Dermatoremediation of Iron Overload

铁过量的皮肤修复

• 批准号: 7142329
• 负责人: LEONARD M MILSTONE
• 金额: $ 31.24万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142329
• 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

DESCRIPTION (provided by applicant): 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. This proposal focuses on iron as a model toxin. Iron is essential for life, but too much iron causes the disease hemochromatosis. Normally, 20% of absorbed iron is eliminated through epidermal desquamation. The central hypothesis is that if epidermis can be made to act as a sink for internal iron, then epidermal shedding might reduce the body burden of iron. AIM I. tests the feasibility of this approach by experiments designed to reduce the systemic iron burden in the Hfe null mouse model of heriditary hemochromatosis. A. We will cause epidermis to act as a sink or sponge for iron and then measure the effect on iron stores in internal organs: 1. by breeding experiments leading to over-expression of the transferrin receptor in epidermis; 2. by topical application of iron ionophores or iron chelators; B. We will accelerate cutaneous iron loss through increased epidermal turnover and desquamation: 1. by breeding experiments leading to over-expression of the viral E7 protein in epidermis; 2. by systemic administration of a synthetic retinoid; AIM II investigates the physiology and pathophysiology of iron in mouse keratinocyte cultures and in mouse epidermis. The goal is to identify better ways of causing epidermis to act as a sink for iron and to test whether elevated iron in epidermis is toxic. A. We will identify additional ways to increase iron accumulation in epidermis 1. by characterizing expression and function of iron export protein ferroportin in epidermis; 2. by using hepcidin to regulate expression of ferroportin; B. We will evaluate whether epidermal iron increases the risk for phototoxicity, DNA mutagenesis or skin cancer, using our transgenic mice in which iron accumulation is restricted to epidermis. Relevance: This proposal represents a novel approach to the elimination of systemic toxins by causing them to be shed from the skin surface. By focusing on iron, it also will provide basic new information to fill existing gaps in knowledge about the physiology and pathophysiology of iron in the epidermis. Since iron is increasingly suspected of having a role in inflammatory and neoplastic diseases of skin, this new information should assist in devising preventative and treatment measures for those types of diseases.

描述（由申请人提供）：这项工作的目标是证明表皮脱屑的正常过程可以用来消除体内的全身毒素。该建议将铁作为模型毒素。铁是生命所必需的，但过多的铁会导致血色病。正常情况下，20%的吸收铁通过表皮脱落消除。核心假设是，如果表皮可以作为内部铁的水槽，那么表皮脱落可能会减少铁的身体负担。 AIM岛通过设计用于减少遗传性血色病的Hfe缺失小鼠模型中的全身铁负荷的实验来测试这种方法的可行性。 A.我们将使表皮充当铁的水槽或海绵，然后测量对内脏中铁储存的影响： 1.通过繁殖实验导致表皮中转铁蛋白受体的过度表达; 2.通过局部施用铁离子载体或铁螯合剂; B。我们将通过增加表皮更新和脱屑来加速皮肤铁流失： 1.通过繁殖实验导致病毒E7蛋白在表皮中过表达; 2.通过全身施用合成类维生素A; 目的研究铁在小鼠角质形成细胞培养物和小鼠表皮中的生理和病理生理。目的是确定更好的方法，使表皮作为铁的水槽，并测试表皮中升高的铁是否有毒。 A.我们将确定增加表皮铁积累的其他方法 1.通过表征铁输出蛋白ferroportin在表皮中的表达和功能; 2.利用铁调素调控膜铁转运蛋白的表达; B。我们将评估表皮铁是否增加光毒性，DNA诱变或皮肤癌的风险，使用我们的转基因小鼠，其中铁的积累仅限于表皮。 相关性：该提案代表了一种通过使全身毒素从皮肤表面脱落来消除全身毒素的新方法。通过关注铁，它还将提供基本的新信息，以填补有关铁在表皮中的生理学和病理生理学知识的现有空白。由于铁越来越多地被怀疑在皮肤炎症和肿瘤疾病中发挥作用，这一新信息应有助于为这些类型的疾病制定预防和治疗措施。