Glaucoma is one of the leading causes of irreversible blindness for which the lowering of intraocular pressure
(IOP) is the only proven treatment. Since elevated IOP is a critical risk factor for glaucoma, several animal models
have been developed to study the cellular, vascular, and electrophysiologic responses of the retina to acute IOP
elevation. While these models have elucidated the relationship between ocular perfusion and retinal function as
well as many of the cellular pathways activated in response to acute IOP related exposure, there are significant
differences in optic nerve structure and composition across species, limiting the translation of these findings to
the human disease. This project will study the impact of IOP elevation in the living human eye for the first time
by utilizing the unique resources developed by the Living Eye Project. This project provides experimental access
to the human eye in vivo in research-consented brain-dead organ donors prior to organ procurement. Following
enucleation, the Living Eye Project provides access to the same eyes for ex vivo analysis of cellular and tissue
responses. Our principal hypothesis is that acute IOP elevation results in deformation of the optic nerve head
(ONH), and this deformation drives mechanosensitive mechanisms within the lamina cribrosa (LC) and
peripapillary sclera that initiate pathologic remodeling of the LC, which injures the axons of retinal ganglion cells
traversing this mechanically dynamic region. These mechanosensitive pathways will be characterized using
spatial transcriptomics for the first time in the human eye alongside immunohistochemistry and protein analysis.
We predict that increased IOP initiates a profibrotic, inflammatory phenotype and transcriptomic alterations that
regionally colocalize with the connective tissue density within the LC and are associated with the magnitude of
IOP-induced deformation of the ONH measured in vivo. Our unprecedented opportunity to measure structural
and biomechanical parameters of the human ONH in vivo and perform ex vivo evaluation of the cellular
mechanobiology of the same tissues will provide the first direct experimental link between ONH mechanical
strain and the molecular and cellular responses of ONH tissues that drive remodeling, which is critical to the
development and progression of glaucomatous optic neuropathy. Defining this “mechanotranscriptome” in the
human ONH will critically assess the translational value of animal models for studying mechanotransduction as
well as define the human cellular and molecular mechanisms of ONH remodeling needed to guide the
development of novel therapeutics designed to enhance the resilience of the ONH to pressure-related stress.