Mediating effects of hepcidin on iron requirements with undernutrition

贫血常见于营养不良，并与更严重的并发症和较差的预后（包括死亡）相关。与没有贫血的儿童相比，营养不良的贫血儿童康复的可能性更小。在感染的情况下，这代表炎症性贫血，表现为铁调节激素hepcidin对炎症信号的反应增加。然而，大多数营养不良病例并不复杂，没有感染或其他潜在疾病的迹象，但他们仍然表现出类似的临床表现，包括血清铁水平低，但铁储存完好或升高。此外，与表面上健康的儿童相比，营养不良的儿童反而吸收了更少的铁，这也许可以解释为什么贫血对补充铁具有极强的抵抗力。这一建议的总体目标是确定贫血的潜在机制，发展无并发症的营养不良和它的贡献缺乏目前的治疗方案的有效性。我们的初步数据表明，来自食物限制的糖异生信号增加了hepcidin并导致功能性贫血（即低铁血症，但增加了组织铁浓度）。我们将使用野生型和hepcidin敲除小鼠来确定食物限制后hepcidin的增加是否会导致营养不良引起的贫血。铁供应受限不仅可能导致营养不良引起的贫血，还可能限制在重新进食恢复期间正常红细胞团的重建。我们将确定再喂养对营养不良患者贫血恢复的影响。了解贫血伴非复杂性营养不良的发展机制，可以为营养不良儿童贫血制定更有效的预防和治疗策略提供信息，从而有可能改善预后并降低死亡率。此外，研究结果可能为优化用于预防或治疗营养不良的脂质营养补充剂的铁含量提供指导。

Anemia is commonly observed with undernutrition and is associated with more severe complications and poorer outcomes, including death. Undernourished children with anemia are also less likely to recover than those without anemia. In the presence of infection, this represents the anemia of inflammation and manifests from increases in the iron regulatory hormone hepcidin in response to inflammatory signals. However, most cases of undernutrition are uncomplicated where there is no sign of infection or other underlying condition, yet they still present a similar clinical manifestation that includes low serum iron levels but intact or elevated iron stores. In addition, undernourished children paradoxically absorb less iron compared to apparently healthy children, which may explain why the anemia is extremely resistant to iron supplementation. The overall objective of this proposal is to determine the mechanism underlying the anemia that develops with uncomplicated undernutrition and its contribution to the lack of effectiveness of current treatment regimens. Our preliminary data demonstrate that gluconeogenic signals from food restriction increase hepcidin and lead to functional anemia (i.e., hypoferremia, but increased tissue iron concentrations). We will use wildtype and hepcidin knockout mice to determine whether increases in hepcidin in response to food restriction contribute to the anemia observed with undernutrition. Restricted iron supply may not only contribute to the anemia observed with undernutrition, but may also limit the re-establishment of a normal red blood cell mass during recovery with refeeding. We will determine the effects of refeeding on recovery from the anemia observed with undernutrition. Understanding the mechanism by which anemia develops with uncomplicated undernutrition may inform the development of more effective prevention and treatment strategies for anemia in undernourished children, potentially leading to improved outcomes and reduced mortality rates. Additionally, findings may guide recommendations for optimizing the iron content of lipidbased nutrient supplements used to prevent or treat undernutrition.