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G. Inana, Y. Ishiba, M. J. McLaren; Identification of Causative Genes for AMD: MT1-MMP Fits the Profile. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3005.
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To discover pathogenic genes involved in AMD by identifying genes that 1) are differentially expressed in AMD-affected vs normal eyes, and 2) are also involved in OS phagocytosis by RPE cells.
We hypothesized that genes involved in RPE phagocytosis could play a central role in the pathogenesis of AMD. We constructed a custom ("CHANGE") array of genes expressed in RPE/choroid. The array was screened using RNA samples from 1) human RPE/choroid from normal eyebank eyes, and eyes with AMD pathology, and 2) RPE cells (BPEI-1) undergoing synchronized binding and ingestion of OS in a "living" assay. Differential expression of candidate phagocytosis-related and AMD-related genes was confirmed by northern and western blot analyses, and cellular localization was determined. A conditional over-expression Tg mouse model was constructed for a candidate gene identified by CHANGE, i.e., membrane type-matrix metalloproteinase 1 (MT1-MMP).
MT1-MMP was differentially expressed at various stages of phagocytosis in vitro, peaking around the time of synchronous ROS ingestion. In vivo, MT1-MMP showed peak activity in RPE around the time of light onset. MT1-MMP mRNA levels were progressively increased in AMD in correlation with the severity of the pathology (graded by modified AREDS system). Over-expression of MT1-MMP in adult Tg mice from 1 day to several months resulted in a wide range of pathologies, including hypertrophy of RPE, focal degradation of IPM appearing by LM as "RCS-like" bubbles that displaced OS, RPE atrophy and degeneration, elongation of OS overlying abnormal RPE, proliferation and migration of RPE, invasion of the retina by RBCs and other cell types of the choroid, and possible formation of neovascular membranes.
Over-expression, or dysregulated expression, of MT1-MMP, a gene normally involved in ROS phagocytosis, may be central to the pathogenesis of AMD, providing a new therapeutic target for this disease.
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