Exosomes and Conventional Outflow Homeostasis

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Project Summary Glaucoma is an optic neuropathy in which the primary risk factor is elevated intraocular pressure (IOP). Dysregulation of conventional outflow homeostasis results in elevated IOP. Key elements of outflow homeostasis are the turnover of extracellular matrix (ECM), which also determines preferential flow passageways through the tissue. In fact, there is recent evidence of differential ECM gene expression between regions of low and high flow in the trabecular meshvvork (TM). In cancer, dysregulation of ECM homeostasis has been demonstrated to involve extracellular nanovesicles, known as exosomes. Exosome release is tightly regulated, and they are differentiated from other nanovesicles based on their size, cell type-specific function and cargo. Amongst others, their functions include waste management, cell-cell signaling and ECM turnover. As a result, we hypothesize that exosomes released from TM cells play a role in opsonizing ECM in the outflow pathway, contributing to segmental flow, and altered ECM homeostasis in glaucoma. This study aims to investigate the role of exosomes in regulating ECM by human TM cells and in TM tissues. During the independent phase, I will examine how IOP effects exosome release and regulation in the conventional outflow pathway in terms of segmental flow. Next, using human TM cells and TM tissues, I will investigate how exosomes can be used to ameliorate a glaucoma phenotype and ocular hypertension. As outcomes of this research we expect to (i) identify a role for exosomes in segmental flow (ii) determine the effect of IOP on exosome release and function (iii) identify ECM targets for exosome regulation and, (iv) ascertain if exosomes can be used to normalize ECM homeostasis.