The Role of the Retinal Pigment Epithelium and Serpinf1 in Visual Outcomes after Light Damage Exposure Open Access
Shelton, Debresha (Fall 2024)
Abstract
Increasing evidence highlights the retinal pigment epithelium (RPE) in ocular inflammation and the complex, nuanced presentation of retinal degenerative diseases involving RPE pathobiology. Multiple retinal degenerative diseases, characterized by significant loss of retinal function and supportive tissue, demonstrate either primary or secondary RPE involvement in disease progression. Mammalian systems, including humans, lack the ability to regenerate damaged RPE cells, making it crucial to understand how the RPE modulates inflammation to protect visual structures and preserve vision. RPE cells serve dual roles in inflammation, exhibiting both immunogenic and immunosuppressive functions depending on the conditions. Many immunosuppressive properties of RPE are mediated by secreted factors, such as Pigment epithelium-derived factor (PEDF), encoded by serpinf1, and Insulin-like growth factor-1 (IGF-1). However, the expression of these factors is altered in disease, leading to a more advanced pathological state. Studies have linked up-regulated Galectin-3 (Gal-3) expression to poor prognosis in retinal degeneration, particularly in subretinal immune cells interacting with RPE.
This study aimed to 1) characterize changes in RPE morphometric features related to structural and functional vision aberrations with age, and 2) explore the immunomodulatory effects of PEDF on Galectin-3 signaling and RPE-microglia interactions after damage. While the roles of these factors in various diseases have been examined, there is limited data on their interactions in ocular damage. The findings from this study indicated that loss of PEDF increased the vulnerability of C57BL/6J mice to light damage, led to severe retinal degeneration, elevated recruitment of subretinal immune cells, and resulted in defects in damage-associated IGF-1 expression after light stress. Additionally, without damage, PEDF-deficient mice showed lower Gal-3 expression at both gene and protein levels compared to wildtypes. Interestingly, light damage exposure significantly increased Galectin-3 expression in PEDF-deficient mice, a phenotype opposite of PEDF wildtypes after the initial insult. Additionally, pharmacological inhibition of Gal-3 in PEDF wildtype mice mimicked the effects seen in PEDF-deficient mice. These results suggest that PEDF and Galectin-3 may co-regulate ocular inflammatory responses and influence visual outcomes following light damage.
Table of Contents
Chapter I.
Abstract
4
Introduction
9
Premise of this dissertation
15
Premise for Aim 1: The role of Lsd1 in normal retinal development
16
Premise of Aim 2: Lsd1 is a potential therapeutic target in retinoblastoma
16
Outline of the dissertation
16
Chapter II
Deletion of histone demethylase Lsd1(Kdm1a) during retinal development leads to visual function and morphological defects
18
Abstract
19
Introduction
20
Methods
22
Results
29
Discussion
32
Figures and Tables
36
References
42
Chapter III
Age-related RPE Changes in C57BL/6J Mice Between 2 and 32 Months of Age
46
Abstract
47
Introduction
48
Methods
50
Results
55
Discussion
58
Figures & tables
64
Chapter IV
Comparing Light Damage-Induced Phenotype Variation in RPE65 hyper- and hypomorphs
72
Abstract
73
Introduction
75
Methods
77
Results
85
Discussion
87
Figures & tables
89
Chapter V
Loss of Pigment Epithelium Derived Factor Sensitizes C57BL/6J to Light-Induced Retinal Damage
100
Abstract
101
Introduction
103
Methods
104
Results
113
Discussion
120
Figures & Tables
126
Chapter VI
Discussion and Summary
144
Future Directions
148
Significant and Impact
149
References (Chapter 1, 3-5)
150
About this Dissertation
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