Newborn iron deficiency

据估计，缺铁症影响着20亿人，尤其是孕妇及其婴儿。ID对早期大脑发育有害，并导致儿童学习和记忆缺陷。从公共卫生的角度来看，更令人不安的是，在未经治疗和治疗的人群中，学习和记忆障碍持续到成年。婴儿期铁治疗后持续存在的脑损伤意味着单独的铁治疗不足以完全恢复，或者铁治疗本身可能是有害的。早期智力缺陷的这些长期影响是社会的真实的成本，因为失去了教育和就业潜力。胎儿/新生儿的大脑是高度代谢的，占全身耗氧量的60%。海马是新生儿大脑中代谢率最高的区域之一。铁为电子传递和能量产生所需的酶提供催化成分。在小鼠中，早期海马神经元ID减少神经元能量代谢，包括氧化磷酸化和糖酵解，减缓线粒体募集到生长树突/棘的活性位点，增加活性氧（ROS）并截断树突和突触发育。这些发现持续到成年期，尽管铁补充。发育性ID如何导致长期神经元结构缺陷的细胞机制以及这些缺陷是否可以预防或治疗尚不清楚。我们将测试的总体假设，即海马能量代谢，这是一个潜在的适应性反应胎儿/新生儿ID的早期生活重编程，成为适应不良的长期和结果在以前的ID成人海马结构异常。在目标1中，我们将利用一种独特的慢性新生儿海马神经元ID的体外模型来测试治疗方法，这些治疗方法解决了在发育过程中被ID破坏的基本能量过程，以防止神经元结构缺陷。为了做到这一点，我们将在遗传学上、营养学上或生物学上操纵铁充足和铁缺乏的新生海马神经元培养物中的特定代谢功能。线粒体耗氧速率和细胞糖酵解速率，线粒体募集到生长树突/棘的活性位点和ROS将响应于操作而测量。将评估所得树突复杂性和棘密度/形态作为结局指标。Aim 2将Aim 1的体外研究结果转化为体内小鼠模型，以测试向新生小鼠提供的治疗可预防成年期线粒体功能，树突结构和神经认知行为的永久性异常。我们独特的非贫血、海马神经元特异性显性/阴性TfR-1小鼠模型为评估翻译效应提供了完美的平台。这一建议非常重要，因为它首次定义了独立于贫血的早期ID诱导的神经元能量代谢的特定缺陷如何导致线粒体代谢和神经功能缺损的长期异常。它测试机制和经验衍生的疗法，以防止他们。

Iron deficiency (ID) affects an estimated 2 billion people, especially pregnant women and their infants. ID is harmful to early-life brain development and causes learning and memory deficits in children. More troubling from a public health perspective is that the learning and memory impairments persist into adulthood in both untreated as well as treated populations. Persistence of brain impairment following iron treatment in infancy implies that iron therapy alone is not sufficient for full recovery or that iron therapy itself may be harmful. These long-term effects of early-life ID are the real cost to society because of lost education and job potential. The fetal/neonatal brain is highly metabolic, accounting for 60% of total body oxygen consumption. The hippocampus has one of the highest regional metabolic rates in the neonatal brain. Iron provides the catalytic component for enzymes required for electron transport and energy production. In mice, early-life hippocampal neuronal ID reduces neuronal energy metabolism including oxidative phosphorylation and glycolysis, slows mitochondrial recruitment to active sites of growing dendrites/spines, increases reactive oxygen species (ROS) and truncates dendrite and synapse development. These findings persist into adulthood despite iron repletion. The cellular mechanisms of how developmental ID causes long-term neuronal structural deficits and whether these can be prevented or treated are unclear. We will test the overall hypothesis that early-life reprogramming of hippocampal energy metabolism, which is a potentially adaptive response to fetal/neonatal ID, becomes maladaptive in the long-term and results in structural abnormalities in the formerly ID adult hippocampus. In Aim 1, we will utilize a unique in vitro model of chronic neonatal hippocampal neuronal ID to test therapies that address fundamental energy processes disrupted by ID during development in order to prevent neuronal structural deficits. To do this, we will genetically, nutritionally or pharmacologically manipulate specific metabolic functions in iron-sufficient and -deficient neonatal hippocampal neuron cultures. Mitochondrial oxygen consumption rate and cellular glycolytic rate, mitochondrial recruitment to active sites of growing dendrites/spines and ROS will be measured in response to the manipulations. Resultant dendrite complexity and spine density/morphology will be assessed as outcome measures. Aim 2 translates Aim 1's in vitro findings to an in vivo mouse model to test which therapies delivered to the neonatal mouse prevent permanent abnormalities in mitochondrial function, dendrite structure and neurocognitive behavior in adulthood. Our unique non-anemic, hippocampal neuron-specific dominant/negative TfR-1 mouse model provides the perfect platform to assess the translational effects. This proposal is highly significant because it defines for the first time how the specific deficits in neuronal energy metabolism induced by early-life ID independent of anemia lead to long-term abnormalities in mitochondrial metabolism and neurological deficits. It tests mechanistically and empirically derived therapies to prevent them.