Complement System and Choroidal Neovascularization

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DESCRIPTION (provided by applicant): Long-term objective of the current proposal is to find a cure for age-related macular degeneration (AMD), which is the leading cause of irreversible blindness in the Western world among the elderly. Choroidal neovascularization (CNV) is the hallmark of wet AMD, and is responsible for the sudden and disabling loss of central vision. Unfortunately, treatment options currently available to AMD patients have limitations due to their short-term and serious side effects. Therefore, future investigations are needed so that AMD could be prevented, its progression be delayed and effective therapeutic strategies could be developed. A substantial body of evidence supports a role of complement in the pathogennesis of both human and experimental AMD. Our studies have demonstrated that the formation of membrane attack complex (MAC) via the activation of alternative pathway was essential for the release of growth factors that drive the development of laser- induced CNV in mice. We have also shown that the expression of factor H, the major regulator of the alternative pathway was down-regulated during the growth of laser-induced CNV. In the current proposal we wish to establish the dependence of MAC formation on factor H levels within the eye during laser-induced CNV. Our results further demonstrated that regulation of MAC formation by CD59 plays a crucial role in the development of laser-induced CNV. Thus, we propose to explore the effect of recombinant, membrane- targeted CD59 on the growth of CNV complex. Various cytokines and chemokines have been suggested to play a role in AMD pathogenesis and several studies have suggested that the expression of these molecules is affected by the presence of MAC. In the current proposal we intend to investigate the relationship between MAC, cytokines/chemokines and growth factors in mouse model of laser-induced CNV. The specific aims of this proposal are: 1. To investigate the role of factor H, the key regulator of alternative complement pathway in laser- induced CNV - Relationship between factor H and MAC formation. 2. To explore the therapeutic potential of recombinant membrane-targeted form of MAC regulator CD59 in laser-induced CNV. 3. To analyze the relationship between MAC, cytokines/chemokines and angiogenic growth factors in laser-induced CNV. We believe that the proposed studies are essential to gain insights into the pathogenesis as well as the risk factors associated with wet-AMD. Furthermore, these studies will be immensely helpful in the development of effective therapy for AMD based on selective inhibition at the terminal stage of complement activation.