The goal of this work is to demonstrate that the normal process of epidermal desquamation can be harnessed to eliminate systemic toxins from the body. The central hypothesis is that if epidermal keratinocytes can be manipulated to accumulate a systemic toxin, then that toxin will be removed from the body by the eventual desquamation of those keratinocytes. This proposal focuses on remediating iron overload. Iron is essential for life, but too much iron causes the disease hemochromatosis. Four key questions need to be answered. First, are there pharmacological or genetic ways to increase iron content of epidermis? Second, can keratinocytes accumulate sufficient iron to expect that enough iron could be eliminated through epidermis to ease the burden of excess iron expected in hemochromatosis? Third, can sufficient iron be delivered from the circulation to the epidermis to reduce systemic iron in a model of iron overload? Fourth, how much excess iron can the epidermis tolerate before showing signs of local toxicity? We believe our preliminary data have answered the first two questions in the affirmative. This proposal focuses on the third question and has two specific aims: 1) to devise methods to increase iron accumulation in mouse epidermis a) genetically by creating a transgenic mouse that overexpresses the transferrin receptor in epidermis b) pharmacologically by topical application of nitrosopine, a derivative of nifedipine. 2) to test whether these methods of increasing iron in epidermis are able to reduce the iron burden in a mouse model of iron overload a) by breeding the transgenic, transferrin receptor overexpressor mouse to Hfe null mice; b) by topical application of nitrosopine, a derivative of nifedipine, to Hfe null mice.
| Milstone, Leonard M; Hu, Rong-Hua; Dziura, James D et al. (2012) Impact of epidermal desquamation on tissue stores of iron. J Dermatol Sci 67:9-14 |
| Milstone, Leonard M; Adams, Brian D; Zhou, Jing et al. (2006) Stratum-specific expression of human transferrin receptor increases iron in mouse epidermis. J Invest Dermatol 126:648-52 |
| Adams, Brian D; Lazova, Rossitza; Andrews, Nancy C et al. (2005) Iron in skin of mice with three etiologies of systemic iron overload. J Invest Dermatol 125:1200-5 |
