Quantitative assessment of glaucomatous conventional outflow dynamics

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Project Summary Intraocular pressure (IOP) control is a dynamic process that is regulated by the conventional outflow tissues; effectively maintaining intraocular pressure within a couple of millimeters of mercury in most people over a lifetime. In some, however, defects in conventional outflow function result in ocular hypertension, a primary risk factor for damage to retinal ganglion cell axons and the development of glaucoma. Until now, our understanding of conventional outflow tissue dynamics has relied on indirect measurements or fixed/processed tissues, capturing only snapshots of information. Hence, visualization and quantification of outflow dynamics in vivo has not been possible. For the present study, we have developed novel perfusion methods and Optical Coherence Tomography (OCT) instrumentation, techniques, and image processing procedures that enable direct visualization, integration, and quantification of conventional outflow dynamics over time in living mice (an established model of conventional outflow anatomy, physiology, and pharmacology). Armed with such technology, we can specifically tackle longstanding questions about conventional outflow (dys)function in aging and glaucoma. The current proposal is guided by the hypothesis that the dynamic and integrated conventional outflow function diminishes with age and disease; these are changes that can be reversed by drug treatment and are quantifiable. To address this hypothesis, we have designed three specific aims to (i) Examine conventional outflow tissue behavior in adult and elderly mice challenged with IOP elevations or conventional outflow drugs; (ii) Monitor changes in conventional outflow tissue behavior in two established mouse models of ocular hypertension (corticosteroid- induced and caveolin-1 knockout); (iii) Optimize newly developed OCT hardware, software, and perfusion techniques for better evaluation of the conventional outflow pathway. Knowledge gained from these fundamental experiments in a pliable model will be used toward our ultimate goal of improving glaucoma management in humans, including: early diagnosis, detecting minor changes in outflow function; monitoring response to medical treatment, enabling personalization of treatment; mapping of flow patterns to enable effective placement of shunts; and subtyping of glaucoma disease.