Iron Pathobiology in β-thalassemia Pregnancy

项目概要 铁超负荷是铁负荷性贫血（例如β-地中海贫血）发病和死亡的主要原因。铁 由于铁调节激素铁调素的产生不当而导致超负荷，从而导致 肠道铁吸收增加。输血进一步加剧铁负荷。怀孕是自然现象 改变铁稳态以满足与扩张相关的铁需求增加的情况 母体红细胞生成和胎儿发育。尽管铁代谢已被广泛研究 健康妊娠、地中海贫血妊娠如何改变以及铁超负荷在多大程度上导致 不良妊娠结局尚不清楚。 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，该领域的研究具有重要的临床意义。 在此，研究了 β-地中海贫血（Th3/小鼠）的临床前动物模型，以定义病理生理学 与怀孕相关的结果。关键试验数据表明，地中海贫血会导致高度紊乱 母体和胎儿的铁稳态。与野生型 (WT) 母鼠相比，地中海贫血母鼠体内铁含量较高 并改变了系统性铁处理。母鼠高血清铁在胎盘子宫铁负荷中沉淀 以及 WT 和 Th3/胎儿。铁负荷反过来又改变了胎儿的铁调节系统。这个初始的 本次调查将扩大地中海贫血妊娠的特征，并产生新的 将加速新发现的小鼠模型。在目标 1 中，假设母体因素导致胎儿 地中海贫血妊娠中的铁不平衡将受到测试。该方法是量化铁、氧的生物标志物 整个怀孕期间的血液学状态以及胎儿铁负荷程度。额外的实验 将确定铁调节激素赤铁酮 (ERFE)、输血和母体是否 贫血/缺氧影响胎儿铁稳态。在目标 2 中，假设地中海贫血患者的胎儿铁负荷 将考虑怀孕加剧产前和产后病症的发展。方法 包括在整个怀孕期间检查母体、胎盘和胎儿氧化应激的生物标志物 以及出生后发育期间。还将评估胎盘和胎儿内皮细胞损伤。对的影响 将通过分析整体表观遗传变化和突变负担来评估 DNA。生理学 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 Th3/母鼠中的血清铁将阻止胎儿铁负荷的检测。将采用两种方法： 口服 递送纳米颗粒/siRNA复合物以减弱主要肠道铁转运蛋白DMT1的表达（以 阻止铁的吸收）；和铁调素模拟物的全身给药（以减少铁的吸收和释放 储铁）。这两种方法都有望降低血清铁，从而减少胎盘铁转移。这个 调查将描述与地中海贫血妊娠相关的病理生理变化并定义 可以靶向减轻胎儿铁负荷的分子途径，从而减轻终生疾病负担。

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.