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: 9176092
• 负责人: YATRIK M SHAH
• 金额: $ 34.15万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176092
• 关键词: Anemia; Apical; Area; Cues; Cytochromes b; Data; Dietary Iron; Disease; Disease model; Erythropoiesis; Ferritin; Foundations; Gene Targeting; Genes; Genomics; Goals; Health; Hematological Disease; Hemochromatosis; Hepatic; Hereditary hemochromatosis; Heredity; Homeostasis; Hypoxia; Hypoxia Inducible Factor; In Vitro; Inflammatory; Intestinal Absorption; Intestines; Iron; Iron Metabolism Disorders; Iron Overload; MADH3 gene; Mediator of activation protein; Modeling; Monitor; Mus; Nuclear; Patients; Play; Pregnancy; Proteins; Regulation; Research; Resistance; Response Elements; Role; SLC11A2 gene; Sickle Cell Anemia; Signal Transduction; Smad Proteins; Small Intestines; Testing; Thalassemia; Therapeutic; Tissues; Work; absorption; bHLH-PAS factor HLF; base; beta Thalassemia; hepcidin; high throughput screening; improved; in vivo; inhibition of autophagy; inhibitor/antagonist; intestinal epithelium; iron deficiency; metal transporting protein 1; mouse model; novel; novel therapeutic intervention; promoter; receptor; response; screening; therapeutic target; transcription factor

ABSTRACT Dysregulation of intestinal iron absorption is a primary feature in iron overload disorders. Hypoxia-inducible factor 2 (HIF2) is a critical regulator of iron absorption during increased systemic iron demands (i.e. iron deficiency, erythropoiesis, and pregnancy). HIF2 regulates expression of the apical iron transport machinery, divalent metal transporter 1 (DMT-1) and duodenal cytochrome b (Dcytb), and regulates the basolateral iron exporter ferroportin independent of hepcidin, the master systemic regulator of iron homeostasis. Disrupting intestinal HIF2 decreases tissue iron accumulation in iron overload disorders, such as -thalassemia and heredity hemochromatosis. Moreover, in -thalassemia, disruption of intestinal HIF2 also improves anemia. This has laid the foundation for HIF2-based therapeutics for -thalassemia and heredity hemochromatosis, an area actively being researched by Peloton Therapeutics. Although our results demonstrate a central role for HIF2 in intestinal iron absorption, the underlying mechanisms behind its overlapping and distinct roles in iron deficiency, -thalassemia, and heredity hemochromatosis are still unclear. We hypothesize that a decrease in systemic hepcidin triggers HIF2 activation in intestinal epithelia, leading to an iron-absorptive response, which is critical for tissue iron accumulation in iron overload disorders. Our long-term goals are to improve existing HIF2-based therapies and identify novel HIF2-based therapies in iron-related disorders. The major goal of this proposal is to assess the precise mechanisms by which HIF2 selectively regulates iron absorption and determine if inhibition of HIF2 signaling and downstream mediators can be used to restrict tissue iron overload. We will pursue our objectives through three interconnected Specific Aims. Aim 1 will identify mechanisms leading to rapid activation of HIF2 in hereditary hemochromatosis. Our data suggest a crosstalk between the systemic iron regulator, hepcidin, and intestinal HIF2. This concept will be tested in novel mouse models that allow us to acutely and temporally regulate the hepcidin-ferroportin axis. Aim 2 will characterize precise mechanisms leading to an iron-absorptive HIF2 response. We have identified mothers against decapentaplegic homolog 3 (SMAD3) as a novel factor that is essential for expression of iron- absorptive (but not glycolytic, angiogenic, or inflammatory) HIF2 target genes. We will elucidate the specific role and underlying mechanisms behind SMAD3 regulation of HIF2 signaling. Aim 3 will assess the requirement for HIF2-induced intestinal ferritinophagy in systemic iron homeostasis and iron overload disorders. Nuclear coactivator-4 (NCOA4), the major regulator of ferritinophagy, is directly regulated by HIF2 and is highly induced in iron deficiency, -thalassemia, and heredity hemochromatosis. We will examine the role that autophagic ferritin turnover plays in iron absorption using novel mouse models. Together, the proposed in vivo and in vitro studies will identify fundamental roles of HIF2 in iron absorption and iron overload disorders and lay the foundation for pursuing new therapeutic strategies targeting HIF2.

抽象的 肠道铁吸收失调是铁过载疾病的主要特征。缺氧诱导 因子 2 (HIF2) 是全身铁需求增加期间铁吸收的关键调节剂（即铁 缺乏、红细胞生成和妊娠）。 HIF2 调节顶端铁转运机制的表达， 二价金属转运蛋白 1 (DMT-1) 和十二指肠细胞色素 b (Dcytb)，并调节基底外侧铁 输出铁转运蛋白独立于铁调素，铁调素是铁稳态的主要系统调节剂。扰乱 肠道 HIF2 会减少铁超载疾病（例如  地中海贫血和 遗传性血色病。此外，在 β 地中海贫血中，肠道 HIF2α 的破坏也能改善贫血。 这为基于 HIF2α 的 β 地中海贫血和遗传性血色素沉着病的治疗奠定了基础， Peloton Therapeutics 正在积极研究这一领域。尽管我们的结果表明了其核心作用 HIF2α在肠道铁吸收中的作用及其在铁中重叠和独特作用背后的潜在机制 缺乏症、-地中海贫血和遗传性血色素沉着症仍不清楚。我们假设减少 全身性铁调素触发肠上皮细胞中的 HIF2α 激活，从而导致铁吸收 反应，这对于铁过载疾病中的组织铁积累至关重要。我们的长期目标 旨在改善现有的基于 HIF2α 的疗法，并在铁相关疾病中识别新的基于 HIF2α 的疗法 失调。该提案的主要目标是评估 HIF2 选择性地发挥作用的精确机制 调节铁吸收并确定是否可以抑制 HIF2α 信号传导和下游介质 用于限制组织铁过载。我们将通过三个相互关联的具体目标来实现我们的目标。 目标 1 将确定导致遗传性血色素沉着病中 HIF2α 快速激活的机制。我们的数据 表明全身性铁调节剂、铁调素和肠道 HIF2α 之间存在串扰。这个概念将是 在新型小鼠模型中进行了测试，使我们能够快速、暂时地调节铁调素-铁转运蛋白轴。 目标 2 将描述导致铁吸收 HIF2α 反应的精确机制。我们已经确定 母亲反对十五麻痹同源物 3 (SMAD3) 作为铁表达所必需的新因子 吸收性（但不是糖酵解、血管生成或炎症）HIF2α 靶基因。我们将具体阐明 SMAD3 调节 HIF2α 信号传导的作用和潜在机制。目标 3 将评估 HIF2α诱导的肠道铁蛋白自噬在全身铁稳态和铁过载中的需要 失调。核辅激活因子 4 (NCOA4) 是铁蛋白自噬的主要调节因子，受 HIF2 直接调节 在缺铁、-地中海贫血和遗传性血色素沉着症中高度诱发。我们将检查 使用新型小鼠模型研究自噬铁蛋白周转在铁吸收中的作用。在一起， 拟议的体内和体外研究将确定 HIF2α 在铁吸收和铁中的基本作用 超负荷疾病，并为寻求针对 HIF2α 的新治疗策略奠定基础。