Sunday, October 27, 2024
10/27/2024
Glaucoma is a progressive, irreversible, blinding condition of the eye that affects millions worldwide, and intraocular pressure (IOP) remains the only modifiable risk factor for glaucoma progression. However, we still do not understand how IOP fluctuations are controlled centrally. Our interest is in identifying central nervous system (CNS) nuclei responsible for controlling circadian IOP fluctuation with the hope that this knowledge may identify novel targets for glaucoma therapy. Our previous studies have shown that chemical stimulation of the dorsomedial hypothalamus and surrounding perifornical region (DMH/PeF) transiently, but dramatically, elevates IOP. Further, orexins are highly localized to the DMH/PeF, and orexin neurotransmitters are implicated in control of circadian rhythms. We have extensive data extending the role of the orexin neurotransmitter system in the regulation of IOP. Additionally, our studies have shown that the brainstem raphe pallidus (RP) receives projections from the DMH/PeF neurons. Further, when injected into the RP, orexins stimulated a sustained rise in IOP directly implicating the orexins and the RP in IOP regulation. While a CNS orexinergic pathway that eventually stimulates autonomic ganglia may be the most obvious pathway regulating IOP fluctuation after DMH/PeF stimulation, an alternative orexinergic pathway controlling IOP may exist. Data suggests that orexin receptors are located on the ciliary body and ciliary muscle of the eye's anterior segment. Thus, we will investigate both. We will examine the role of the RP on DMH/PeF induced IOP elevations by measuring the degree to which local orexin receptor antagonists in the RP attenuate the IOP response (Aim 1). We will further assess the degree to which orexin receptor antagonists administered directly within the anterior chamber attenuate the CNS-mediated IOP stimulation (Aim 2). We will also address mechanism of action and examine the effect of CNS-mediated IOP stimulation on the flow dynamics of the aqueous humor (Aim 2). With unique data demonstrating a role for the orexin system in attenuating CNS-mediated IOP stimulation, further exploration of the association between allelic variations of the orexin neurotransmitter and its receptors with the IOP trait is justified and appropriate. Thus, we will use a candidate gene approach and Mendelian randomization analysis to investigate the three genes encoding the orexin signaling system using the NIH All of Us database and the UK Biobank which offers genomic sequence data for over 100,000 participants with matching IOP and medical data (Aim 3). Finally, IOP and IOP dynamics in transgenic mice lacking a functional orexin peptide allele or lacking functioning alleles of either of the orexin receptors will be tested for circadian IOP rhythm disruption, as well as for significant differences in IOP elevation, in our validated CNS stimulation methodologies (Aim 4). Together, these aims establish a comprehensive approach to identify potential mechanisms of action for the orexin system in mediating IOP increases caused by stimulation of the DMH/PeF region and may provide additional insights into CNS control of IOP and its circadian dynamics.
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