Iron-induced Complement Dysregulation in the Retinal Pigment Epithelium: Implications for Age-Related Macular Degeneration

摘要: Age-related macular degeneration (AMD), typically manifesting as a loss of central vision in elderly persons, is leading cause blindness highly developed nations. AMD multifactorial disease associated with aging, oxidative stress, complement dysregulation, dsRNA toxicity, among many other possible factors. The formation extracellular deposits, termed drusen, below the retinal pigment epithelial (RPE) cell layer outer retina pathognomonic hallmark AMD. composition drusen complex, but identified elements include iron, components, and amyloid protein derivatives. This suggests that iron may be involved pathophysiology Further support for this hypothesis comes from mice lacking ferroxidases Ceruloplasmin (Cp) Hephaestin (Heph), which have primary genetic defect homeostasis. These develop some AMD-like morphological features telling molecular feature: activated component 3 (C3) fragment deposition at basolateral aspect RPE (the location AMD). In our studies, we investigated mechanisms by C3 upregulated cells. ERK1/2, SMAD3, CCAAT/enhancer-binding protein-δ (C/EBP-δ) are part non-canonical TGF-β signaling pathway responsible iron-induced expression. Pharmacologic inhibition either ERK1/2 or SMAD3 phosphorylation decreased expression levels. Knockdown blocked up-regulation nuclear accumulation C/EBP-δ, transcription factor known to promote binding basic leucine zipper (bZIP1) domain gene promoter. We show herein mutation reduced promoter activity. events iron-C3 represent therapeutic targets To better understand relative contribution systemic local dysregulation homeostasis accumulation, used Bmp6 KO WT found hepcidin levels not changed, fact slightly greater compared mice. As such, overload intravenous supplementation resulted increased labile suggesting lead despite presence an intact blood barrier. Systemic status appears determinant status. Degree Type Dissertation Name Doctor Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Joshua L. Dunaief