Investigating Optic Nerve Head Remodeling in Glaucoma

We aim to evaluate the optic nerve head (ONH) biomechanics and develop a hydrogel construct for studying ONH mechanobiological remodeling due to mechanical loading in glaucomatous optic neuropathy. In specific aim 1, we will evaluate the viscoelastic properties of the ONH using mechanical testing, modeling, and structural imaging. In specific aim 2, to study ONH mechanobiology, we will create a three-dimensional (3D) hydrogel system with tunable mechanical properties based on a combination of collagen and hyaluronic acid (HA) that matches the dynamic mechanical properties of the ONH. We will test cell-seeded Collagen/HA hydrogels using different constituent concentrations to identify a gel composition with mechanical properties matching the ONH.

Glaucoma is a leading cause of blindness, with c. 3 million patients in the USA and c. 76 million patients worldwide at risk of blindness from this disease. The current gold standard for glaucoma treatment is to lower intraocular pressure; however, despite a wide range of treatment methods, vision loss continues to progress in many patients, indicating a pressing need to better understand glaucomatous optic neuropathy and to develop modern systems to test and develop new drugs to treat this condition, e.g., neuroprotection and regenerative strategies. We know that biomechanics due to elevated intraocular pressure is important in glaucoma, yet the cellular pathways by which biomechanical insult leads to vision loss remain unknown. In this project we will: (1) provide the most accurate characterization of the mechanical properties and mechanobiology of the optic nerve head, the primary site of damage in glaucomatous optic neuropathy, and (2) will develop a physiologically-appropriate ex vivo 3D culture model to study the mechanobiologic response of ONH cells, thought to drive characteristic changes in glaucoma. This system will eventually form the basis of a high-throughput drug discovery system, accelerating the development of future treatments for glaucomatous optic neuropathy.

This project will be the first to characterize the dynamic biomechanical behavior of the ONH, critical to understanding the response of the ONH to the dynamic IOP changes at different timescales. Further, the in vitro system to be developed in this project has the potential to become a novel high-throughput drug discovery platform for screening new glaucoma treatment options.

This project will provide an improved understanding of ONH biomechanics and will lay the groundwork for studies of LC cell mechanobiology and its role in glaucoma, and for ex vivo studies of candidate drugs for modulating LC cell phenotype in glaucomatous optic neuropathy. This project will both utilize the applicant’s background and allow him to gain new skills (e.g. cell culture/phenotyping) to pursue his independent academic career.