UBC Theses and Dissertations
Polyphosphate : a novel negative regulator of complement and its therapeutic potential in age-related macular degeneration Ocariza, Linnette Mae
The innate mammalian response to injury involves the initiation of activation of two major blood-borne proteolytic systems; coagulation and complement. Recent studies have revealed that there is considerable crosstalk and interplay between these two systems. Polyphosphate (polyP) is a naturally occurring inorganic linear polymer that co-regulates these two systems, acting as a promoter of coagulation and an inhibitor of complement. This thesis aims to further characterize the mechanisms by which polyP regulates the complement system, and to test its physiological relevance in a model of human disease, age-related macular degeneration (AMD), the pathogenesis of which involves excess complement activation and oxidative stress. Based on data from our lab and studies in bacteria that polyP dampens complement activation and interferes with oxidative stress, I hypothesized that polyP would protect against AMD. To test this hypothesis, I used hemolytic assays to measure the complement activity in response to polyP, in vitro studies with AMD-associated cell lines to examine protective properties of polyP, and an in vivo model of AMD to evaluate the therapeutic efficacy of polyP. I showed that polyP dampens complement activation by interfering with the terminal pathway of complement, and that it also interferes with oxidative stress-induced cellular damage. The mechanisms by which it exerts this effect have not yet been determined. However, in vivo, in rodent models of AMD, polyP protects against laser-induced choroidal neovascularization (CNV), a feature of AMD, with reduced deposition of complement. An agent such as polyP, that simultaneously suppresses complement activation and protects against oxidative stress, holds potential therapeutic value. The findings in this thesis raise awareness of the potential importance of a ubiquitous, naturally occurring inorganic compound that has largely been overlooked. Most important, the findings reveal a promising use for polyP as a treatment for AMD, a common and devastating disease that affects millions of people worldwide.
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