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.

项目摘要 铁超负荷是贫血（例如β-丘脑贫血）发病率和死亡率的主要原因。铁 超负荷发展是由于铁调节性马肝素的不适当产生而导致的，导致 肠道滥用升高。输血进一步加剧了铁载。怀孕是自然的 改变铁稳态以满足与扩张相关的铁需求增加的条件 孕产妇的红细胞生成和胎儿发育。尽管铁代谢已在 健康的怀孕，丘脑血症怀孕的改变以及铁超负荷有助于 不良妊娠结局尚不清楚。 β-丘脑贫血患者越来越能够生育儿童 但是，这些怀孕被认为是高风险。因此，该领域的研究具有临床意义。 在这里，β-thalass-贫血（TH3/+小鼠）的临床前动物模型已研究以定义病理生理 与怀孕有关的结果。主要的飞行员数据表明​​，丘脑贫血导致高度无序 产妇和胎儿铁稳态。与野生型（wt）大坝相比，thalassmetic母亲是熨烫的 并改变了全身铁处理。在子宫铁载体中沉淀的水坝中的高血清铁 WT和TH3/+胎儿。铁负荷反过来改变了胎儿铁调节系统。这个初始 在这项投资中将扩大丘脑血症妊娠的特征，并产生新的。 将加速新发现的鼠标模型。在AIM 1中，材料因素引起胎儿的假设 将测试丘脑血症妊娠的铁不平衡。该方法是量化铁，氧的生物标志物 整个怀孕期间，血液学状态以及胎儿载荷的程度。其他实验 将定义铁调节的马龙红螺旋酮（ERFE），输血和母体是否 贫血/缺氧会影响胎儿铁稳态。在AIM 2中，假设胎儿铁载在丘脑血症 妊娠将加剧产前和产后病理的发展。方法 包括检查整个怀孕的大坝，斑点和胎儿中氧化物胁迫的生物标志物 并在产后发展期间。还将评估胎盘和胎儿内皮细胞损伤。影响 DNA将通过测定全球表观遗传变化和突变负担来评估。生理 表型将包括对认知和肾功能的详细分析。在AIM 3中，降低的假设 Th3/+大坝中的血清铁将预防胎儿铁负荷。将使用两种方法：Peroral 将纳米颗粒/siRNA复合物传递到主肠铁转运蛋白DMT1的钝器表达（TO 阻止铁抽样）；和全身给药肝素模拟物（以减少铁的抽象和释放 储存铁）。预计两种方法都降低了血清铁，从而降低了斑点铁的转移。这 调查将描述与丘脑妊娠有关的病理生理变化并定义 可以针对减轻胎儿铁负荷的分子途径，从而减少终身疾病伯嫩。