Dermatoremediation of Iron Overload

铁过量的皮肤修复

• 批准号: 7469571
• 负责人: LEONARD M MILSTONE
• 金额: $ 31.18万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469571
• 关键词: Address; Blood; Blood Circulation; Body Burden; Breeding; Chelating Agents; Class; Cutaneous; DNA; Disease; Epidermis; Functional disorder; Funding; Genes; Genetic; Genetic Engineering; Goals; Hemochromatosis; Hereditary hemochromatosis; Homeostasis; Human; Hydroxamic Acids; Inflammatory; Ionophores; Iron; Iron Overload; Iron-Regulatory Proteins; Knockout Mice; Knowledge; Life; Liver; Measures; Methods; Modeling; Mus; Mutagenesis; Nifedipine; Organ; Papillomavirus Transforming Protein E7; Phototoxicity; Physiology; Porifera; Process; Protein Export Pathway; Rate; Regulation; Research Personnel; Response Elements; Retinoids; Risk; Role; SLC11A2 gene; Skin; Skin Cancer; Standards of Weights and Measures; Surface; Testing; Tissues; Topical application; Toxic effect; Toxin; Transferrin; Transferrin Receptor; Transgenes; Transgenic Mice; Translating; UVB induced; Work; base; chemical carcinogenesis; design; divalent metal; expectation; hepcidin; human WNT2 protein; involucrin; keratinocyte; metal transporting protein 1; mouse model; neoplastic; novel strategies; programs; research study; skin disorder; tool

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皮的正常过程可以被利用来消除体内的全身毒素。这项提议的重点是铁作为一种模型毒素。铁是生命所必需的，但过多的铁会导致血色素沉着症。正常情况下，20%被吸收的铁通过表皮脱屑被清除。中心假设是，如果表皮可以充当体内铁的接收器，那么表皮脱落可能会减少体内铁的负担。 目的一、通过减少遗传性血色素沉着症HFE基因缺失小鼠模型全身铁负荷的实验，验证该方法的可行性。 答：我们会让表皮充当铁的水槽或海绵，然后测量它对体内器官铁储存的影响： 1.通过育种实验导致转铁蛋白受体在表皮中过度表达； 2.局部使用铁离子载体或铁络合剂； B.我们将通过增加表皮周转率和脱屑来加速皮肤铁流失： 1.通过育种实验导致病毒E7蛋白在表皮中过度表达； 2.全身注射合成维甲酸； 目的研究铁在培养的小鼠角质形成细胞和小鼠表皮中的生理学和病理生理学。其目的是找出更好的方法来使表皮充当铁的接收器，并测试表皮中升高的铁是否有毒。 答：我们将寻找其他方法来增加表皮中铁的积累。 1.研究铁输出蛋白铁蛋白在表皮中的表达和功能； 2.用海普西丁调节铁蛋白的表达； B.我们将使用我们的转基因小鼠来评估表皮铁是否会增加光毒性、DNA突变或皮肤癌的风险，在转基因小鼠中，铁的积累仅限于表皮。 相关性：这项建议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。通过对铁的关注，它还将提供基本的新信息，以填补关于表皮中铁的生理学和病理生理学知识的现有空白。由于越来越多的人怀疑铁在皮肤的炎症性和肿瘤性疾病中起作用，这一新的信息应该有助于为这些类型的疾病制定预防和治疗措施。