Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY Regulation of intraocular pressure (IOP) is a subject of considerable scientific, clinical, and pharmaceutical interest. High IOP is an established risk factor for glaucoma, an insidious disease that causes blindness by killing retinal ganglion cells, so lowering IOP is a primary focus of all current treatments. The first approach in clinical care is to prescribe patients medicines that alter the production and outflow of aqueous fluid in the eye. Many of these medicines achieve a therapeutic effect by targeting signals from the autonomic nervous system, which dynamically modulates aqueous humor dynamics for reasons that are not entirely known. One of the strongest modulators is the suprachiasmatic nucleus in the brain, which coordinates a circadian rhythm in mean IOP. Other autonomic neuromodulators include stress and intracranial pressure (ICP). Their collective actions cause IOP to fluctuate continually, sometimes reaching levels that would cause glaucoma in some individuals if maintained for extended periods. Involvement of ICP in IOP modulation is particularly intriguing because ICP contributes to the translaminar pressure gradient across the optic nerve head, which determines the mechanical stress and strain profiles experienced by retinal ganglion cell axons as they exit the eye to the brain. ICP could therefore factor into glaucoma pathophysiology as well. The proposed research is directed at advancing our understanding of circadian and autonomic mechanisms of IOP modulation and the potential involvement of these mechanisms in disease onset and progression. To do this, one-of-a-kind technologies are used that provide researchers the ability to record or control IOP or ICP round-the-clock in rats. IOP, ICP, body temperature, locomotor activity, aqueous outflow facility, and ocular compliance will be concurrently recorded in various combinations as ambient light-dark cycle is altered, sympathetic nerve agonists and antagonists are administered, and variable pressure loads are transiently applied to the eye. In so doing, new insights will be gained about the origin and control of ocular rhythms, about efferent control of IOP by ICP, and about possible roles of circadian and autonomic systems in glaucoma. These insights could lead to new approaches and targets for disease treatment.
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