All ETDs from UAB

Advisory Committee Chair

Christine A Curcio

Advisory Committee Members

Dennis M Dacey

Massimo A Fazio

K Bailey Freund

Christopher A Girkin

Cynthia Owsley

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) School of Optometry

Abstract

The outer retinal metabolic ecosystem is a complex interplay among photoreceptors, RPE and blood supply from the retinal and choroidal microcirculation. Breakdown of any component of this ecosystem has detrimental effects and can lead to cellular dysfunction. For example, in age-related macular degeneration a major cause of vision loss in older adults, breakdown of this metabolic unit has severe structural and functional implications. Thus, every feature and component of this ecosystem seems to be optimized to protect non-replicating, terminally differentiated cells from being damaged. Remarkably, much of the cellular and subcellular organization of this system is available for observation in living people through contemporary clinical imaging with optical coherence tomography and allied technologies. Using laboratory and clinical imaging techniques, this dissertation (1) explores the specialized morphology and distribution of mitochondria that play key energetic roles at the outer plexiform layer, (2) characterizes distinct regional adaptations of retinal pigment epithelium basal transport complex that facilitate a high metabolic exchange rate with the choriocapillaris, (3) investigates the role of choriocapillaris in visual function impairment in age-related macular degeneration, a vascular originating, deposit-driven outer retinal disease. Using connectomics, our findings highlight a remarkable organization and morphological heterogeneity of mitochondria at the first synapses of human vision. Using high-resolution optical coherence tomography, we provide a novel in vivo imaging correlate for assessing mitochondrial distribution. Basal infoldings of the retinal pigment epithelium in the fovea had significantly higher surface area for exchange than the parafoveal regions. In eyes with early age-related macular degeneration, we described significant loss of basal infoldings with the accumulation of basal laminar deposit. Using optical coherence tomography angiography imaging, we found that choriocapillaris impairment was associated with worse disease severity and impaired visual function in age-related macular degeneration, especially rod-mediated dark adaptation. Together these findings suggest potential mechanistic links between morphological adaptations for light-evoked photoreceptor energy utilization in retinal health and disease. Disruptions in the outer retinal metabolic ecosystem can lead to impairment or loss of visual function. This information may be applicable to monitoring structure and function of outer retina in clinic populations with age-related macular degeneration, in the near term.

Video S1 (away EM).mp4 (653262 kB)
Video - S1 Away EM

Video S2 (3D reconstructions).mp4 (73512 kB)
Video - S2 3D Reconstructions

Video S3 (near EM).mp4 (672445 kB)
Video - S3 Near EM

Video S4a (SCP pericyte).avi (125921 kB)
Video - S4a SCP Pericyte

Video S4b (DCP pericyte).avi (130313 kB)
Video - S4b DCP Pericyte

Video S5 (complex pericyte mito).avi (15593 kB)
Video - S5 Complex Pericyte Mito

Video S6 (saturated OPL mito).mp4 (55745 kB)
Video - S6 Saturated OPL Mito

Video S7 (mito occupancy 3D).mp4 (35357 kB)
Video - S7 Mito Occupancy 3D

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