Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency

项目摘要 缺铁(ID)在美国很常见，会导致严重的发病率。不能充分吸收 由于需求增加(例如，月经失血过多)或受损而摄入的膳食铁量 利用(例如，胃旁路手术后铁吸收不良)，通常是ID的基础。 生育年龄、孕妇、老年人(其中酸中毒很常见)以及儿童和青少年 通常缺铁；在这些人中，可以推荐补充铁。在.期间 怀孕，贫血很常见，因为饮食中的铁吸收往往不足以满足对铁的需求 补充发育中的胎儿和扩大母亲的血液供应；因此，补充铁质 几乎是普遍推荐的。重要的是，我们最近注意到，高膳食铁导致严重的铜 缺乏，在大鼠和小鼠身上，会造成病理后果。这些初步研究利用了超生理学。 铁含量(&gt；100倍过剩)，但随后的一项实验表明，铁含量是需要量的~4倍 导致大鼠中度铜缺乏。ID人类从饮食中摄入的铁可能是RDA的4倍 和补充资料。此前有人建议，高铁摄入量可以对抗铜，但这一点 还没有在动物或人类身上进行严格的实验来验证。此背景随后提供了 这项研究的理论基础是，我们将检验补充营养素消费的中心假设 铁的水平与人类可能摄入的ID相似，可能会扰乱铜的新陈代谢 病理结果。值得注意的是，铜缺乏与ID相似，因为这两种情况都会导致小红细胞， 低色素性贫血。缺乏足够的铁损害了ID的红细胞生成，同时也损害了铁的利用 红细胞发育是缺铜性贫血的基础。医生可能会推荐更高的铁摄入量 患者对补充铁有抵抗力，从而加剧了铜缺乏。这项调查 可以改变现有的铁补充范例，添加铜可以加速解决 还可以预防铜缺乏的其他病理生理影响，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 扰乱大鼠和小鼠铜稳态的最低铁补充量。目标2 将确定补充铁扰乱铜稳态的机制(S)，可能涉及 抑制肠道铜转运蛋白。目的3评价铁+铜预防铜中毒的效果 在人类ID的临床前模型中，与高铁摄入量相关的耗竭：这项研究可能建立 在铁的补充剂中添加铜的论点。消费额外的铜应该没有负面影响 生理后果，并可增加补铁计划的有效性，特别是 因为许多美国人的膳食铜摄入量可能微乎其微。这项调查可以作为前奏。 对人体的干预试验，这将是这里提出的实验的合乎逻辑的扩展。

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.