Hypothalamic Control of IOP, ICP, and the Translaminar Pressure Gradient

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DESCRIPTION (provided by applicant): Glaucoma is one of the leading causes of blindness worldwide, yet we are still trying to develop a fundamental understanding of the mechanisms that cause retinal ganglion cell death. Intraocular pressure (IOP) fluctuation has recently been identified as a risk factor for glaucoma progression. There is ample evidence demonstrating that IOP varies in a cyclical manner over a 24-hour period in both human and rodents, with the peak pressure occurring in the morning hours upon awakening. Further, decreases in intracranial pressure (ICP), with postulated increases in the translaminar pressure gradient across the lamina cribrosa, has been reported in glaucoma patients. The PI recently identified that chemical stimulation of dorsomedial and perifornical hypothalamic neurons with bicuculline methoidide (BMI; 30pmol/75nl) evokes substantial increases in IOP, ICP, and the translaminar pressure gradient in the rat model. Because DMH/PeF neurons receive direct and indirect projections from the suprachiasmatic nucleus, his laboratory has hypothesized that the DMH/PeF neurons may be a key effector pathway for circadian fluctuation of IOP and control of the translaminar pressure gradient. The PI is a fellowship trained glaucoma specialist and clinician-scientist with graduate training in neurobiology. Under this mechanism, the PI proposes a mentored clinical-scientist research career development program that will provide him with additional training to help characterize this model and identify potential neurotransmitters involved in the IOP and ICP changes. Specific Aim #1 will include training in fluorophotometric analysis of aqueous humor production and in vivo recording of outflow facility immediately following chemical stimulation of the DMH/PeF neurons. Specific Aim #2 will focus on the incorporation of animal models of glaucoma into his current research and learning key molecular biology techniques that will help identify potential neurotransmitters involved in hypothalamically mediated increases in IOP and ICP following chemical stimulation of the DMH/PeF region. The results of this research will advance our understanding of the neurophysiology mediating fluctuations in IOP and shifts in the translaminar pressure gradient. We anticipate that further defining this pathway and the neurotransmitters involved will provide targets for novel glaucoma therapies aimed at reducing IOP fluctuations.