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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：
James F. Collins
金额：
$ 10万
依托单位：
UNIVERSITY OF FLORIDA
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

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

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