DERMATOREMEDIATION OF IRON OVERLOAD

这项工作的目的是证明表皮脱屑的正常过程可以被利用来消除全身毒素。中心假设是，如果表皮角质形成细胞可以被操纵来积累系统性的毒素，那么这种毒素将通过这些角质形成细胞的最终脱屑而从体内清除。这个建议的重点是修复铁超载。铁是生命所必需的，但过量的铁会导致血色素沉着症。需要回答四个关键问题。首先，有没有药物或基因的方法来增加表皮的铁含量？其次，角化细胞能否积累足够的铁，从而通过表皮消除足够的铁，从而减轻血色素沉着症中过量铁的负担？第三，在铁超载的模型中，足够的铁能从循环输送到表皮以减少全身铁吗？第四，表皮能承受多少过量的铁，才会出现局部中毒的迹象？我们相信我们的初步数据已经肯定地回答了前两个问题。本研究的重点是第三个问题，并有两个具体目标：1)设计增加小鼠表皮铁积累的方法；a)通过在表皮中创建过表达转铁蛋白受体的转基因小鼠；b)通过局部应用硝苯地平衍生物亚硝索碱的药理学方法。2)测试这些增加表皮铁的方法是否能够减轻铁过载小鼠模型中的铁负荷a)通过将转铁蛋白受体过表达转基因小鼠与Hfe缺失小鼠杂交；b)局部应用硝苯地平的衍生物亚硝基sopine给Hfe小鼠。

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.