The Aqueous Humor Outflow Resistance

Oregon Health & Science University, Portland OR

Investigators

Linked publications & trials

Abstract

Project Summary Glaucoma stands as a formidable adversary in the realm of ocular diseases, chiefly because elevated intraocular pressure (IOP) is both its primary risk factor and the sole controllable parameter. The regulation of IOP is a complex ballet, orchestrated primarily in the outflow pathway by juxtacanalicular (JCT) and Schlemm’s canal endothelial (SCE) cells. These cellular maestros modulate the resistance to aqueous humor outflow, largely through the construction and maintenance of the SCE cells’ expansive basement membrane, a specialized extracellular matrix (ECM). When IOP rises, a cascade of biological responses is triggered, prompting JCT cells to create strategic discontinuities in the SCE basement membrane. This ingenious adaptation facilitates the transcellular movement of aqueous humor into Schlemm’s canal, effectively reducing the IOP. Our research initiative is poised to explore the frontiers of glaucoma treatment by manipulating molecules crucial to the outflow resistance mechanism and discerning their effects on the basement membrane discontinuities and fluid dynamics, with the overarching goal of diminishing IOP. Utilizing cutting-edge immunohistochemical techniques, our study will meticulously map the alterations in basement membrane discontinuities induced by pressure fluctuations and our molecular interventions. Versican, a large proteoglycan brimming with negative charges, emerges as a pivotal figure in this narrative. It fills the newly formed discontinuities, subtly modulating the fluid flow and thereby influencing IOP in the aftermath of fluid translocation. Additionally, the tissues involved in this process exhibit a fascinating array of biomechanical properties, particularly in terms of outflow and basement membrane discontinuity variations. To probe the depths of this biomechanical enigma, we will employ ultra-high- resolution serial block-face scanning electron microscopy, capturing detailed images of the outflow resistance region. Armed with these images, we will apply sophisticated fluid-structure interaction and finite element biomechanical models to unravel the tissue properties at play. Our simulations will include the virtual insertion of Versican into the basement membrane discontinuities using our cutting-edge electrical FSI (EFSI) method, enabling us to predict the subsequent effects on fluid biomechanics. This comprehensive, two-pronged approach is anticipated to yield critical insights, paving the way for the identification of molecular targets for manipulation. Such targets hold immense promise for the development of novel therapeutic strategies aimed at the precise control of IOP. By venturing into this uncharted territory, our project aspires not only to contribute to the existing body of knowledge but also to revolutionize the treatment paradigm for glaucoma. The potential to attenuate glaucomatous optic nerve damage and avert blindness is more than an academic triumph; it's a beacon of hope for millions worldwide. With meticulous research and a commitment to innovation, we stand on the precipice of a breakthrough that could redefine ocular healthcare and safeguard the vision of future generations.