independent manner. In collaboration with an international team, we have now identified 20 unique loss-of-function mutations in the TEK and ANGPT1 genes in 20 individuals, providing a new genetic cause of PCG and confirming the importance of this pathway in human disease. In adult patients with primary open angle glaucoma (POAG), risk variants in the Angpt/TEK pathway have been identified and a pepti-body targeting Angiopioetin ligands causes rapid onset of high pressure OAG in adult monkeys by reducing outflow facility, extending importance of this pathway beyond childhood glaucoma. Altogether, our findings, largely funded by the first cycle of this grant, have led to major new insights into the pathogenesis of glaucoma and development of the outflow tract and have led directly to the identification of a new genetic cause of glaucoma. In this competitive renewal, we propose to leverage these seminal discoveries to:1) fully characterize the cellular basis of Angpt-TEK signaling in development of the outflow tract and pathogenesis of glaucoma through single cell analysis 2) functionally annotate 2 new disease genes identified in patients with PCG and POAG and determine how they modulate Angpt/TEK signal strength and 3) test the ability of a novel ANGPT1-mimetic to repair defective SC and TM in glaucoma models and enhance outflow facility. By the end of the next cycle, we will have characterized specific cell populations in the TM and SC, identified new genes responsible for glaucoma and provide lead compounds to take forward to clinical development.

Public Health Relevance

Glaucoma is a leading cause of blindness afflicting more than 60 million people worldwide and is linked to elevated pressure within the eye. We discovered the molecular building blocks (known as the Angiopoietin- Tie2/TEK pathway) needed to drain fluid from the eye to maintain a healthy, low pressure. We subsequently found gene mutations in this pathway cause severe glaucoma and blindness in children and increase risk of glaucoma in adults. In this proposal, we will characterize the role of two new glaucoma genes in this pathway and test effectiveness of a novel Angpt/TEK-targeted therapy to lower eye pressure, treat glaucoma and prevent blindness.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Liberman, Ellen S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
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
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
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