. Glaucoma is a common blinding disease that affects over 66 million people worldwide and is frequently associated with elevated intraocular pressure (IOP). However, a homeostatic mechanism to adjust elevated IOP must exist since less than 10% of people develop glaucoma. Elevated IOP is caused by increased resistance to aqueous humor outflow through the trabecular meshwork (TM). When TM cells are subjected to sustained elevated IOP, they initiate remodeling of the extracellular matrix (ECM) by releasing specific proteinases including matrix metalloproteinases (MMPs). ECM turnover produces a new, reduced resistance to allow greater aqueous humor outflow through the TM and decrease IOP. Examination of the molecules involved in remodeling, their proteolytic targets and modes and sites of action is critical in order for us to understand how IOP is adjusted. Our long-term goal is to determine the molecular mechanisms by which elevated IOP is homeostatically adjusted in normal eyes. The goal of this current proposal is to further elucidate the function of two ECM components, ADAMTS4 and hyaluronan, and their roles in IOP homeostasis. ADAMTS4 (A Disintegrin and Metalloproteinase with Thrombospondin motifs) is a proteolytic enzyme that degrades ECM components in the TM. ADAMTS4 increases outflow facility in anterior segment perfusion culture suggesting a role for ADAMTS4 in normal homeostatic responses to elevated IOP. Here, we propose a working model whereby ADAMTS4 is activated at specialized cellular structures, then cleaves its target molecules and is internalized into the cell in endosomes. These endosomes may be recycled to the cell surface to release active ADAMTS4 back into the ECM. We will investigate how ADAMTS4 is proteolytically activated and its cellular fate following activation in TM cells. Hyaluronan concentrations in TM decrease during aging and in POAG, which may be due to decreased synthesis, increased degradation or increased cellular hyaluronan uptake. Recently, three genes involved in hyaluronan synthesis and six genes responsible for hyaluronan degradation have been identified and we will investigate their mRNA levels in response to pressure. We will also determine how decreased hyaluronan concentration affects outflow facility in anterior segment perfusion culture. Finally, the effects of hyaluronan concentration on ADAMTS4/MMP expression, localization and/or activation in TM cells will be determined. Investigation into the molecular mechanisms by which ADAMTS4 and hyaluronan are regulated in the TM will provide new information on the complex series of events that leads to homeostatic adjustment of IOP. Studying the molecular details of normal IOP homeostasis should facilitate development of novel therapies targeted at reducing IOP in glaucoma patients.

Public Health Relevance

Glaucoma is a leading cause of vision loss, affecting approximately 67 million people worldwide, but the underlying cause(s) of this disease is poorly understood. Current treatments for glaucoma are directed toward treating the symptoms but not the cause of the disease. This study focuses on understanding how glaucoma develops at the molecular level and thus may facilitate development of new therapies targeted at reducing elevated intraocular pressure.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Chin, Hemin R
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Oregon Health and Science University
Schools of Medicine
United States
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Raghunathan, Vijay Krishna; Benoit, Julia; Kasetti, Ramesh et al. (2018) Glaucomatous cell derived matrices differentially modulate non-glaucomatous trabecular meshwork cellular behavior. Acta Biomater 71:444-459
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Yang, Yong-Feng; Sun, Ying Ying; Acott, Ted S et al. (2016) Effects of induction and inhibition of matrix cross-linking on remodeling of the aqueous outflow resistance by ocular trabecular meshwork cells. Sci Rep 6:30505
Vranka, Janice A; Bradley, John M; Yang, Yong-Feng et al. (2015) Mapping molecular differences and extracellular matrix gene expression in segmental outflow pathways of the human ocular trabecular meshwork. PLoS One 10:e0122483
Vranka, Janice A; Kelley, Mary J; Acott, Ted S et al. (2015) Extracellular matrix in the trabecular meshwork: intraocular pressure regulation and dysregulation in glaucoma. Exp Eye Res 133:112-25
Sun, Ying Ying; Keller, Kate E (2015) Hyaluronan cable formation by ocular trabecular meshwork cells. Exp Eye Res 139:97-107

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