Age-related macular degeneration (AMD) is a scourge of the elderly, with some stage of this potentially blinding disease present in approximately a third of individuals over 75 years of age in the US. There is substantial evidence that AMD is an inflammatory disease involving dysregulation of the complement pathway. We found that the hapten, CEP (carboxyethylpyrrole), generated by oxidative damage to docosahexaenoic acid (DHA), is present as an adduct on drusen proteins in AMD donor eyes. In addition, autoantibodies against CEP were more abundant in the circulation (plasma) of individuals with AMD than in age-matched individuals without AMD. Because DHA is abundant in the outer retina where light and high oxygen levels provide a permissive environment for oxidative damage, this tissue is a likely source of CEP-adducts. Since CEP-adducts is antigenic, we speculated that as the outer retina generates these adducts, the immune system becomes responsive to these new epitopes and over time begins to attack the cells that are the source of this fragment. To test this hypothesis we immunized normal mice with CEP-adducted mouse serum albumin (CEP-MSA). Our prediction was that systemic immunization with CEP would sensitize mice to endogenous CEP-adducts generated in the outer retina during the normal course of aging. In turn the immune system would respond by attacking the cells where CEP epitopes are most readily generated. We found that immunized mice develop antibodies to CEP, fix complement component-3 in Bruch's membrane, accumulate drusen below the RPE during aging, and develop lesions in the RPE mimicking geographic atrophy, the end-stage condition characteristic of dry AMD. The research proposed here uses this mouse model for mechanistic studies on the role of complement activation pathways in producing the pathology, the role of antibody in causing the lesions observed, and the possibility of prevention of the lesions through manipulation of complement activation or suppression of the pathology with oral tolerance. Outcomes from these studies have the potential to lead to the identification of new therapeutic pathways to prevent AMD.

Public Health Relevance

The loss of central vision from age-related macular degeneration is the bane of the elderly in industrialized nations. Until recently so little was known about the mechanism of this disease that there was no potential for developing animal models for this disorder. This has now changed with the findings that oxidative damage to retinal lipids is a source of an inflammatory signal that may target this tissue for immune system mediated pathology. This inflammatory signal has been identified, synthesized and used to produce AMD-like lesions in mice. Studies proposed in this grant use this mouse model to understand several aspects of the disease process and explore possible routes of therapeutic intervention.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Biology and Diseases of the Posterior Eye (BDPE)
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Shen, Grace L
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
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Bell, Brent A; Kaul, Charles; Bonilha, Vera L et al. (2015) The BALB/c mouse: Effect of standard vivarium lighting on retinal pathology during aging. Exp Eye Res 135:192-205
Bonilha, Vera L; Rayborn, Mary E; Bell, Brent A et al. (2015) Retinal histopathology in eyes from patients with autosomal dominant retinitis pigmentosa caused by rhodopsin mutations. Graefes Arch Clin Exp Ophthalmol 253:2161-9
Bonilha, Vera L; Rayborn, Mary E; Bell, Brent A et al. (2015) Histopathological comparison of eyes from patients with autosomal recessive retinitis pigmentosa caused by novel EYS mutations. Graefes Arch Clin Exp Ophthalmol 253:295-305
Bonilha, V L; Rayborn, M E; Bell, B A et al. (2015) Histopathology of the Retina from a Three Year-Old Suspected to Have Joubert Syndrome. Austin J Clin Ophthalmol 2:
Bell, Brent A; Kaul, Charles; Hollyfield, Joe G (2014) A protective eye shield for prevention of media opacities during small animal ocular imaging. Exp Eye Res 127:280-7
Bell, Brent A; Xie, Jing; Yuan, Alex et al. (2014) Retinal vasculature of adult zebrafish: in vivo imaging using confocal scanning laser ophthalmoscopy. Exp Eye Res 129:107-18
DiCicco, Rose M; Bell, Brent A; Kaul, Charles et al. (2014) Retinal regeneration following OCT-guided laser injury in zebrafish. Invest Ophthalmol Vis Sci 55:6281-8
Shadrach, Karen G; Rayborn, Mary E; Hollyfield, Joe G et al. (2013) DJ-1-dependent regulation of oxidative stress in the retinal pigment epithelium (RPE). PLoS One 8:e67983
Cruz-Guilloty, Fernando; Saeed, Ali M; Echegaray, Jose J et al. (2013) Infiltration of proinflammatory m1 macrophages into the outer retina precedes damage in a mouse model of age-related macular degeneration. Int J Inflam 2013:503725
Bonilha, Vera L; Shadrach, Karen G; Rayborn, Mary E et al. (2013) Retinal deimination and PAD2 levels in retinas from donors with age-related macular degeneration (AMD). Exp Eye Res 111:71-8

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