Ferristatin: A New Small Molecule Inhibitor of Iron Transport

Ferristatin：一种新的铁转运小分子抑制剂

基本信息

批准号：
7941874
负责人：
Marianne Wessling-Resnick
金额：
$ 39.82万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7941874
关键词：
Address Alleles Anemia Area Binding Biochemical Process Biochemistry Caucasians Caucasoid Race Country Development Diagnostic Dietary Iron Disease Drug Kinetics Emerging Technologies Endosomes Enterocytes Erythroid Erythroid Cells Fluorescence Foundations Genes Genetic Models Goals Health Hemochromatosis Hepatic Hereditary Disease Hereditary hemochromatosis Homeostasis Intestines Iron Iron Overload Iron-Binding Proteins Knockout Mice Knowledge Mediating Modeling National Institute of Diabetes and Digestive and Kidney Diseases Nutritional Pathogenesis Pathway interactions Population Predisposition Rattus Research SLC11A2 gene Screening procedure Serum Therapeutic Transferrin Translating Translational Research Transport Process absorption apical membrane base chemical genetics genetic variant high throughput screening in vivo inhibitor/antagonist novel therapeutics public health relevance receptor mediated endocytosis small molecule tool transport inhibitor uptake

项目摘要

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area 15, Translational Sciences, and specific challenge topic 15-DK-103: Translate discovery of new molecules and pathways in pathogenesis of NIDDK diseases into potential therapies, diagnostics, or research tools. The biochemistry of iron transport is not thoroughly understood. Although iron deficiency is the most prevalent nutritional problem in the U.S., 1 in 20 Caucasians carry genetic variants of HFE alleles that promote susceptibility to iron overload. Thus, there is a need to develop new therapeutic strategies for diseases of both iron deficiency and overload. Through high-throughput fluorescence-based screening, our lab recently discovered that ferristatin (NSC306711) inhibits both of the major iron transport processes that maintain homeostasis: transferrin- mediated iron uptake and non-transferrin-bound iron uptake by Divalent Metal Transporter 1 (DMT1). Chlorazol black (NSC8679) is structurally similar and has comparable effects on transport. This project will further investigate the impact of these two small molecules and related compounds in vivo, on a) pharmacokinetics of intestinal iron uptake to the vasculature; b) iron uptake into erythroid cells and hepatic non-transferrin bound iron uptake; and c) iron homeostasis and reversal of overload. These efforts will further our goals to elucidate the biochemical processes regulating iron homeostasis, and to provide a foundation for the development of targeted small-molecule therapies for states of anemia and hemochromatosis. PUBLIC HEALTH RELEVANCE: Iron deficiency remains the most prevalent nutritional problem in our country, yet recent identification of the gene responsible for hereditary hemochromatosis indicates that 1 in 20 Caucasians carry the defective allele and thus 1 in 400 may be susceptible to iron overload. Increased knowledge about the transport factors and how they protect against iron deficiency and overload is essential to more broadly address these significant health problems.

描述（由申请人提供）：此申请解决了广泛的挑战领域15，转化科学和特定挑战主题15-DK-103：在NIDDK疾病的发病机理中转化新分子和途径的发现，为潜在的治疗疗法，诊断或研究工具。铁运输的生物化学尚未完全理解。尽管铁缺乏症是美国最普遍的营养问题，但20名高加索人中有1个具有HFE等位基因的遗传变异，可促进铁超载的易感性。因此，有必要为铁缺乏症和超负荷的疾病制定新的治疗策略。通过基于高通量荧光的筛选，我们的实验室最近发现，铁脂蛋白（NSC306711）抑制了维持体内稳态的主要铁运输过程：转铁蛋白介导的铁摄取和非转移蛋白结合的铁摄取，并通过占卜的金属转运蛋白1（DMT1）（DMT1）。白藻黑色（NSC8679）在结构上相似，对运输具有可比的影响。该项目将进一步研究这两个小分子和相关化合物在体内的影响，对a）肠铁吸收对脉管系统的药代动力学； b）铁摄取进入红细胞细胞和肝非转移蛋白结合的铁摄取； c）铁稳态和超负荷的逆转。这些努力将进一步阐明调节铁稳态的生化过程，并为开发靶向小分子疗法的贫血和血糖症状态提供基础。公共卫生相关性：铁缺乏症仍然是我国最普遍的营养问题，但最近对负责遗传性血色素沉着症的基因的鉴定表明，有1只高加索人携带缺陷的等位基因，因此400中的1个可能容易受到铁超载的影响。对运输因素及其防御能力缺乏和超负荷的越来越多的知识对于更广泛地解决这些重大健康问题至关重要。