Browsing by Subject "retinal ganglion cell"
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Item Retinal ganglion cell death in acute and chronic models of glaucoma: Is the degeneration subtype specific?(2018-12) Daniel. Steffi; McDowell, Colleen; Clark, Abbot F.; Pang, Iok-Hou; Krishnamoorthy, Raghu R.Glaucoma, the world's leading cause of irreversible blindness, is a group of optic neuropathies with multifactorial etiologies that lead to optic nerve degeneration and retinal ganglion cell (RGC) death, severing the communication between the eye and the brain causing vision loss. As glaucoma is a progressive disease, many ocular changes occur before the actual vision loss and needs comprehensive eye examination to detect these changes. One of the major risk factors of glaucoma is elevated intraocular pressure (IOP), a modifiable factor which is targeted by current therapeutic strategies. None of the available therapies cure the disease but are used to manage it by slowing its progression. Because glaucoma is such a complex disease with many different cellular and molecular pathways at play, a therapy to cure or reverse the disease is not yet developed. RGC neurons are the ones affected in glaucoma. There are about 50000 RGCs per retina. Nerve fibers from these neurons combine together in an optic nerve and relay visual cues transported from other neurons of the retina to the brain. There are more than 30 different subtypes of RGCs that differ in morphology, dendritic arborization, physiological properties and molecular signatures. These RGCs detect different visual signals and project to their respective visual centers in the brain. As these RGCs differ in so many aspects, a lot of studies postulate that they their response to glaucomatous injury also differs in a way that some RGCs are more susceptible to injury than the others. We hypothesize that RGC subtypes are differentially susceptible to glaucomatous injury. To test this hypothesis, we used transgenic animals expressing GFP in individual RGC subtypes and subjected them to glaucomatous insults by using optic nerve crush model (induced model of glaucoma) or nee model (experimental glaucoma model of early onset glaucoma). Our data suggests that RGCs do have a specific pattern of degeneration in under glaucomatous insults. In our induced and inherent models, we found that melanopsin positive RGCs are the most resilient to injury. We also found that axonal degeneration in RGC subtypes after glaucomatous insult is independent of their respective somal degradation. In this study we have also discussed degeneration and regeneration in the central nervous system (CNS) as well as utilized imaging techniques to evaluate individual RGC subtype projections in the brain through its retinorecipient areas.Item The ketogenic diet and hypoxia promote mitophagy in the context of glaucoma(Frontiers Media S.A., 2024-05-22) Morgan, Autumn B.; Fan, Yan; Inman, Denise M.Mitochondrial homeostasis includes balancing organelle biogenesis with recycling (mitophagy). The ketogenic diet protects retinal ganglion cells (RGCs) from glaucoma-associated neurodegeneration, with a concomitant increase in mitochondrial biogenesis. This study aimed to determine if the ketogenic diet also promoted mitophagy. MitoQC mice that carry a pH-sensitive mCherry-GFP tag on the outer mitochondrial membrane were placed on a ketogenic diet or standard rodent chow for 5 weeks; ocular hypertension (OHT) was induced via magnetic microbead injection in a subset of control or ketogenic diet animals 1 week after the diet began. As a measure of mitophagy, mitolysosomes were quantified in sectioned retina immunolabeled with RBPMS for RGCs or vimentin for Muller glia. Mitolysosomes were significantly increased as a result of OHT and the ketogenic diet (KD) in RGCs. Interestingly, the ketogenic diet increased mitolysosome number significantly higher than OHT alone. In contrast, OHT and the ketogenic diet both increased mitolysosome number in Muller glia to a similar degree. To understand if hypoxia could be a stimulus for mitophagy, we quantified mitolysosomes after acute OHT, finding significantly greater mitolysosome number in cells positive for pimonidazole, an adduct formed in cells exposed to hypoxia. Retinal protein analysis for BNIP3 and NIX showed no differences across groups, suggesting that these receptors were equivocal for mitophagy in this model of OHT. Our data indicate that OHT and hypoxia stimulate mitophagy and that the ketogenic diet is an additive for mitophagy in RGCs. The different response across RGCs and Muller glia to the ketogenic diet may reflect the different metabolic needs of these cell types.