Preferred Name
Jonathan Miller
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Date of Graduation
5-15-2025
Semester of Graduation
Spring
Degree Name
Master of Science (MS)
Department
Department of Biology
First Advisor
Ray Enke
Second Advisor
Marquis Walker
Third Advisor
Mark Gabriele
Abstract
Age-related macular degeneration (AMD) is a leading cause for vision loss across the world, as disease pathology remains irreversible. Better characterization of AMD will aid in early detection methods to combat disease development, as a proper animal model for studying this disease is not readily available. The Mcoln1-/- mouse may serve as a model for studying retinal degeneration in humans by comparative characterization of genomics data. Previous research has determined Mcoln1-/- mice suffer from retinal dysfunction, decreased expression and mis-localization of photoreceptor (PR)-specific proteins, and downregulation of phototransduction transcripts. Previous unpublished data in our lab demonstrates that human PR-specific genes have increased levels of DNA methylation and decreased transcription in AMD-affected tissues. The goal of this study was to determine if PR-specific genes and proteins are similarly dysregulated in Mcoln1-/- mice. Transcriptome analysis of Mcoln1−/− mice revealed global gene dysregulation. Biological pathways involved in immune responses were significantly upregulated, while phototransduction genes were downregulated. Several key phototransduction proteins of older Mcoln1-/- mice exhibited distinct mis-localization in PRs, along with increased methylation of their gene’s promoter regions. Western blot experiments of RHO and PDE6B detected no significant loss of phototransduction proteins in Mcoln1-/- mice, suggesting overall dysfunction occurring in mutant mice is not due to global loss of phototransduction protein. These experiments suggest that the retinal dysfunction in Mcoln1-/- mice is from overall dysregulation of phototransduction components, rather than major cell loss in the retina as determined through H&E-stained mutant retinas. Mcoln1-/- mice exhibit continuous retinal dysfunction through age, which is similar to early dysfunction of the human retina in AMD. These mutant mice may serve as an effective tool for investigating early human retinal dysfunction, instead of traditional mouse models that exhibit global cell type loss.
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