Iron Metabolism in Ts65Dn mice, a Model of Down syndrome

项目摘要/摘要 唐氏综合征(DS)是一种发育障碍，通常由21号染色体的三倍体引起 每700名活产儿中就有1名。21号染色体三倍体可能改变正常基因表达和 导致智力残疾，早发性阿尔茨海默病，先天性心脏病，血液系统疾病， 在其他条件中。铁稳态机制的失调可能是临床的一个潜在因素 与DS相关的结果。铁是一种微量元素，因其与生理功能有关而闻名 包括氧气运输、炎症反应、能量代谢和DNA合成的过程。 DS患者铁平衡失调可能导致血浆铁水平和组织铁水平受损 催化产生活性氧自由基(ROS)的堆积。尽管有关于铁的报道 DS的状态参数缺乏对铁稳态的明确和全面的了解 在这群个体中进行管理。Ts65Dn鼠标是DS的成熟模型，可以 对于研究调节DS中铁稳态的机制因素具有相当的价值。这样做的目的是 该项目旨在描述成年后铁稳态调节中与性别和年龄相关的变化 Ts65Dn小鼠，并将铁调节的变化与组织铁水平和氧化应激联系起来。在这些 研究，来自Ts65Dn小鼠的组织(脑、肝脏和血浆)和野生型(WT)群体对照在3、12和 18个月龄的研究将解决两个综合的具体目标：1)描绘铁的动态平衡 Ts65Dn小鼠整个成年寿命的表型，以及2)决定低氧暴露的影响(10% 激发氧)对小鼠全身和组织铁稳态、血液学特征和组织氧化应激的影响 Ts65Dn小鼠。这项提议的第一个目的是建立Ts65Dn小鼠模型来研究铁的实用价值 缺铁性贫血的状态和铁平衡调节。据推测，Ts65Dn小鼠将表现出更大的 炎症，将促进铁调节反应，导致较低的血浆铁和 储藏室里的高铁。Ts65Dn小鼠体内组织铁升高被认为与 更严重的氧化损伤。第二个目标将使用低氧暴露来改变铁的动态平衡调节 Ts65Dn和WT小鼠测试低氧引起的铁分布从储存转移到 血浆舱可降低Ts65Dn组织铁毒性，改善血液学特征。此外， 据推测，雄性小鼠的铁状态和氧化应激程度将高于雌性小鼠，Ts65Dn 显示出比WT控件更高的级别。由于铁代谢失调和组织铁积累可以 随着年龄的增长变得更加突出，了解DS中的铁代谢是至关重要的 在过去的几十年里，这一群体的预期水平有了极大的提高。

PROJECT SUMMARY/ABSTRACT Down syndrome (Ds) is a developmental disability that typically results from the triplication of chromosome 21 with an occurrence of 1 in 700 live births. Chromosome 21 triplication may alter normal gene expression and lead to intellectual disability, early onset Alzheimer’s disease, congenital heart disease, hematologic disorders, among other conditions. Dysregulation of iron homeostatic mechanisms may be an underlying factor in clinical outcomes associated with Ds. Iron is a trace element well-known for its involvement with physiological processes that include oxygen transport, inflammatory response, energy metabolism, and DNA synthesis. Iron homeostatic dysregulation in Ds could lead to compromised plasma iron levels and tissue iron accumulation that catalyzes the production of reactive oxygen radical species (ROS). Despite reports of iron status parameters in Ds there is a lack of clear and comprehensive understanding of iron homeostatic regulation among this population of individuals. The Ts65Dn mouse is an established model of Ds that may hold considerable value to study mechanistic factors that regulate iron homeostasis in Ds. The objective of this project is to delineate sex and age-related alterations in iron homeostatic regulation over the adult lifespan of Ts65Dn mice and to associate changes in iron regulation with tissue iron levels and oxidative stress. In these studies, tissues (brain, liver, and plasma) from Ts65Dn mice and wild-type (WT) colony controls at 3, 12, and 18 months of age will be studied to address two integrated Specific Aims: 1) Depict the iron homeostatic phenotype of Ts65Dn mice across the adult lifespan, and 2) Determine the impact of hypoxia exposure (10% inspired O2) on systemic and tissue iron homeostasis, hematologic profile, and tissue oxidative stress in Ts65Dn mice. The first aim of this proposal will establish the utility of the Ts65Dn mouse model to study iron status and iron homeostatic regulation in Ds. It is hypothesized that Ts65Dn mice will show greater inflammation that will promote an iron regulation response leading to lower plasma compartment iron and elevated iron in the storage compartment. Elevated tissue iron in Ts65Dn mice is postulated to associate with greater oxidative injury. The second aim will employ hypoxia exposure to alter iron homeostatic regulation of Ts65Dn and WT mice to test the hypothesis that hypoxia induced iron distribution shifts from storage to the plasma compartment will reduce Ts65Dn tissue iron toxicity and improve the hematologic profile. Furthermore, it is hypothesized that male mice will display greater iron status and oxidative stress than females, with Ts65Dn showing greater levels than WT controls. As iron metabolism dysregulation and tissue iron accumulation can become more prominent with aging, understanding iron metabolism in Ds is of utmost importance as life expectancy of this population has dramatically improved over the past several decades.