Investigating the role of epigenetics in the development of myopia and retinal degeneration in the interphotoreceptor retinoid-binding protein deficient mouse model Öffentlichkeit

Abstract

Little is known about the role of histone modifying proteins in the development of myopia and retinal degeneration (RD). Here we begin to phenotypically characterize the effects of histone deacetylase inhibitors (HDACi) Trichostatin-A (TSA) and Valproic Acid (VPA) in an interphotoreceptor retinoid-binding protein (IRBP) knockout (KO) mouse model, a model known to rapidly induce myopia and retinal degeneration in mice. To determine how these HDACi impacts these deteriorating eye conditions, we randomly assigned IRBP KO mice to experimental and control groups. In the TSA condition, mice were injected daily with TSA (2.5mg/kg) or vehicle (10% DMSO) intraperitoneally using a double-blind system over the course of 5 days. In the VPA condition, mice were injected daily with VPA (350mg/kg) or vehicle (1XPBS) intraperitoneally using a double-blind system over the course of 5 days. Whole-eye biometry was utilized to observe retinal layers, and electroretinography (ERG) was performed to provide additional information regarding how retinal function is affected, both of which showed that the chosen dosage of VPA or TSA made no significant improvement to visual function or the myopic phenotype. TSA (1mg/kg) was further tested for its preventative effects in young mice IRBP KO mice, yet again no improvement in retinal morphology or function could be detected following treatment. Immunofluorescence, enzymatic assays, and western blots were conducted to reveal endogenous levels of HDAC3 deacetylate activity in IRBP KO mice as grounds for a possible underlying mechanism but was revealed that the absence of IRBP does not affect HDAC3 activity or quantity. Data from these experiments will provide critical information on what role epigenetics plays in myopia and RD and the importance IRBP plays in the normal development of the eye.

Table of Contents

Introduction……………………………………………………………………………………………………………………………...1

Results………………………………………………………………………………………………………………………………….….4

Discussion………………………………………………………………………………………………………………………………...7

Methods………………………………………………………………………………………………………………………………….10

References………………………………………………………………………………………………..…………………………..…15

Figure 1………………………………………………………………………………………………………………………………..…18

Figure 2………………………………………………………………………………………………………………………………..…19

Figure 3………………………………………………………………………………………………………………………………..…20

Figure 4…………………………………………………………………………………………………………………………………..21

Figure 5….……………………………………………………………………………………………………………………………....22

Figure 6…………………………………………………………………………………………………………………………………..23

Figure 7…………………………..………………………………………………………………………………………………..….…25

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Molecular Biology, General Biology, Genetics
Stichwort	VPA Retinal Degeneration Epigenetics HDAC Ophthalmology IRBP Myopia Eye TSA
Committee Chair / Thesis Advisor	John Nickerson, Emory University
Committee Members	Arri Eisen, Emory University Davide Fossati, Emory University

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