Mediating effects of hepcidin on iron requirements with undernutrition

铁调素对营养不良铁需求的中介作用

• 批准号: 10996638
• 负责人: Stephen R. Hennigar
• 金额: $ 3.7万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10996638
• 关键词: Mediating; effects; hepcidin; iron; requirements

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.

贫血通常在营养不良时观察到，并与更严重的并发症和更差的结局（包括死亡）相关。患有贫血的营养不良儿童也比没有贫血的儿童更不可能康复。在感染的存在下，这代表了炎症性贫血，并表现为铁调节激素铁调素响应炎症信号的增加。然而，大多数营养不良的病例并不复杂，没有感染或其他潜在疾病的迹象，但它们仍然表现出类似的临床表现，包括血清铁水平低，但铁储存完整或升高。此外，营养不良的儿童与明显健康的儿童相比，吸收的铁反而更少，这可能解释了为什么贫血对铁补充剂具有极强的抵抗力。本提案的总体目标是确定无并发症营养不良引起贫血的潜在机制及其对当前治疗方案缺乏有效性的贡献。我们的初步数据表明，来自食物限制的促血管生成信号增加铁调素并导致功能性贫血（即，低铁血症，但组织铁浓度增加）。我们将使用野生型和hepcidin基因敲除小鼠，以确定是否增加hepcidin响应食物限制有助于观察营养不良的贫血。铁供应受限不仅可能导致营养不良时观察到的贫血，还可能限制恢复期间再喂养时正常红细胞质量的重建。我们将确定再喂养对营养不良贫血恢复的影响。了解贫血与简单营养不良的发展机制可能会为营养不良儿童贫血的更有效预防和治疗策略的制定提供信息，可能会改善结果并降低死亡率。此外，研究结果可以指导建议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。