Novel Mouse Models of Age-Related Macular Degeneration

  • Ambati, Jayakrishna (PI)

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Description

Age related macular degeneration (AMD) is the leading cause of irreversible blindness in industrialized nations, affecting 30-50 million people worldwide. The earliest clinical hallmark of AMD is the presence of drusen, extracellular deposits that accumulate beneath the retinal pigmented epithelium (RPE). Although drusen nearly always precede and increase the risk of choroidal neovascularization (CNV), the late vision-threatening stage of AMD, it is not known whether drusen contribute to the development ofCNV. Both in patients with AMD and in a recently described mouse model, early sub-RPE deposition of complement components C3 and C5 has been demonstrated, suggesting a contributing role for these inflammatory proteins in the development of AMD. Here we show that C3 and C5 induce vascular endothelial growth factor (VEGF) expression in vivo. Further we demonstrate that C3 and C5 are expressed early in the course oflaser-induced CNV, an accelerated model ofneovascular AMD driven by VEGF and recruitment of leukocytes into the choroid. We also show that genetic ablation of receptors for activated C3 and C5 reduces VEGF expression, leukocyte recruitment, and CNV formation following laser injury. Collectively these findings establish a mechanistic basis for the clinical observation that drusen predispose to CNV, both revealing a novel role for immunological phenomena in angiogenesis and providing new therapeutic targets for AMD.
StatusFinished
Effective start/end date6/1/045/31/10

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