The Role of the Retinal Pigment Epithelium and Serpinf1 in Visual Outcomes after Light Damage Exposure Open Access

Shelton, Debresha (Fall 2024)

Permanent URL: https://etd.library.emory.edu/concern/etds/dn39x2965?locale=en++PublishedPublished
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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

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