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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由申请人提供）：铁超负荷是遗传性血色素沉着病和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。肠道对铁的过度吸收是导致组织铁超载的关键机制，抑制肠道铁吸收是一个潜在的目标。缺氧诱导因子 (HIF) 是异二聚体转录因子，由 α 亚基（HIF1-α 或 HIF2-α）和 β 亚基（芳烃核转位子 (ARNT)）组成。使用 HIF 信号传导的遗传小鼠模型和细胞系，我们已经证明肠道 HIF2-α 是铁吸收的关键调节因子，最近我们证明 HIF2-α（但不是 HIF1-α）是调节肠道铁所需的核心转录因子。此外，肠道特异性 HIF-α 过度表达的小鼠会出现自发性铁超载，根据这些观察，我们推测肠道 HIF2-α 诱导的铁吸收至关重要。铁过载和血液疾病的发病机制，并提出了一个新的治疗靶点。拟议研究的长期目标是阐明 HIF2-α 如何调节肠道的精确机制。铁的吸收推动了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。目标 1 将确定肠道 HIF2-α 在铁超载和血液疾病期间被激活的机制。这将分别在遗传性血色素沉着症、中间型β地中海贫血和库利贫血（重型β地中海贫血）的肠源性细胞系和 Hfe-/-、Hbbth3/+ 和 Hbbth3/th3 模型中进行检查。目标 2 将评估 HIF2-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 HIF2-α 铁吸收靶基因。该目标还将利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 HIF2-α 的新靶基因。目标 3 和 4 将确定血色素沉着病和 β 地中海贫血小鼠模型中组织铁超载进展中对 HIF2-α 的需求。这将在 Hfe-/-、Hbbth3/+ 和 Hbbth3/th3 小鼠模型中进行检查，这些模型含有肠道中 HIF2-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如何调节的理解，并为铁过载和血液疾病患者寻求新的治疗策略奠定基础。