Iron Metabolism in Ts65Dn mice, a Model of Down syndrome

唐氏综合症模型 Ts65Dn 小鼠的铁代谢

• 批准号: 10439300
• 负责人: Keith C DeRuisseau
• 金额: $ 46.53万
• 依托单位: ST. LOUIS COLLEGE OF PHARMACY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439300
• 关键词: Address; Adult; Age-Months; Aging; Alzheimer' s Disease; Area; Attenuated; Brain; Brain Pathology; Cardiopulmonary; Characteristics; Chromosome 21; Clinical; Cognitive; Congenital Heart Defects; Control Groups; DNA biosynthesis; Development; Developmental Disabilities; Down Syndrome; Early Onset Alzheimer Disease; Energy Metabolism; Etiology; Exhibits; Exposure to; Female; Gene Expression; Generations; Goals; Hematocrit procedure; Hematological Disease; Hematology; Hemoglobin; Homeostasis; Human; Hypoxia; Individual; Inflammation; Inflammatory Response; Intellectual functioning disability; Iron; Lead; Life Expectancy; Live Birth; Liver; Longevity; Modeling; Mus; Muscle Weakness; Outcome; Oxidative Stress; Pathology; Pathway interactions; Phenotype; Physiological Processes; Plasma; Population; Production; Public Health; Publishing; Reactive Oxygen Species; Regulation; Reporting; Research; Role; Testing; Tissues; Toxic effect; Trace Elements; Treatment Efficacy; Wild Type Mouse; Work; age group; age related; congenital heart disorder; craniofacial; efficacy testing; experimental study; hepcidin; improved; inflammatory marker; insight; iron metabolism; male; mouse Ts65Dn; mouse model; oxidative damage; oxygen transport; response; sex; systemic inflammatory response; tissue injury

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.

项目概要/摘要 唐氏综合症 (Ds) 是一种发育障碍，通常由 21 号染色体三倍体引起 21 号染色体三倍体的发生率为 700 例中的​​ 1 例，可能会改变正常的基因表达和 导致智力障碍、早发性阿尔茨海默病、先天性心脏病、血液系统疾病、 除其他情况外，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 铁是一种因参与生理而闻名的微量元素。 包括氧运输、炎症反应、能量代谢和 DNA 合成的过程。 Ds 中的铁稳态失调可能导致血浆铁水平和组织铁受损 尽管有报道称铁的积累会催化活性氧自由基（ROS）的产生。 Ds中的状态参数对铁稳态缺乏清晰和全面的了解 Ts65Dn 小鼠是 Ds 的既定模型。 研究调节 Ds 铁稳态的机制因素具有相当大的价值。 该项目旨在描述成年寿命期间铁稳态调节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。 研究，Ts65Dn 小鼠的组织（脑、肝和血浆）以及 3、12 和 3 岁的野生型 (WT) 群体对照 将研究 18 个月大的婴儿，以解决两个综合具体目标：1) 描绘铁稳态 Ts65Dn 小鼠在整个成年寿命中的表型，以及 2) 确定缺氧暴露的影响（10% 吸入氧）对全身和组织铁稳态、血液学特征和组织氧化应激的影响 Ts65Dn 小鼠 该提案的首要目标是建立 Ts65Dn 小鼠模型在铁研究中的效用。 Ds 中的状态和铁稳态调节 重新认识到 Ts65Dn 小鼠将表现出更大的能力。 炎症会促进铁调节反应，导致血浆室铁降低， Ts65Dn 小鼠中储存室中铁含量升高被认为与此相关。 第二个目标是利用缺氧来改变铁的稳态调节。 Ts65Dn 和 WT 小鼠检验缺氧诱导铁分布从储存转移到储存的假设 血浆室将降低 Ts65Dn 组织铁毒性并改善血液学特征。 研究发现，使用 Ts65Dn 时，雄性小鼠会比雌性小鼠表现出更高的铁状态和氧化应激 由于铁代谢失调和组织铁积累，显示出比 WT 对照更高的水平。 随着年龄的增长变得更加突出，了解 Ds 中的铁代谢对于生命至关重要 在过去的几十年里，这一人群的预期得到了显着提高。