Hepcidin therapy for iron overload and hematologic disorders

铁调素治疗铁过载和血液系统疾病

• 批准号: 8145680
• 负责人: TOMAS GANZ
• 金额: $ 61.46万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145680
• 关键词: Agonist; Amino Acids; Anemia; Animal Disease Models; Animal Model; Biological Assay; Blood Circulation; Bone Marrow; C57BL/6 Mouse; Cardiac Myocytes; Cells; Chronic; Congenital dyserythropoietic anemia; Cooley' s anemia; Data; Dependence; Development; Disease; Disulfides; Dose; Drug Delivery Systems; Engineering; Erythropoiesis; Funding; Gerbils; Hematology; Hemochromatosis; Hepatocyte; Hereditary hemochromatosis; Investigation; Iron; Iron Overload; Islet Cell; Islets of Langerhans; Knock-out; Knockout Mice; Liver; Liver Cirrhosis; Location; Mediating; Medical; Modeling; Morbidity - disease rate; Mus; NIH Program Announcements; Oral; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Prevention approach; Relative (related person); Resistance; Route; Series; Structure; Testing; Thalassemia; Thalassemia intermedia; Therapeutic; Tissues; Toxic effect; Transfusion; United States National Institutes of Health; Weaning; absorption; base; drug candidate; hepcidin; improved; iron metabolism; macrophage; metal transporting protein 1; mortality; mouse model; novel; overexpression; pre-clinical; prevent; public health relevance; response

DESCRIPTION (provided by applicant): Iron overload is the main cause of morbidity and mortality in hereditary hemochromatosis, 2-thalassemia and various anemias that require chronic transfusions. Alternatives to current treatments of iron overload are a high priority, as reflected in a recent NIH initiative (PAS-10-046). Hepcidin deficiency is the direct cause of iron overload in nearly all cases of hereditary hemochromatosis and in ?-thalassemia intermedia, and may contribute to iron overload and maldistribution in ?-thalassemia major. Hepcidin therapy is a rational experimental approach to the prevention and treatment of iron overload in these disorders. Natural hepcidin is expensive, rapidly cleared from circulation and not orally absorbable. We developed 7-9 amino acid peptides, "minihepcidins" that mimic the activity of hepcidin and exceed its potency. Some have been engineered for oral absorption, and have shown considerable activity by oral route in mice. We will determine the potential of minihepcidins to prevent iron overload or reverse its toxic effects in hemochromatosis and ?-thalassemia, and examine the effects of hepcidin agonists on ?-thalassemic erythropoiesis in mouse models and in bone marrow cultures and identify those mechanisms that could ameliorate anemia. Specifically, we will: 1. Select a parenteral and an oral minihepcidin for subsequent studies based on the dose-response relationship and duration of hypoferremic effect in C57BL/6 mice and hepcidin knockout mice. 2. Define the effects of minihepcidins in animal models of hereditary hemochromatosis. a. Can minihepcidins started after weaning prevent the development of iron overload in mouse models of severe (hepcidin knockout) or moderate (HFE knockout) hereditary hemochromatosis? b. Can minihepcidin treatment of mice with established iron overload (hepcidin or HFE knockouts) redistribute iron away from vulnerable cells and tissues (hepatocytes, pancreatic islet cells, cardiomyocytes) to relatively iron-resistant macrophages? c. Can minihepcidins reverse iron overload-related liver damage in the gerbil model of iron-induced hepatic cirrhosis? 3. Define the effects of minihepcidins in animal models of ?-thalassemia. a. Can minihepcidins prevent iron overload in a mouse model of ?-thalassemia intermedia, while improving (or not worsening) anemia? b. Can minihepcidins ameliorate iron overload in transfused mice with ?-thalassemia major and redistribute iron to less vulnerable locations, without worsening anemia? c. Identify mechanisms by which minihepcidins can improve ?-thalassemic erythropoiesis. This project would establish minihepcidins as viable drug leads for further development, and would eventually help patients with iron overload disorders by providing them with improved therapeutic options. PUBLIC HEALTH RELEVANCE: Iron overload diseases are an important medical problem in need of new treatments. Building on recent advances in the understanding of iron metabolism, we propose to develop and test new kinds of medications for the treatment of iron overload in hereditary hemochromatosis and Cooley's anemia.

描述（由申请人提供）：铁超负荷是遗传性血色素沉着症，2-甲性质症和各种需要慢性输血的贫血的发病率和死亡率的主要原因。正如最近的NIH计划（PAS-10-046）所反映的那样，当前铁超负荷治疗的替代方案是高度优先级。在几乎所有遗传性血色素症和 - thalassymia Intermedia中，肝素缺乏症是铁超载的直接原因，并且可能导致铁无症主要的铁超负荷和玛尔代分布。肝素治疗是预防和治疗这些疾病中铁超负荷的合理实验方法。天然肝素很昂贵，可以迅速清除循环，而不是口服吸收。我们开发了7-9个氨基酸肽，即模仿肝素活性并超过其效力的“ minhepcidins”。有些已经设计用于口服吸收，并在小鼠中表现出了大量的口腔途径。我们将确定MinHepcidins防止铁超负荷或逆转其在血红素沉着症和the-馆中的毒性作用的潜力，并检查肝素素激动剂对小鼠模型和骨髓培养物中的 - 丘脑血症性红细胞生成的作用，并在骨髓培养物中，并确定可能会减轻脑力甲状腺素的机制。具体而言，我们将：1。根据C57BL/6小鼠和肝素基因敲除小鼠的剂量反应关系和低肥力作用的持续时间，选择肠胃外和口服微米素进行随后的研究。 2。定义了迷你炎症素在遗传性血色素沉着症动物模型中的影响。一个。在断奶后，可以从Minihepcidins开发MinHepcidins，以防止在严重（肝素敲除）或中度（HFE基因敲除）遗传性血色素沉着症的小鼠模型中发展铁超负荷？ b。 Minihepcidin可以用已建立的铁超载（肝素或HFE敲除）对小鼠的治疗，将铁从脆弱的细胞和组织（肝细胞，胰岛胰岛细胞，心肌细胞）中重新分配到相对抗铁的巨噬细胞？ c。在铁诱导的肝肝硬化模型中，MinHihepcidins可以反向铁超载相关的肝脏损伤吗？ 3。定义微炎素在甲性疾病的动物模型中的作用。一个。在改善（或不加重）贫血的同时，MinHihepcidins可以防止thalassemia Intermedia的小鼠模型中的铁超负荷吗？ b。 MinHihepcidins可以用？ - 丘脑大调和将铁重新分配到较小的脆弱位置而不会加重贫血的贫民窟中，可以改善输血小鼠的铁超负荷吗？ c。确定MinHepcidins可以改善的机制？ - 丘脑嗜红细胞肌。该项目将建立Minihepcidins作为可行的药物铅，以进一步发展，并最终通过为他们提供改进的治疗选择来帮助铁超负荷疾病。 公共卫生相关性：铁超负荷疾病是需要新治疗的重要医疗问题。在了解铁代谢方面的最新进展的基础上，我们建议开发和测试新型的药物，以治疗遗传性血色素沉着症和Cooley的贫血中的铁超负荷。