Project 004 (459): Influence of Ocular Biomechanics on Optic Nerve Head Perfusion, Palko, PL PROJECT SUMMARY/ABSTRACT Glaucoma is the leading cause of irreversible blindness worldwide. Intraocular pressure (IOP), the only known modifiable risk factor for glaucoma, is established as a causative variable in the death of retinal ganglion cells at the optic nerve head (ONH). However, it remains to be discovered how IOP interacts with the ONH to produce glaucomatous damage. Evidence suggests that IOP produces direct mechanical damage to the ONH and hypoxic damage by a reduction in blood flow to the ONH. There is a gap in our current understanding of how mechanical deformations of the ONH connective tissue during elevations in IOP influence the vasculature that resides within this ocular region. The hypothesis of this proposal is that eyes that demonstrate greater tissue compression within and around the ONH will demonstrate a greater reduction in ONH perfusion velocity during elevations of IOP. To test this hypothesis, we have developed novel ultrasound imaging techniques that permit the colocalization of measurements of tissue strain (deformation) and perfusion velocity within the region of the ONH, where glaucomatous damage occurs. The proposed aims will demonstrate the degree to which ONH connective tissue strain influences the perfusion rates to the ONH and determine if chemically stiffening the sclera around the ONH will improve perfusion during IOP elevations. Preliminary results using an innovative imaging system have shown localized strain within regions of the perineural sclera containing arterioles that supply the ONH. These initial studies demonstrate the ability of this technique to measure the perfusion velocity within the depth of the lamina cribrosa, a region of the eye that cannot be measured using current optical methods. In Aim 1, we will evaluate the interplay between ocular perfusion pressure, perfusion velocity and tissue strain magnitudes while determining if stiffening of the peripapillary sclera improves ONH perfusion. In Aim 2, a rodent model with a controlled IOP elevation will be used to ascertain the in vivo effect of peripapillary scleral stiffening on ONH perfusion and axonal transport blockade. This information will further our understanding of glaucoma pathophysiology and examine a potential pre-clinical treatment strategy for glaucomatous eyes with reduced perfusion pressures. This research plan was developed with the assistance and support of a multidisciplinary team of mentors. The professional development and preliminary data gained during this award period will enable me to achieve my career goal as a physician-scientist with an independent R01-funded award in this field of ocular research.