Iron Pathobiology in β-thalassemia Pregnancy
妊娠β地中海贫血中的铁病理学
基本信息
- 批准号:10923418
- 负责人:
- 金额:$ 10万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-21 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAnemiaAnimal ModelAntioxidantsAreaBiological AssayBiological MarkersBioluminescenceBlood TransfusionBrainClinical TreatmentComplexDNADataDevelopmentDiseaseEndothelial CellsEpigenetic ProcessEquilibriumErythropoiesisFetal DevelopmentFetal LiverFetal TissuesFetusFunctional disorderGenerationsGenetic ModelsGoalsHematologyHomeostasisHormonesHypoxiaInfusion proceduresInjury to KidneyIntestinesInvestigationIronIron OverloadKnockout MiceLabelMeasuresMediatingMolecularMolecular AnalysisMorbidity - disease rateMothersMusMutationNeonatalOralOrganOutcomeOxidative StressOxygenPathogenesisPathologyPathway interactionsPatientsPhenotypePhysiologicalPilot ProjectsPlacentaPre-Clinical ModelPregnancyProductionRegulationRenal functionReporterResistanceRiskSLC11A2 geneSerumSmall Interfering RNASourceSystemTestingThalassemiaTissuesabsorptionadverse outcomeadverse pregnancy outcomebeta Thalassemiaburden of illnesscell injurychild bearingclinically significantcognitive functiondietaryeffective interventionexperimental analysisfetalfetus hypoxiahealthy pregnancyhepcidinhigh riskhuman modelin uteroin vivoinhibitorinsightiron absorptioniron metabolismmaternal serummimeticsmortalitymouse modelnanoparticle deliveryneonatal outcomenovelnovel therapeutic interventionpharmacologicplacental transferpostnatalpostnatal developmentpre-clinicalprenatalpreventresponse
项目摘要
PROJECT SUMMARY
Iron overload is a major cause of morbidity and mortality in iron-loading anemias, such as β-thalassemia. Iron
overload develops due to inappropriately low production of the iron-regulatory hormone hepcidin, resulting in
elevated intestinal iron absorption. Blood transfusions further exacerbate iron loading. Pregnancy is a natural
condition in which iron homeostasis is altered to meet increased iron demands associated with expansion of
maternal erythropoiesis and fetal development. Although iron metabolism has been extensively investigated in
healthy pregnancy, how it is altered in thalassemic pregnancy and to what extent iron overload contributes to
adverse pregnancy outcomes is unknown. Patients with β-thalassemia are increasingly able to bear children,
however, these pregnancies are considered high risk. Investigation in this area is thus of clinical significance.
Here, a pre-clinical animal model of β-thalassemia (Th3/+ mice) was studied to define pathophysiological
outcomes associated with pregnancy. Key pilot data demonstrated that thalassemia leads to highly disordered
maternal and fetal iron homeostasis. Compared to wild-type (WT) dams, thalassemic mothers were iron-loaded
and had altered systemic iron handling. High serum iron in dams precipitated in utero iron loading of placentas
and WT and Th3/+ fetuses. Iron loading in turn altered the fetal iron-regulatory system. This initial
characterization of thalassemic pregnancy will be expanded upon in this investigation, and generation of new
mouse models that will accelerate novel discovery. In Aim 1, the hypothesis that maternal factors cause fetal
iron imbalance in thalassemic pregnancy will be tested. The approach is to quantify biomarkers of iron, oxygen
and hematological status, and the degree of fetal iron loading, throughout pregnancy. Additional experimentation
will define whether the iron-regulatory hormone erythroferrone (ERFE), blood transfusions, and maternal
anemia/hypoxia impact fetal iron homeostasis. In Aim 2, the hypothesis that fetal iron loading in thalassemic
pregnancies exacerbates development of pre- and postnatal pathologies will be considered. The approach
includes examination of biomarkers of oxidative stress in dams, placentas, and fetuses throughout pregnancy
and during postnatal development. Placental and fetal endothelial cell injury will also be assessed. Effects on
DNA will be evaluated by assaying for global epigenetic changes and mutational burden. Physiological
phenotyping will include detailed analysis of cognitive and renal function. In Aim 3, the hypothesis that lowering
serum iron in Th3/+ dams will prevent fetal iron loading will be tested. Two approaches will be utilized: peroral
delivery of nanoparticle/siRNA complexes to blunt expression of the main intestinal iron transporter DMT1 (to
block iron absorption); and systemic administration of hepcidin mimetics (to decrease iron absorption and release
of storage iron). Both approaches are expected to lower serum iron, thus decreasing placental iron transfer. This
investigation will delineate pathophysiological changes associated with thalassemic pregnancy and define
molecular pathways that could be targeted to mitigate fetal iron loading, thus diminishing lifelong disease burden.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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James F. Collins其他文献
<span class="small-caps">dl</span>-2-[3,4-<sup>3</sup>H]Amino-4-phosphonobutyrate binding sites in the rat hippocampus: distribution and possible physiological role
- DOI:
10.1016/0006-8993(87)90596-8 - 发表时间:
1987-09-01 - 期刊:
- 影响因子:
- 作者:
Steven P. Butcher;Peter J. Roberts;James F. Collins - 通讯作者:
James F. Collins
Independence of sensitivity on different foveal areas
- DOI:
10.3758/bf03214129 - 发表时间:
1973-06-01 - 期刊:
- 影响因子:1.700
- 作者:
James F. Collins - 通讯作者:
James F. Collins
ACELL November 46/5
ACELL 十一月 46/5
- DOI:
- 发表时间:
1999 - 期刊:
- 影响因子:0
- 作者:
Y. Guner;P. Kiela;XU Hua;James F. Collins;F. Ghishan - 通讯作者:
F. Ghishan
Aminoacyltransferase II from Rat Liver: I. PURIFICATION AND ENZYMATIC PROPERTIES
- DOI:
10.1016/s0021-9258(18)62428-7 - 发表时间:
1971-02-25 - 期刊:
- 影响因子:
- 作者:
Samuel Raeburn;James F. Collins;Hong Mo Moon;Elizabeth S. Maxwell - 通讯作者:
Elizabeth S. Maxwell
Molecular cloning, promoter characterization, and gene structure of murine intestinal type IIB sodium-phosphate cotransporter gene
- DOI:
10.1016/s0016-5085(00)80270-x - 发表时间:
2000-04-01 - 期刊:
- 影响因子:
- 作者:
Kayo Arima;James F. Collins;Eric R. Hines;Liqun Bai;Fayez K. Ghishan - 通讯作者:
Fayez K. Ghishan
James F. Collins的其他文献
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{{ truncateString('James F. Collins', 18)}}的其他基金
Mechanisms of Heme and Non-heme Iron Absorption in Murine Models of Iron Overload
铁过载小鼠模型中血红素和非血红素铁吸收的机制
- 批准号:
10701227 - 财政年份:2022
- 资助金额:
$ 10万 - 项目类别:
Divalent Metal-ion Transporter 1 as a Therapeutic Target to Optimize Intestinal Iron Transport
二价金属离子转运蛋白 1 作为优化肠道铁转运的治疗靶点
- 批准号:
9920132 - 财政年份:2016
- 资助金额:
$ 10万 - 项目类别:
Divalent Metal-ion Transporter 1 as a Therapeutic Target to Optimize Intestinal Iron Transport
二价金属离子转运蛋白 1 作为优化肠道铁转运的治疗靶点
- 批准号:
9314563 - 财政年份:2016
- 资助金额:
$ 10万 - 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency
缺铁期间肠道金属离子转运的分子机制
- 批准号:
8506803 - 财政年份:2007
- 资助金额:
$ 10万 - 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency
缺铁期间肠道金属离子转运的分子机制
- 批准号:
9919534 - 财政年份:2007
- 资助金额:
$ 10万 - 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency
缺铁期间肠道金属离子转运的分子机制
- 批准号:
8813554 - 财政年份:2007
- 资助金额:
$ 10万 - 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron-Deficiency
缺铁期间肠道金属离子转运的分子机制
- 批准号:
7706543 - 财政年份:2007
- 资助金额:
$ 10万 - 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron-Deficiency
缺铁期间肠道金属离子转运的分子机制
- 批准号:
7636746 - 财政年份:2007
- 资助金额:
$ 10万 - 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron-Deficiency
缺铁期间肠道金属离子转运的分子机制
- 批准号:
7587761 - 财政年份:2007
- 资助金额:
$ 10万 - 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron-Deficiency
缺铁期间肠道金属离子转运的分子机制
- 批准号:
8098833 - 财政年份:2007
- 资助金额:
$ 10万 - 项目类别:
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