Date on Master's Thesis/Doctoral Dissertation

5-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Anatomical Sciences and Neurobiology

Degree Program

Anatomical Sciences and Neurobiology, PhD

Committee Chair

McCall, Maureen

Committee Member

McGee, Aaron

Committee Member

Gregg, Ron

Committee Member

Borghuis, Bart

Committee Member

Samuelsen, Chad

Author's Keywords

Inherited retinal diseases; vision; mutation-independent treatment; retinitis pigmentosa; plasticity

Abstract

Retinitis Pigmentosa (RP) is an inherited retinal disease characterized by rod and then cone photoreceptor degeneration. ~25% of cases are caused by a genetic mutation that results in autosomal dominant RP (adRP). There has been a lack of exploration of the progression of degeneration in adRP models. In Chapter Two, I examined visual acuity (VA) changes, retinal structure, and function from early to late-stage disease in a murine P23H Rho ‘knock-in’ mouse model (RhoP23H/+), the most common form of adRP in North America. To establish a natural history, I evaluated behavioral VA, using the visual water task, and retinal function using full field electroretinograms (ffERG) at the same scotopic and photopic levels. I quantified the thickness of the outer nuclear layer (ONL) in the retina. I constructed a natural history for each measurement. Compared to C57Bl6/J (WT), I find a significant decline in RhoP23H/+ scotopic VA at early-stage disease and in photopic VA at late-stage disease. RhoP23H/+ scotopic VA decline is significantly slower than ERG decline and VA is retained even when the scotopic b-wave is absent. In Chapter Three, to determine if additional plasticity of the visual system is beneficial during vision loss, I assessed the same measures in RhoP23H/+ mice lacking nogo receptor 1 (NgR1), a gene that restricts visual plasticity. NgR1-/- mice were also assessed. Between RhoP23H/+ and RhoP23H/+/NgR1-/- mice, the RhoP23H/+/NgR1-/- mice decline significantly quicker for photopic and scotopic VA in late-stage disease. Accelerated thinning of the ONL is also observed. The absence of NgR1 in RhoP23H/+mice alters the progressive loss of vision in a detrimental way. In Chapter Four, I used a humanized P23H murine model (hRHOP23H/+) of adRP to evaluate a neuroprotective, mutation-independent oral supplement treatment, deuterated docosahexaenoic acid (D-DHA), to maintain cone-mediated vision. In hRHOP23H/+ mice fed D-DHA, photopic and scotopic VA is maintained 90 and 70 days longer, respectively, than natural docosahexaenoic acid (H-DHA) fed mice. The cone photoreceptors were maintained longer in the D-DHA treated mice. This data suggests that D-DHA may be a possible treatment to aid in maintaining cone-mediated vision in patients with adRP.

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