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

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.
项目摘要 铁超负荷是铁负荷性贫血(如β-地中海贫血)发病率和死亡率的主要原因。铁 由于铁调节激素hepcidin的不适当的低产量,导致超负荷发展, 增加肠铁吸收。输血进一步加重铁负荷。怀孕是一种自然 铁平衡改变以满足与扩张相关的铁需求增加的状况 母体红细胞生成和胎儿发育。虽然铁代谢已被广泛研究, 健康的怀孕,它是如何改变地中海贫血怀孕和在何种程度上铁超载有助于 不良妊娠结局未知。β地中海贫血患者生育能力越来越强, 然而,这些怀孕被认为是高风险的。因此,该领域的研究具有临床意义。 在此,研究了β-地中海贫血的临床前动物模型(Th 3/+小鼠),以确定其病理生理学特征。 与妊娠相关的结果。关键的试点数据表明,地中海贫血导致高度紊乱, 母体和胎儿铁稳态。与野生型(WT)母鼠相比,地中海贫血母鼠铁负荷 并改变了全身的铁处理。母体血清铁升高导致胎盘铁负荷增加 和WT和Th 3/+胎儿。铁负荷反过来改变了胎儿铁调节系统。该初始 地中海贫血妊娠的特征将在这项研究中得到扩展,并产生新的 小鼠模型将加速新的发现。在目标1中,假设母体因素导致胎儿 铁失衡地中海贫血怀孕将进行测试。该方法是量化铁,氧, 和血液学状态,以及胎儿铁负荷的程度。另外的实验 将确定是否铁调节激素erythroferrone(ERFE),输血,和产妇 贫血/缺氧影响胎儿铁稳态。在目的2中,假设地中海贫血患者的胎儿铁负荷 怀孕加剧产前和产后病理的发展将被考虑。的方法 包括检查母体、胎盘和整个妊娠期胎儿的氧化应激生物标志物 以及在出生后的发育过程中。还将评估胎盘和胎儿内皮细胞损伤。影响 将通过测定整体表观遗传变化和突变负荷来评价DNA。生理 表型分析将包括认知和肾功能的详细分析。在目标3中,假设降低 将测试Th 3/+母鼠中的血清铁是否会阻止胎儿铁负荷。将采用两种方法:口服 递送纳米颗粒/siRNA复合物以钝化主要肠铁转运蛋白DMT 1的表达(以 阻断铁吸收);和铁调素模拟物的全身给药(以减少铁吸收和释放 铁的储存)。这两种方法预计会降低血清铁,从而减少胎盘铁转移。这 研究将描述与地中海贫血妊娠相关的病理生理学变化, 分子途径,可以有针对性地减轻胎儿铁负荷,从而减少终身疾病负担。

项目成果

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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
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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