权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
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
项目类别：
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

项目摘要

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.

摘要