Advisory Committee Chair
Thomas T Norton
Advisory Committee Members
Christine A Curcio
Karen L Gamble
Paul D Gamlin
Kent T Keyser
Christianne E Strang
Document Type
Dissertation
Date of Award
2016
Degree Name by School
Doctor of Philosophy (PhD) College of Arts and Sciences
Abstract
Myopia is a significant public health problem. Most juvenile-onset myopia occurs because the eye becomes too long for its own optics. We study mechanisms regulating refractive error in an animal model, the tree shrew (Tupaia glis belangeri), a mammal closely related to primates. We use translucent diffusers to induce form deprivation myo-pia (FDM). A role of the retinal dopaminergic system has been validated during the de-velopment of FDM. In this study, in Specific Aim 1, we used intravitreal injections as a way to deliver sub-stances to the retina to investigate their effect on eye growth and induced myopia. However, a number of variables (daily anesthesia, the brief goggle removal required to make the in-jection, opening of the conjunctiva, puncture of the sclera, contents of the vehicle solution, and volume of the injection) could potentially confound the results. Thus, this aim exam-ined the effect of these variables in tree shrews during FDM. Our hypothesis was that the 0.85% NaCl and water vehicles would have the least effect on FDM. We discovered that procedures associated with this delivery method had no effect on FDM while various vehi-cles all reduced it to an extent. We were correct in our hypothesis that 0.85% NaCl would have the least adverse effect on FDM, however, water by itself reduced FDM significantly. Since 0.85% NaCl had the most minimal effect on FDM, we used it as the vehicle to dis-solve dopamine analogs in Specific Aim 2. With a better understanding of how to minimize confounding factors that affect FDM, we examined the role of dopaminergic signaling in the retina during myopia devel-opment by injecting dopamine receptor agonists and antagonists into the vitreous chamber. We asked which pathway, the dopamine D1-like or D2-like, would affect form depriva-tion myopia development and hypothesized that the D2-like receptor pathway would be involved in regulating axial elongation and refractive error. We found that the D1-like pathway had no significant contribution to FDM while the D2-like did. Our hypothesis was correct and in agreement with studies in chicks, mice, and monkeys. However, it was surprising that injecting either a dopamine D2-like agonist or antagonist both reduced FDM. Since these analogs target all three subtypes (D2, D3, and D4 receptors) of the D2-like pathway, we then found and tested an analog that only binds the D4 receptor. This receptor was chosen due to its abundance in the retina and because this specific analog had never been tested during FDM in any animal model. Results indicated that activation of the D4 receptor reduced FDM on several days of treatment and thus, the entire effect of the D2-like receptor agonist quinpirole may be due to its action at the D4 receptor. This project was the first to inject, via intravitreal delivery route, a D4 agonist and antagonist in tree shrews to tests its effect on FDM. Furthermore, this study was more effective than previous studies in monitoring daily responses to manipulation of the do-paminergic and emmetropization signaling (“GO” and “STOP”) pathways.
Recommended Citation
Ward, Alexander Hadwyn, "Investigating The Mechanisms Of Dopaminergic Signaling In Regulating Refractive Error" (2016). All ETDs from UAB. 3265.
https://digitalcommons.library.uab.edu/etd-collection/3265
