Tongue maturation deficits in a mouse model of Down syndrome

唐氏综合症小鼠模型的舌头成熟缺陷

• 批准号: 10363951
• 负责人: Tiffany Glass
• 金额: $ 130.87万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363951
• 关键词: Affect; Age; Anatomy; Animal Model; Apnea; Awareness; Basic Science; Behavioral; Behavioral Assay; Biological; Biological Markers; Biological Models; Biology; Birth; Brain Stem; Breathing; Cephalic; Characteristics; Child; Childhood; Clinical; Communication; Complex; Data; Deglutition; Deglutition Disorders; Development; Developmental Delay Disorders; Developmental Process; Disease; Down Syndrome; Eating; Evaluation; Failure; Foundations; Future; Gene Expression; Gene Expression Profiling; Goals; Health; Human; Hydration status; Immunofluorescence Immunologic; Impairment; Individual; Intellectual functioning disability; Intervention; Knowledge; Light; Liquid substance; Measures; Modification; Motor; Motor Skills; Movement; Mus; Muscle; National Institute of Child Health and Human Development; Neonatal; Outcome; Peripheral; Phenotype; Quality of life; Reporting; Research; Resolution; Science; Siblings; Speech; Speech Intelligibility; Structure; System; Texture; Time; Tongue; United States National Institutes of Health; Weaning; Work; base; design; developmental disease; drinking; early childhood; feeding; hypoglossal nucleus; mortality risk; mouse Ts65Dn; mouse model; muscular system; neuromuscular; neuromuscular system; nutrition; postnatal; postnatal development; response; targeted treatment; therapeutic evaluation; therapeutic target; therapy development; tool; translational model

PROJECT SUMMARY / ABSTRACT Atypical and delayed oromotor development is a well-known clinical aspect of Down syndrome (DS) and contributes to devastating challenges in speech, feeding, and swallowing. These challenges can affect the majority of individuals with DS, with profound consequences for quality of life and health. The tongue and brainstem are both complex systems that undergo rapid changes during early postnatal development and are critical for speech and swallowing. However, the central and peripheral changes occurring in early childhood that permit postnatal expansion in movement and function of the tongue are poorly understood in typical development and in DS. Because early childhood is a time of rapid development during which the neuromuscular system is plastic, altered tongue activity during this time may also alter the postnatal maturation of the tongue neuromuscular system. However, the impact of altered lingual activity on intrinsic tongue and brainstem maturation in early post-natal development has rarely been studied and is therefore unknown. We hypothesize that DS is associated with developmental delays in maturation of the tongue neuromuscular system. The proposed work is highly significant in using mouse models to advance understanding of a developmental disorder in which atypical tongue function contributes to compromise of speech intelligibility and health. Aim 1 will generate normative data for the study of tongue and brainstem maturation with reference to three consecutive early postnatal ages and will determine how DS impacts lingual development. This will be achieved through behavioral, immunofluorescence, and gene expression studies of tongue muscles and brainstem in the Ts65Dn mouse model of DS in comparison to typical sibling controls. Aim 2 will determine whether lingual activity levels after weaning impact maturation of the tongue neuromuscular system. This aim will be achieved through analysis of tongue and brainstem before weaning and after 2 weeks of an ecologically valid post-weaning condition in which all mice naturally refrain from licking due to a liquid consistency modification. This aim will clarify the extent to which shifts in tongue activity imposed by environmental modifications elicit changes in postnatal maturation of the tongue and brainstem in Ts65Dn mice and in typical sibling controls. Collectively, these aims will further the science underlying both typical and delayed lingual maturation. This work will also shed light on basic biological implications of feeding interventions used with children with DS that alter oromotor activity. As such, this work will provide basic knowledge for future efforts to develop biologically based approaches for successful resolution of pediatric oromotor disorders. These goals will establish an experimental framework to advance biologically informed treatments for developmental speech, feeding, and swallowing disorders.

项目总结/摘要 非典型和延迟的卵巢发育是唐氏综合征（DS）的一个众所周知的临床方面， 在语言、进食和吞咽方面造成了毁灭性的挑战。这些挑战可能会影响 大多数患有DS的个体，对生活质量和健康产生深远的影响。舌头和 脑干是在出生后早期发育期间经历快速变化的复杂系统， 对说话和吞咽很重要。然而，在幼儿期发生的中枢和外周变化 允许出生后舌头的运动和功能扩展的因素在典型的 发展和DS。因为幼儿期是一个快速发展的时期， 神经肌肉系统是可塑性的，在此期间改变舌头活动也可能改变出生后的成熟 舌神经肌肉系统的功能然而，舌活动的改变对固有舌和 出生后早期发育中的脑干成熟很少被研究，因此是未知的。我们 假设DS与舌神经肌肉成熟的发育延迟有关 系统这项工作对于利用小鼠模型来进一步了解 一种发育障碍，其中非典型的舌功能导致言语清晰度受损， 健康目标1将参考为舌和脑干成熟研究提供规范性数据 三个连续的出生后早期年龄，并将确定DS如何影响语言发育。这将是 通过舌肌的行为、免疫荧光和基因表达研究， 与典型的同胞对照相比，DS的Ts 65 Dn小鼠模型中的脑干。目标2将决定 断奶后的舌活动水平是否影响舌神经肌肉系统的成熟。这一目标 将通过分析断奶前和2周后的舌和脑干来实现 有效的断奶后条件，其中所有小鼠由于液体稠度而自然避免舔 改性这一目标将阐明环境因素对舌头活动的影响程度。 修饰引起Ts 65 Dn小鼠和典型小鼠舌和脑干出生后成熟的变化。 兄弟姐妹控制。总的来说，这些目标将促进典型语言和延迟语言的科学基础 成熟这项工作还将阐明与哺乳动物一起使用的喂养干预措施的基本生物学意义。 患有DS的儿童，改变了他们的活动。因此，这项工作将为今后的努力提供基本知识， 开发基于生物学的方法，以成功解决儿科疾病。这些目标 将建立一个实验框架，以推进生物信息治疗的发展 语言、进食和吞咽障碍。