Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. It is characterized by the accumulation of extracellular lipid- and protein-rich deposits between the retinal pigment epithelium (RPE) and Bruch's membrane (BrM). These sub-RPE deposits may be focal (drusen) or diffuse and likely contribute to disease pathogenesis and progression similar to intercellular deposits characteristic of other diseases like Alzheimer's disease, atherosclerosis, and glomerulonephritis. Although the molecular bases of these diseases may be diverse, their pathogenic deposits contain many shared constituents that are attributable, in part, to local inflammation and activation of the complement cascade. The role of complement in AMD pathogenesis is supported by studies identifying complement proteins in drusen and studies implicating variations in the complement factor H (CFH) gene as the strongest genetic factor associated with risk for AMD. The precise molecular components involved in dysregulation of the complement system in AMD are unknown, although there are several candidates. Among these are amyloid beta (A?) and glycosaminoglycans (GAGs), both constituents of drusen, and known modulators of the complement system. We hypothesize that dysregulated complement activity within the RPE/BrM/choroid triggers subRPE deposit formation and AMD progression and that A? and GAGs in this region affect the complement alternative pathway. These factors contribute to inflammatory changes, accumulation of protein- rich deposits and ultimately RPE damage. In support of this hypothesis, we present data establishing A? as a viable therapeutic target for treatment of the dry form of AMD, for which there are currently no effective therapies, and data showing that heparan sulfate GAGs regulate complement. This application will test predictions of this hypothesis in the following three aims:
Specific Aim 1 : Test whether removal of A? will reverse retinal/RPE dysmorphogenesis.
Specific Aim 2 : Test whether dysregulation of the complement system will exacerbate AMD.
Specific Aim 3 : Test whether CFH-associated AMD risk is modulated by components of the extracellular matrix.

Public Health Relevance

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the sixty-five-and-older population, and the devastating impact of its socioeconomic burden cannot be overstated. Using mouse models that faithfully recapitulate many aspects of human AMD, we have demonstrated that observed ocular defects arise from inflammation, amyloid beta (A?) deposition and complement dysregulation - mechanisms implicated in development of human AMD. Our proposed studies will further clarify the contribution of complement and A? to disease onset and progression. Validation of A? as a novel therapeutic target in AMD could lead to a fundamental paradigm shift in the understanding and treatment of AMD. Moreover, unraveling the impact of excess complement activation versus increased complement inhibition on subRPE deposit formation and RPE damage will help shape the development of complement-targeted therapies that could delay or prevent AMD. Finally, elucidating which constituents of the posterior eye extracellular matrix regulate complement should provide additional novel AMD therapy targets.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Shen, Grace L
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Duke University
Schools of Medicine
United States
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Qian, Qingwen; Mitter, Sayak K; Pay, S Louise et al. (2016) A Non-Canonical Role for ?-Secretase in the Retina. Adv Exp Med Biol 854:333-9
Ding, Jin-Dong; Kelly, Una; Landowski, Michael et al. (2015) Expression of human complement factor H prevents age-related macular degeneration-like retina damage and kidney abnormalities in aged Cfh knockout mice. Am J Pathol 185:29-42
Toomey, Christopher B; Kelly, Una; Saban, Daniel R et al. (2015) Regulation of age-related macular degeneration-like pathology by complement factor H. Proc Natl Acad Sci U S A 112:E3040-9
Mitter, Sayak K; Song, Chunjuan; Qi, Xiaoping et al. (2014) Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy 10:1989-2005
Ding, Jin-Dong; Kelly, Una; Groelle, Marybeth et al. (2014) The role of complement dysregulation in AMD mouse models. Adv Exp Med Biol 801:213-9
Bowes Rickman, Catherine; Farsiu, Sina; Toth, Cynthia A et al. (2013) Dry age-related macular degeneration: mechanisms, therapeutic targets, and imaging. Invest Ophthalmol Vis Sci 54:ORSF68-80
Cai, Jun; Qi, Xiaoping; Kociok, Norbert et al. (2012) ?-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO Mol Med 4:980-91
Trotter, Justin H; Klein, Martin; Jinwal, Umesh K et al. (2011) ApoER2 function in the establishment and maintenance of retinal synaptic connectivity. J Neurosci 31:14413-23
Ding, Jin-Dong; Johnson, Lincoln V; Herrmann, Rolf et al. (2011) Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration. Proc Natl Acad Sci U S A 108:E279-87
Liu, Yutao; Munro, Drew; Layfield, David et al. (2011) Serial analysis of gene expression (SAGE) in normal human trabecular meshwork. Mol Vis 17:885-93

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