Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency

项目摘要 铁缺乏症（ID）在美国很常见，导致严重的发病率。无法充分吸收 膳食铁的量，由于需求增加（例如月经失血过多）或受损 利用（如胃旁路手术后铁吸收不良），经常是ID的基础。 育龄期、孕妇、老年人（常见的是无氯血症）、儿童和青少年 通常缺铁;在这些个体中，可能建议补充铁。期间 怀孕期间，贫血是常见的，因为膳食铁同化往往不足以满足铁的需求， 为发育中的胎儿提供铁，并扩大母体的血液供应;因此， 几乎普遍推荐。重要的是，我们最近注意到，高膳食铁引起严重的铜 缺乏症，在大鼠和小鼠，病理后果。这些初步研究利用超生理学 铁水平（>100倍过量），但随后的实验表明，铁在约4倍以上的要求 导致大鼠中度铜缺乏。ID人类可能会消耗铁的4倍RDA从饮食 补充来源。以前有人认为，高铁摄入量可以拮抗铜，但这 还没有经过严格的动物或人体实验的验证。然后，该背景提供了 这项调查的基本原理，我们将测试的中心假设，消费补充 铁，在类似于ID人类可能消耗的水平，扰乱铜代谢， 病理结果。值得注意的是，铜缺乏模拟ID，因为这两种情况都会导致小细胞， 低色素性贫血缺乏足够的铁会损害ID的红细胞生成，同时通过以下方式损害铁的利用： 发育中的红细胞是缺铜性贫血的基础。医生可能会建议更高的铁剂量， 患者难以补充铁，从而加重铜缺乏。这次调查 可能会改变现有的铁补充模式，增加铜加速解决 贫血以及预防铜缺乏的其他病理生理学影响，包括心肌病， 认知功能障碍和免疫力受损将追求三个具体目标。目标1将定义 最低量的补充铁，扰乱铜稳态的大鼠和小鼠的性别。目的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。目的3评价Fe + Cu预防铜中毒的效果 在人类ID的临床前模型中与高铁摄入相关的消耗。这项研究可以建立 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，并可能增加铁补充计划的有效性，特别是 因为许多美国人的膳食铜摄入量可能很低。这次调查可以作为 到人类的干预试验，这将是这里提出的实验的逻辑延伸。

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.