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.
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.
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