DERMATOREMEDIATION OF IRON OVERLOAD

这项工作的目标是证明表皮脱皮的正常过程可以被利用来消除体内的全身毒素。中心假设是，如果表皮角质形成细胞可以被操纵来积累一种全身性毒素，那么这种毒素将通过这些角质形成细胞的最终脱皮从体内被清除。这项建议的重点是补救铁超载。铁是生命所必需的，但过多的铁会导致血色素沉着症。有四个关键问题需要回答。首先，有没有药物或遗传方法来增加表皮的铁含量？其次，角质形成细胞能否积累足够的铁，以期望通过表皮消除足够的铁，以减轻血色素沉着症中预期的过量铁的负担？第三，在铁负荷过重的模型中，是否有足够的铁从循环输送到表皮，以减少全身铁？第四，在出现局部毒性迹象之前，表皮可以耐受多少过量的铁？我们相信，我们的初步数据已经肯定地回答了前两个问题。这项建议侧重于第三个问题，有两个具体目标：1)设计方法，通过创造一种在表皮过度表达转铁蛋白受体的转基因小鼠，从基因上增加小鼠表皮中的铁积累；2)局部应用硝苯地平的衍生物亚硝索平。2)为了测试这些增加表皮铁含量的方法是否能够减少铁超载小鼠的铁负荷，a)通过将转基因转铁蛋白受体过表达的小鼠培育成HFE缺失小鼠；b)对HFE缺失小鼠局部应用硝苯地平的衍生物亚硝索平。

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.