Control of iron absorption by intestinal HIF2 in iron and hematological disorders

铁和血液系统疾病中肠道 HIF2 控制铁吸收

• 批准号: 8824526
• 负责人: YATRIK M SHAH
• 金额: $ 33.27万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824526
• 关键词: ARNT protein; Binding; Cell Line; Clinical Management; Cooley' s anemia; Data; Development; Dietary Iron; Disease; Foundations; Gene Activation; Gene Targeting; Genes; Genetic; Goals; HIF1A gene; Hematological Disease; Hemochromatosis; Hereditary Disease; Hereditary hemochromatosis; Hypoxia; Hypoxia Inducible Factor; Intestinal Absorption; Intestines; Iron; Iron Metabolism Disorders; Iron Overload; Life; Measures; Modeling; Molecular; Morbidity - disease rate; Mus; Nuclear; Oxygen; Pathogenesis; Patients; Prevention; Procollagen-Proline Dioxygenase; Protein Isoforms; Public Health; Regimen; Response Elements; Role; Signal Transduction; Small Intestines; Specificity; Substrate Specificity; Tertiary Protein Structure; Thalassemia; Thalassemia intermedia; Tissues; Work; absorption; base; beta Thalassemia; genome-wide; hypoxia inducible factor 1; mortality; mouse model; novel; novel strategies; novel therapeutics; overexpression; prevent; promoter; targeted treatment; therapeutic development; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Iron overload is the main cause of mortality and morbidity in patients with hereditary hemochromatosis and beta-thalassemia. There is a need for new approaches to prevent and treat these diseases. Intestinal hyperabsorption of iron is a critical mechanism leading to tissue iron overload, and inhibiting intestinal iron absorption presents a potential target. Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors consisting of an alpha-subunit (HIF1-alpha or HIF2-alpha) and beta-subunit (aryl hydrocarbon nuclear translocator (ARNT). Using genetic mouse models and cell lines of HIF signaling, we have shown that intestinal HIF2-alpha is a critical regulator of iron absorption. More recently we demonstrate that HIF2-alpha (but not HIF1-alpha) is the central transcription factor required for regulating intestinal iron absorptive genes and is robustly increased in mouse models of hereditary hemochromatosis and beta-thalassemia. Moreover, intestine-specific HIF-alpha overexpressing mice develop spontaneous iron overload. Based on these observations, we hypothesize that intestinal HIF2-alpha-induced iron absorption is critical in the pathogenesis of iron overload and hematological disorders and presents a novel target for therapy. The long-term objectives of the proposed studies are to elucidate precise mechanisms of how HIF2-alpha regulates intestinal iron absorption as an impetus to the development of therapeutic regimens that can be used to treat hemochromatosis and beta-thalassemia. We will pursue our objectives through four interconnected Specific Aims. Aim 1 will determine mechanisms by which intestinal HIF2-alpha is activated during iron overload and hematological disorders. This will be examined in intestinal-derived cell lines and Hfe-/-, Hbbth3/+, and Hbbth3/th3 models of hereditary hemochromatosis, beta-thalassemia intermedia, and Cooley's anemia (beta-thalassemia major), respectively. Aim 2 will assess the molecular mechanisms of iron absorptive gene activation by HIF2-alpha. This will be examined by promoter analysis with a focus on HIF2-alpha iron absorptive target genes. This Aim will also identify novel target genes of HIF2-alpha using genome-wide promoter binding studies in duodenal tissues from mouse models of hereditary hemochromatosis and beta-thalassemia. Aims 3 and 4 will determine the requirement for HIF2-alpha in the progression of tissue iron overload in mouse models of hemochromatosis and beta-thalassemia. This will be examined in Hfe-/-, Hbbth3/+, and Hbbth3/th3 mouse models that contain a conditional disruption of HIF2-alpha in the intestine. Successful completion of these studies will increase our understanding of how intestinal iron absorption is regulated, and lays the foundation for pursuing new therapeutic strategies in patients with iron overload and hematological disorders.

描述（由申请方提供）：铁超负荷是遗传性血色病和β地中海贫血患者死亡和发病的主要原因。需要新的方法来预防和治疗这些疾病。肠道铁吸收过度是导致组织铁超载的重要机制，抑制肠道铁吸收是一个潜在的靶点。低氧诱导因子（HIF）是由α亚基（HIF 1-α或HIF 2-α）和β亚基（芳烃核转运蛋白（ARNT））组成的异二聚体转录因子。使用遗传小鼠模型和HIF信号传导的细胞系，我们已经表明肠道HIF 2-α是铁吸收的关键调节因子。最近，我们证明了HIF 2-α（而不是HIF 1-α）是调节肠道铁吸收基因所需的中央转录因子，并在遗传性血色素沉着症和β地中海贫血的小鼠模型中显著增加。此外，精氨酸特异性HIF-α过表达小鼠发生自发性铁过载。基于这些观察结果，我们假设肠道HIF 2-α诱导的铁吸收在铁过载和血液系统疾病的发病机制中至关重要，并提出了一种新的治疗靶点。拟议研究的长期目标是阐明HIF 2-α如何调节肠道铁吸收的精确机制，以推动可用于治疗血色素沉着症和β地中海贫血的治疗方案的开发。我们将通过四个相互关联的具体目标来实现我们的目标。目的1将确定铁过载和血液系统疾病期间肠道HIF 2-α被激活的机制。这将分别在生殖细胞衍生的细胞系和遗传性血色病、中间型β地中海贫血和库利贫血（重型β地中海贫血）的Hfe-/-、Hbbth 3/+和Hbbth 3/th 3模型中进行检查。目的2探讨HIF 2-α激活铁吸收基因的分子机制。这将通过启动子分析进行检查，重点是HIF 2-α铁吸收靶基因。本目标还将使用遗传性血色素沉着症和β-地中海贫血小鼠模型的十二指肠组织中的全基因组启动子结合研究来鉴定HIF 2-α的新靶基因。目的3和4将确定在血色素沉着症和β-地中海贫血小鼠模型中组织铁过载进展中对HIF 2-α的需求。这将在Hfe-/-、Hbbth 3/+和Hbbth 3/th 3小鼠模型中进行检查，这些小鼠模型含有肠中HIF 2-α的条件性破坏。这些研究的成功完成将增加我们对肠道铁吸收是如何调节的理解，并为在铁过载和血液病患者中寻求新的治疗策略奠定基础。