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.
项目总结 铁负荷过高是β-地中海贫血等铁负荷性贫血发病和死亡的主要原因。铁 超负荷是由于铁调节激素海普西丁的产量过低造成的,导致 肠道铁吸收增加。输血会进一步加重铁负荷。怀孕是一种自然现象 铁稳态被改变以满足与扩张相关的增加的铁需求的状态 母体红细胞生成与胎儿发育。尽管铁的新陈代谢已经在 健康妊娠,它在地中海贫血妊娠中是如何改变的,以及铁超载在多大程度上导致了 不良妊娠结局未知。β-地中海贫血患者的生育能力越来越强, 然而,这些怀孕被认为是高风险的。因此,对这一领域的研究具有临床意义。 在这里,临床前的β-地中海贫血动物模型(Th3/+小鼠)被研究以确定病理生理学。 与怀孕有关的结局。关键的试点数据表明,地中海贫血会导致高度紊乱 母体和胎儿体内的铁平衡。与野生型(WT)水坝相比,地中海贫血母亲体内的铁含量较高 并改变了全身铁的处理。胎盘宫铁负荷致母鼠血清铁过高 WT和Th3/+胎儿。铁负荷反过来又改变了胎儿的铁调节系统。这个首字母 地中海贫血妊娠的特征将在这项研究中展开,并产生新的 将加速新发现的老鼠模型。在目标1中,母体因素导致胎儿 将对地中海贫血妊娠的铁失衡进行测试。方法是对铁、氧的生物标志物进行量化 以及整个怀孕期间的血液学状态和胎儿铁负荷的程度。额外的实验 将定义铁调节激素红铁酮(ERFe)、输血和母体 贫血/缺氧影响胎儿铁稳态。在目标2中,地中海贫血的胎儿铁负荷假设 怀孕加剧了产前和产后病理的发展将被考虑在内。该方法 包括在整个妊娠期间对母体、胎盘和胎儿的氧化应激生物标记物的检查。 在出生后的发育过程中。胎盘和胎儿内皮细胞损伤也将被评估。对……的影响 DNA将通过分析全球表观遗传变化和突变负担来评估。生理学 表型分析将包括对认知和肾功能的详细分析。在目标3中,假设降低 血清铁在Th3/+母细胞中是否会阻止胎儿铁负荷将被检测。将使用两种方法:口头交流 纳米颗粒/siRNA复合体钝化主要肠道铁转运蛋白DMT1(TO)的表达 阻断铁吸收);以及全身应用海普西丁模拟物(以减少铁的吸收和释放 储藏铁)。这两种方法都有望降低血清铁,从而减少胎盘铁转移。这 调查将描绘与地中海贫血妊娠相关的病理生理变化,并确定 可针对减轻胎儿铁负荷的分子途径,从而减少终生疾病负担。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

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

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:

相似国自然基金

基于构建骨骼类器官模型探究Fanconi anemia信号通路调控电刺激诱导神经化成骨过程的机制研究
  • 批准号:
    82302715
  • 批准年份:
    2023
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目
FANCM蛋白在传统Fanconi anemia通路以外对保护基因组稳定性的功能
  • 批准号:
  • 批准年份:
    2021
  • 资助金额:
    10.0 万元
  • 项目类别:
    省市级项目
范可尼贫血(Fanconi Anemia)基因FANCM在复制后修复中的作用及FA癌症抑制通路的机制研究
  • 批准号:
    31200592
  • 批准年份:
    2012
  • 资助金额:
    23.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Investigation of crosstalk between Fanconi Anemia pathway and ATM for novel therapeutic strategies of chemoresistant ALT-positive high-risk neuroblastoma
范可尼贫血通路与 ATM 之间的串扰研究,用于化疗耐药 ALT 阳性高危神经母细胞瘤的新治疗策略
  • 批准号:
    24K10442
  • 财政年份:
    2024
  • 资助金额:
    $ 10万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Immune escape mechanisms in BCOR/BCORL1 mutant hematopoietic stem cells from patients with aplastic anemia
再生障碍性贫血患者 BCOR/BCORL1 突变型造血干细胞的免疫逃逸机制
  • 批准号:
    23K15297
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Fanconi anemia経路に着目したiPS細胞における高レベル複製ストレスの原因解明
阐明 iPS 细胞中高水平复制应激的原因,重点关注范可尼贫血途径
  • 批准号:
    23K14452
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Analysis of the mechanism of hemolytic anemia in canine babesiosis and development of novel therapeutic measures
犬巴贝斯虫病溶血性贫血机制分析及新治疗措施开发
  • 批准号:
    23KJ0074
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Brain blood flow, oxygenation, and cognition in adult onset iron deficiency anemia
成人缺铁性贫血的脑血流量、氧合和认知
  • 批准号:
    10735765
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
Chromatin State Alterations in Fanconi Anemia Hematologic Disease and Bone Marrow Failure
范可尼贫血血液疾病和骨髓衰竭中的染色质状态改变
  • 批准号:
    10735366
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
Liver-Gut Axis in Neonatal Anemia and Its Role in RBC Transfusion Associated Gut Injury
新生儿贫血中的肝肠轴及其在红细胞输注相关肠道损伤中的作用
  • 批准号:
    10583807
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
Small Molecule Therapeutics for Sickle Cell Anemia
镰状细胞性贫血的小分子疗法
  • 批准号:
    10601679
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
Accuracy and Feasibility of Non-Invasive Anemia Screening Assistant (ASIST) Device in Resource-Limited Settings
资源有限环境中非侵入性贫血筛查辅助 (ASIST) 设备的准确性和可行性
  • 批准号:
    10575222
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
Mobile phone-based screening for anemia in young children in western Kenya
基于手机的肯尼亚西部幼儿贫血筛查
  • 批准号:
    10752968
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了