DERMATOREMEDIATION OF IRON OVERLOAD

这项工作的目标是证明表皮脱落的正常过程可以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以积累全身性毒素，那么该毒素将通过这些角质形成细胞的最终脱落而从体内去除。 该建议的重点是纠正铁超载。 铁是生命所必需的，但过多的铁会导致血色病。 需要回答四个关键问题。 首先，是否有药理学或遗传学方法来增加表皮的铁含量？ 第二，角质形成细胞是否能积累足够的铁，以期望足够的铁可以通过表皮消除，以减轻血色病中预期的过量铁的负担？第三，在铁过载模型中，是否可以将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，表皮能容忍多少过量的铁？ 我们相信我们的初步数据已经肯定地回答了前两个问题。 该提案集中于第三个问题，并具有两个具体目标：1）设计增加小鼠表皮中铁积累的方法a）通过遗传方式产生在表皮中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的衍生物亚硝基平来抑制。2)为了测试这些增加表皮中铁的方法是否能够降低铁超负荷小鼠模型中的铁负荷，a）通过将转基因转铁蛋白受体过表达小鼠培育成Hfe缺失小鼠; B）通过向Hfe缺失小鼠局部施用亚硝基碱（硝苯地平的衍生物）。

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.