Publication Date

2014-05-20

Availability

Open access

Embargo Period

2014-05-20

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2014-04-28

First Committee Member

Abigail S. Hackam

Second Committee Member

Robert W. Keane

Third Committee Member

R. Grace Zhai

Fourth Committee Member

Sanjoy K. Bhattacharya

Fifth Committee Member

Janet Blanks

Abstract

Major factors in the pathogenesis of age-related macular degeneration (AMD) include dysregulated innate immunity, inflammation, and elevated oxidative stress. Abnormalities in toll-like receptor (TLR) signaling, mediators of innate immunity, have recently been implicated in the progression of the disease. Several reports show that TLR3 activation leads to retinal cell death, but other studies indicate that TLR3 has cytoprotective activity in different contexts. However, how TLR3 signaling behaves during oxidative stress, or the exact conditions in which TLR3 signaling is protective or pathogenic are still not known. This thesis examines how TLR3 activation during oxidative stress regulates RPE and photoreceptor viability and function. I demonstrated that TLR3 signaling increased RPE and photoreceptor survival, protected against loss of photoreceptor function, and increased overall visual acuity during oxidative injury to the retina, whereas TLR3 activation in the absence of injury was toxic. Furthermore, I showed that the protective effects of TLR3 during injury were mediated by Stat3 pathway activation. Knockdown of Stat3 signaling eliminated the protective effect of TLR3 during oxidative stress and exacerbated retinal degeneration, indicating that Stat3 activation controls whether TLR3 activation results in protective or pathogenic behavior. Overall, the findings of this dissertation indicate that TLR3 activation in the context of injury is protective via STAT3, indicating that combining inflammatory pathways and oxidative stress triggers protective instead of pathogenic signaling. This study identifies TLR3 as a potential novel therapeutic strategy for AMD, retinal degenerations, and other diseases of the central nervous system in which oxidative stress is a major contributor.

Keywords

Age-related macular degeneration; Retina; Neuroprotection; Innate immunity; Oxidative stress

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