Angiopoietin-1 is required for Schlemm's canal development in mice and humans.
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2017-12
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Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm's canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.
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Thomson, Benjamin R, Tomokazu Souma, Stuart W Tompson, Tuncer Onay, Krishnakumar Kizhatil, Owen M Siggs, Liang Feng, Kristina N Whisenhunt, et al. (2017). Angiopoietin-1 is required for Schlemm's canal development in mice and humans. The Journal of clinical investigation, 127(12). 10.1172/jci95545 Retrieved from https://hdl.handle.net/10161/16647.
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Tomokazu Souma
Terri Lois Young
Terri L. Young, M.D., M.B.A. is a board-certified clinician-scientist ophthalmologist. She is a Professor of Ophthalmology, Pediatrics, and Medicine at Duke University School of Medicine. She is a Professor of Neuroscience at the Duke- National University of Singapore Graduate Medical School, with adjunct appointments at the Singapore Eye Research Institute and the Saw Swee Hock School of Public Health, National University of Singapore. She is the founding Director of the Duke Eye Center Ophthalmic Genetics Program. She is also the Associate Director of the Duke School of Medicine Clinical and Translational Sciences Award Predoctoral Research TL1 Training Award.
Dr. Young's clinical interests include ophthalmic genetics, pediatric eye disease including pediatric cataracts and retinal disorder, and the surgical correction of strabismus/ eye misalignment in children and adults. Her laboratory research focuses on the genetic studies of refractive errors, eye development and growth, primary congenital glaucoma, retinal and corneal dystrophies, and other heritable disorders. Her research program includes the development of animal models in zebrafish and mice for ocular diseases based on our understanding of genetic influences in humans.
Dr. Young is an editorial board member of Experimental Eye Research, World Journal of Ophthalmology, Journal of Ophthalmology, and past editorial board member of the Journal of the Association of Pediatric Ophthalmology and Strabismus. She has published over 180 scientific refereed articles, and multiple book chapters, reviews and abstracts. Dr. Young has served as a strategic consultant to the National Eye Institute (NEI) and the National Human Genome Research Institute. She has served as a National Institutes of Health (NIH) study section member for 14 years, and is currently a permanent member of the Diseases and Pathophysiology of the Visual System study section. She also presently serves as a board member of the NIH NEI Scientific Board of Counselors. She is the American Association of Ophthalmology Pediatric Ophthalmology Program Committee Chair, and the Association for Research in Vision and Ophthalmology Program Committee Vice Chair of the Biochemistry and Molecular Biology Section. She is the Treasurer of Women in Ophthalmology, Inc.
Dr. Young has garnered several prestigious awards as a Fellow of the Philadelphia College of Physicians, the American Ophthalmological Society, and the Association of Research in Vision and Ophthalmology. She has garnered an Honor Award from the American Association of Pediatric Ophthalmology and Strabismus, and a Senior Honor Award from the American Association of Ophthalmology. She is an international speaker, with multiple named lectureships. She has been honored with citations of "Best Doctors in North Carolina", "America's Top Ophthalmologists", and in Becker's Review of "135 Leading Ophthalmolgists in America" for several years. She has also been featured in the NIH National Library of Medicine "Changing the Face of Medicine" exhibit. (2004)
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