Control of iron absorption by intestinal HIF2 in iron and hematological disorders
Control of iron absorption by intestinal HIF2 in iron and hematological disorders
批准号:
9176092
负责人:
YATRIK M SHAH
金额:
$34.15万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-04-01 至 2021-05-31
关键词:
AnemiaApicalAreaCuesCytochromes bDataDietary IronDiseaseDisease modelErythropoiesisFerritinFoundationsGene TargetingGenesGenomicsGoalsHealthHematological DiseaseHemochromatosisHepaticHereditary hemochromatosisHeredityHomeostasisHypoxiaHypoxia Inducible FactorIn VitroInflammatoryIntestinal AbsorptionIntestinesIronIron Metabolism DisordersIron OverloadMADH3 geneMediator of activation proteinModelingMonitorMusNuclearPatientsPlayPregnancyProteinsRegulationResearchResistanceResponse ElementsRoleSLC11A2 geneSickle Cell AnemiaSignal TransductionSmad ProteinsSmall IntestinesTestingThalassemiaTherapeuticTissuesWorkabsorptionbHLH-PAS factor HLFbasebeta Thalassemiahepcidinhigh throughput screeningimprovedin vivoinhibition of autophagyinhibitor/antagonistintestinal epitheliumiron deficiencymetal transporting protein 1mouse modelnovelnovel therapeutic interventionpromoterreceptorresponsescreeningtherapeutic targettranscription factor
中文摘要
摘要
英文摘要
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.
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