Modifiers of hepcidin expression as new therapies for iron overload

铁调素表达的修饰剂作为铁过载的新疗法

• 批准号: 8185580
• 负责人: PAULA GOODMAN FRAENKEL
• 金额: $ 43.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185580
• 关键词: Address; Adverse effects; Affect; Age; BMP2 gene; Binding; Blood Circulation; Blood Transfusion; Cardiomyopathies; Cause of Death; Chelation Therapy; Chemicals; Child; Chronic; Cooley' s anemia; Dietary Iron; Disease; Dose; Elements; Embryo; Enterocytes; Erythropoiesis; Estrogen Antagonists; Exhibits; Gene Expression; Genetic Transcription; Genistein; Goals; Heart failure; Hemochromatosis; Hemoglobin; Hemoglobinopathies; Hepatocyte; Hereditary Disease; Hereditary hemochromatosis; Homeostasis; Human; Human body; Individual; Inflammation; Inherited; Intestines; Intravenous; Iron; Iron Overload; Lead; Life; Live Birth; Liver Failure; Measures; Modeling; Morphologic artifacts; Mus; New Agents; Oral; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Phytoestrogens; Proteins; RNA Sequences; Regimen; Regulation; Reticuloendothelial System; Severities; Signal Pathway; Signal Transduction; Source; Syndrome; System; Thalassemia; Tissues; Transcript; Transcription factor genes; Transferrin; Transfusion; Venous blood sampling; Zebrafish; absorption; bone morphogenic protein; chromatin immunoprecipitation; compliance behavior; hepcidin; human data; immortalized cell; improved; in vivo; intravenous administration; macrophage; mouse model; novel therapeutic intervention; peptide hormone; prevent; promoter; response; small molecule; small molecule libraries; soy; transcription factor; uptake

DESCRIPTION (provided by applicant): Iron overload syndromes remain important causes of heart and liver failure in patients with thalassemia or hereditary hemochromatosis, which are common genetic diseases worldwide. Current therapy for these conditions includes serial phlebotomy (hemochromatosis) or chelation therapy (thalassemia), both of which are associated with poor patient compliance because of inconvenience and significant side effects. Both thalassemia and hereditary hemochromatosis are associated with inappropriately low levels of hepcidin, the key regulator of intestinal iron absorption and cellular iron storage, resulting in excessive dietary iron absorption. Hepcidin, produced in response to tissue iron loading and inflammation, binds the iron exporter ferroportin1, causing internalization of both proteins and reduced iron release from enterocytes to the circulation and from macrophages to other tissues. We hypothesize that raising hepcidin expression will enhance the efficacy of chelation therapy in thalassemia by reducing dietary iron absorption and promoting storage of iron in the reticuloendothelial system and could eliminate the need for phlebotomy treatment in patients with hemochromatosis. We have previously demonstrated that ferroportin1 is required for iron export and iron cycling through enterocytes and macrophages in zebrafish. We have also demonstrated that the regulation of hepcidin expression in zebrafish embryos resembles that observed in mammalian systems, in that it is responsive to transferrin-bound iron and the BMP pathway. Recently, we have also discovered that treatment with the phytoestrogen, genistein, results in increased hepcidin transcript levels in zebrafish embryos and in human hepatocytes. We propose to screen for additional small molecules that regulate hepcidin expression by conducting a chemical screen in zebrafish embryos. To elucidate the mechanism of action of molecules identified in the screen, we will characterize the modulators' effects on mammalian cellular iron transport, chromatin immunoprecipitation, RNA expression, and signaling pathways. The best candidate regulators will be evaluated in mouse models of thalassemia and hemochromatosis for their effects on iron overload and erythropoiesis. These studies will lead to the identification of molecules and pathways that may be adapted to generate treatments for patients with thalassemia or hereditary hemochromatosis. PUBLIC HEALTH RELEVANCE: Symptomatic hemoglobin disorders, also known as thalassemia major, affect 2.4 per 1000 live births each year. The majority of these patients die from complications of iron accumulation in vital organs. The goal of this project is to identify new therapeutic approaches to prevent and treat the accumulation of iron in patients with thalassemia and other syndromes associated with iron overload.

描述（由申请人提供）：铁超载综合征仍然是地中海贫血或遗传性血色素沉着症患者心力衰竭和肝功能衰竭的重要原因，而地中海贫血或遗传性血色素沉着症是世界范围内常见的遗传病。目前针对这些病症的治疗包括连续放血（血色素沉着症）或螯合疗法（地中海贫血），这两种疗法都因不便和显着副作用而导致患者依从性差。地中海贫血和遗传性血色素沉着症都与铁调素（肠道铁吸收和细胞铁储存的关键调节剂）水平过低有关，导致膳食铁吸收过多。铁调素是响应组织铁负荷和炎症而产生的，它与铁输出蛋白膜转运蛋白 1 结合，导致两种蛋白质的内化，并减少从肠上皮细胞到循环系统以及从巨噬细胞到其他组织的铁释放。我们推测，提高铁调素表达将通过减少膳食铁吸收和促进网状内皮系统中铁的储存来增强地中海贫血螯合疗法的疗效，并且可以消除血色素沉着症患者进行静脉切开术治疗的需要。我们之前已经证明，斑马鱼的铁输出和铁通过肠细胞和巨噬细胞的循环需要铁转运蛋白1。我们还证明，斑马鱼胚胎中铁调素表达的调节与在哺乳动物系统中观察到的类似，因为它对转铁蛋白结合的铁和 BMP 途径有反应。最近，我们还发现，用植物雌激素金雀异黄素治疗会导致斑马鱼胚胎和人类肝细胞中铁调素转录物水平增加。我们建议通过在斑马鱼胚胎中进行化学筛选来筛选调节铁调素表达的其他小分子。为了阐明筛选中鉴定的分子的作用机制，我们将表征调节剂对哺乳动物细胞铁转运、染色质免疫沉淀、RNA 表达和信号传导途径的影响。将在地中海贫血和血色素沉着症小鼠模型中评估最佳候选调节剂对铁超负荷和红细胞生成的影响。这些研究将确定可能适合为地中海贫血或遗传性血色素沉着病患者提供治疗方法的分子和途径。 公共卫生相关性：有症状的血红蛋白疾病（也称为重型地中海贫血）每年影响每 1000 名活产儿中 2.4 人。这些患者大多数死于重要器官铁积聚的并发症。该项目的目标是确定新的治疗方法来预防和治疗地中海贫血和其他与铁超载相关的综合征患者的铁积累。