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Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency

缺铁期间肠道金属离子转运的分子机制

基本信息

批准号：
9919534
负责人：
James F. Collins
金额：
$ 48.22万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919534
关键词：
Achlorhydria Adolescent Adult Aging American Anemia Animal Feed Animals Assimilations Biological Availability Biological Markers Cardiomyopathies Chemicals Child Consumption Copper Diet Dietary Copper Dietary Iron Disease Outcome Dose Effectiveness Elderly Erythrocytes Erythropoiesis Family Female Female of child bearing age Fetal Development Follow-Up Studies Gastritis Genetic Models Hemorrhage Homeostasis Human Immunity Impaired cognition Impairment Individual Intake Intervention Trial Intestines Investigation Ion Transport Ions Iron Iron Overload Iron deficiency anemia Knockout Mice Literature Low income Malabsorption Syndromes Metabolism Metals Molecular Morbid Obesity Morbidity - disease rate Mus Oral Outcome Pathologic Patients Physicians Physiological Pilot Projects Pre-Clinical Model Pregnancy Pregnant Women Proton Pump Inhibitors Rattus Refractory Resolution Rodent Rodent Model Role Source Suggestion Supplementation Testing Time Vascular blood supply absorption adolescent patient bariatric surgery copper transporter 1 dietary supplements divalent metal experimental study human model hypocupremia improved in vivo iron deficiency iron supplement iron supplementation microcytic/hypochromic anemia minority children mouse model oral supplementation pregnant prevent programs sex weanling animal

项目摘要

Project Summary Iron deficiency (ID) is common in the U.S, causing significant morbidity. The inability to assimilate adequate amounts of dietary iron, due to increased demands (e.g. with excessive menstrual blood loss) or impaired utilization (e.g. iron malabsorption after gastric bypass surgery), frequently underlies ID. Women of child- bearing age, pregnant women, the elderly (in whom achlorhydria is common), and children and adolescents are commonly iron deficient; in these individuals, iron supplementation may be recommended. During pregnancy, anemia is common since dietary iron assimilation is often inadequate to meet iron demands to supply the developing fetus and for expansion of the maternal blood supply; iron supplementation is thus almost universally recommended. Importantly, we recently noted that high dietary iron caused severe copper deficiency, in rats and mice, with pathological consequences. These initial studies utilized supraphysiologic iron levels (>100-fold excess), but a subsequent experiment demonstrated that iron at ~4X above requirements resulted in moderate copper deficiency in rats. ID humans may consume iron at 4 times the RDA from dietary and supplemental sources. It was previously suggested that high-iron intake can antagonize copper, but this has not been validated by rigorous experimentation in animals or humans. This background then provides the rationale for this investigation in which we will test the central hypothesis that consumption of supplemental iron, at levels similar to what ID humans may consume, disrupts copper metabolism with likely pathological outcomes. Notably, copper deficiency mimics ID, as both conditions cause microcytic, hypochromic anemia. Lack of adequate iron impairs erythropoiesis in ID, while impaired iron utilization by developing erythrocytes underlies copper-deficiency anemia. Physicians may recommend higher iron dosing in patients that are refractory to supplemental iron, thus potentiating the copper deficiency. This investigation could change the existing paradigm of iron supplementation, with added copper accelerating resolution of the anemia and also preventing other pathophysiological effects of copper deficiency, including cardiomyopathy, cognitive dysfunction, and impaired immunity. Three specific aims will be pursued. Aim 1 will define the minimum amount of supplemental iron that perturbs copper homeostasis in rats and mice of both sexes. Aim 2 will identify the mechanism(s) by which supplemental iron perturbs copper homeostasis, possibly involving inhibition of intestinal copper transporters. Aim 3 will evaluate the efficacy of Fe + Cu for preventing the copper depletion associated with high-iron intake in preclinical models of human ID. This investigation may establish an argument for adding copper to iron supplements. Consuming extra copper should be without negative physiologic consequence, and could increase the effectiveness of iron supplementation programs, especially since many Americans may have marginal dietary copper intakes. This investigation could serve as a prelude to intervention trials in humans, which would be a logical extension of the experimentation proposed here.

项目概要缺铁 (ID) 在美国很常见，导致高发病率。无法吸收足够的由于需求增加（例如经期失血过多）或受损而导致膳食铁含量增加利用率（例如胃绕道手术后铁吸收不良）通常是 ID 的基础。妇女的孩子- 生育年龄、孕妇、老年人（胃酸缺乏常见）以及儿童和青少年通常缺铁；对于这些人，可能建议补充铁剂。期间怀孕期间，贫血很常见，因为饮食中的铁同化往往不足以满足铁的需求供应发育中的胎儿并扩大母体血液供应；因此补铁是几乎普遍推荐。重要的是，我们最近注意到高膳食铁会导致严重的铜中毒缺乏，在大鼠和小鼠中会产生病理后果。这些初步研究利用了超生理学铁含量（超过 100 倍），但随后的实验表明，铁含量比要求高出约 4 倍导致大鼠中度铜缺乏。 ID 人类摄入的铁可能是膳食中 RDA 的 4 倍和补充来源。之前有人提出，高铁摄入量可以对抗铜，但这尚未在动物或人类身上经过严格的实验验证。这个背景提供了这项调查的基本原理，我们将检验中心假设，即补充品的消费铁的含量与人类可能消耗的铁含量相似，会扰乱铜的代谢，并可能病理结果。值得注意的是，铜缺乏症与 ID 类似，因为这两种情况都会导致小细胞性、低色素性贫血。缺乏足够的铁会损害 ID 中的红细胞生成，同时也会损害铁的利用红细胞发育是缺铜性贫血的基础。医生可能会建议更高的铁剂量难以补充铁从而加剧铜缺乏的患者。此次调查可以改变现有的补铁模式，添加铜可以加速解决问题贫血，还可以预防铜缺乏的其他病理生理效应，包括心肌病，认知功能障碍、免疫力受损。将追求三个具体目标。目标 1 将定义扰乱两性大鼠和小鼠铜稳态的补充铁的最低量。目标2 将确定补充铁扰乱铜稳态的机制，可能涉及抑制肠道铜转运蛋白。目标 3 将评估 Fe + Cu 防止铜沉积的功效人类 ID 临床前模型中与高铁摄入量相关的耗竭。这项调查可能会确定在铁补充剂中添加铜的争论。消耗额外的铜应该没有负面影响生理后果，并可以提高铁补充剂计划的有效性，特别是因为许多美国人的膳食铜摄入量可能有限。这项调查可以作为前奏对人类进行干预试验，这将是此处提出的实验的逻辑延伸。