DERMATOREMEDIATION OF IRON OVERLOAD

铁过量的皮肤修复

• 批准号: 6621151
• 负责人: LEONARD M MILSTONE
• 金额: $ 19.79万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6621151
• 关键词: animal breeding; detoxification; excretion; genetically modified animals; human tissue; ion transport; iron metabolism; iron poisoning; keratinocyte; laboratory mouse; metabolism disorder chemotherapy; nifedipine; nonhuman therapy evaluation; skin absorption; skin circulation; tissue /cell culture; topical drug application; transferrin receptor

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.

这项工作的目的是证明可以利用表皮脱落的正常过程来消除体内的全身毒素。 中心假设是，如果可以操纵表皮角质形成细胞积聚全身毒素，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清除。 该提案的重点是修复铁过载。 铁是生命所必需的，但过多的铁会导致血色素沉着症。 需要回答四个关键问题。 首先，是否有药理学或遗传方法可以增加表皮的铁含量？ 其次，角质形成细胞能否积累足够的铁，以期望足够的铁可以通过表皮消除，从而减轻血色素沉着症中过量铁的负担？第三，在铁超负荷模型中，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，表皮可以承受多少过量的铁？ 我们相信我们的初步数据已经对前两个问题做出了肯定的回答。 该提案侧重于第三个问题，有两个具体目标：1）设计增加小鼠表皮铁积累的方法a）通过基因方法创建在表皮中过度表达转铁蛋白受体的转基因小鼠b）通过药理学方法局部应用亚硝基平，a）硝苯地平的衍生物。 2) 测试这些增加表皮铁的方法是否能够减少铁超载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与 Hfe 缺失小鼠交配； b)通过向Hfe缺失小鼠局部施用亚硝基平（硝苯地平的衍生物）。