Iron Pathobiology in β-thalassemia Pregnancy

妊娠β地中海贫血中的铁病理学

• 批准号: 10923418
• 负责人: James F. Collins
• 金额: $ 10万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10923418
• 关键词: Acceleration; Anemia; Animal Model; Antioxidants; Area; Biological Assay; Biological Markers; Bioluminescence; Blood Transfusion; Brain; Clinical Treatment; Complex; DNA; Data; Development; Disease; Endothelial Cells; Epigenetic Process; Equilibrium; Erythropoiesis; Fetal Development; Fetal Liver; Fetal Tissues; Fetus; Functional disorder; Generations; Genetic Models; Goals; Hematology; Homeostasis; Hormones; Hypoxia; Infusion procedures; Injury to Kidney; Intestines; Investigation; Iron; Iron Overload; Knockout Mice; Label; Measures; Mediating; Molecular; Molecular Analysis; Morbidity - disease rate; Mothers; Mus; Mutation; Neonatal; Oral; Organ; Outcome; Oxidative Stress; Oxygen; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Physiological; Pilot Projects; Placenta; Pre-Clinical Model; Pregnancy; Production; Regulation; Renal function; Reporter; Resistance; Risk; SLC11A2 gene; Serum; Small Interfering RNA; Source; System; Testing; Thalassemia; Tissues; absorption; adverse outcome; adverse pregnancy outcome; beta Thalassemia; burden of illness; cell injury; child bearing; clinically significant; cognitive function; dietary; effective intervention; experimental analysis; fetal; fetus hypoxia; healthy pregnancy; hepcidin; high risk; human model; in utero; in vivo; inhibitor; insight; iron absorption; iron metabolism; maternal serum; mimetics; mortality; mouse model; nanoparticle delivery; neonatal outcome; novel; novel therapeutic intervention; pharmacologic; placental transfer; postnatal; postnatal development; pre-clinical; prenatal; prevent; response

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。