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: 8607546
• 负责人: YATRIK M SHAH
• 金额: $ 33.28万
• 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 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607546
• 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; 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（由申请人提供）：铁超负荷是遗传性血色素沉着病和β-丘无血症患者死亡率和发病率的主要原因。需要采用新方法来预防和治疗这些疾病。铁的肠度超吸收是导致组织铁超负荷的关键机制，并且抑制肠道吸收是潜在的靶标。低氧诱导因子（HIF）是由α-亚基（HIF1-ALPHA或HIF2-ALPHA）组成的异二聚体转录因子和β-亚基（Aryl碳氢化合物核转运剂（ARNT）。使用HIF信号的基因和细胞的遗传型，我们已经表现出了iNFIRESTICAL HEESTIRAL WEESTIRESTIRAL WEIF 2-2-AS A IS A IS A IS A IS A IS A IS A IS A IS A IS A IS A IS A IS A IS A iS AM ARM PROPHATION。 HIF2-Alpha（但不是HIF1-Alpha）是调节肠道吸收基因所需的中心转录因子，并且在遗传性血流量病和β-杂菌症的小鼠模型中会增加。 HIF2-Alpha诱导的铁吸收在铁超负荷和血液学疾病的发病机理中至关重要，并提出了一种新的治疗目标。我们将通过四个相互联系的特定目标来追求我们的目标。 AIM 1将确定在铁超负荷和血液学疾病期间激活肠道HIF2-α的机制。这将在肠道衍生的细胞系和HFE - / - ，HBBTH3/+和HBBTH3/TH3模型的遗传性血糖症，β-丘脑中核中介质和Cooley的Anemia（Beta-Thalassemia Major）的HBBTH3/TH3模型中进行了检查。 AIM 2将评估HIF2-Alpha铁吸收基因激活的分子机制。这将通过启动子分析来检查，重点是HIF2-Alpha铁吸收靶基因。该目标还将使用全基因组启动子结合研究在十二指肠组织中的遗传性血色素沉着症和β-丘脑甲状腺肿的小鼠模型中使用全基因组启动子结合研究来鉴定HIF2-Alpha的新型靶基因。 AIM 3和4将确定在血色素沉着症和β-甲0ALASBALSASSCH的小鼠模型中组织铁超载进展中HIF2-Alpha的要求。这将在HFE - / - ，HBBTH3/+和HBBTH3/TH3鼠标模型中进行检查，该模型包含肠中HIF2-Alpha的有条件破坏。这些研究的成功完成将提高我们对肠道吸收如何受到调节的理解，并为在铁超负荷和血液学疾病患者中寻求新的治疗策略奠定了基础。