P5C reductase, retroviral transfection, Toxicity Assay, Intracellular Proline Concentration
metabolic disease include night blindness, myopia, cataracts, and progressive reduction in peripheral vision culminating in blindness by the age of forty. The loss of OAT leads to high plasma levels of the amino acid ornithine and low levels of proline and creatine (Valle & Simell, 2001). Our knowledge about the pathophysiology of GA is very limited: we do not know the mechanism for toxicity or the primary toxic species. However, we do know the following: first, the initial cells affected are the retinal pigmented epithelial (RPE) cells (Wang et al., 1996); second, ornithine enters the cells primarily through the cationic amino acid transporter (CAT)-1 (Kaneko et al., 2007); third, lowering plasma levels of ornithine prevents the progression of the disease (Wang et al., 2000). . . . Based on the research by Ueda and colleagues (1998), I will investigate the toxic effect of low proline levels in human RPE cells. I will render the cells incapable of biosynthesizing proline, which will enable me to control the level of proline in the cell by varying its concentration in the serum. Secondly, I will vary the intracellular proline levels and correlate any toxicity observed with the amount of proline inside the cell. If low levels of intracellular proline cause toxicity, cell death should be independent of OAT activity but inversely proportional to the level of proline in the cell. It is therefore unnecessary to mimic the Ueda et al study and inhibit OAT in the cells (1998).
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