Mechanisms of Down syndrome-associated swallowing dysfunction in mouse models

小鼠模型中唐氏综合症相关吞咽功能障碍的机制

• 批准号: 10444405
• 负责人: NADINE P CONNOR
• 金额: $ 205.19万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-13 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444405
• 关键词: Address; Adult; Age; Aging; Animal Model; Aspiration Pneumonia; Automobile Driving; Behavioral; Biological; Biological Assay; Brain Stem; Breathing; Cessation of life; Chromosome 21; Chromosomes; Clinical; Collaborations; Deglutition; Deglutition Disorders; Development; Dose; Down Syndrome; Elements; Engineering; Etiology; Functional disorder; Future; Gene Dosage; Gene Duplication; Genes; Genetic; Genetic Diseases; Glass; Goals; Human; Human Chromosomes; Impairment; Incidence; Investigation; Knowledge; Laboratories; Longevity; Modeling; Molecular; Mus; Muscle; Persons; Phenotype; Plant Roots; Population; Prevalence; Quality of life; Research; Risk; Role; Speech; Testing; Therapeutic Intervention; Tongue; Trisomy; Trisomy 3; Uncertainty; United States National Institutes of Health; Work; age effect; age related; base; design; effective therapy; experimental study; molecular phenotype; mouse Ts65Dn; mouse model; neglect; novel; response

ABSTRACT Down syndrome (DS), a genetic disorder, is associated with accelerated aging and high levels of swallowing impairments (dysphagia). This is a critical concern given the increased survival of people with DS to older ages, and the association of dysphagia, aspiration pneumonia, and death. Although dysphagia is a prominent feature of DS, little is known about its age-related progression or the genetic mechanisms that underly its etiology. There are significant knowledge gaps in DS research regarding how the extra copy of the human 21st chromosome known to be present is driving DS phenotypes. The proposed research will address these gaps through a collaboration between two laboratories with substantial expertise in translational animal models of aging, DS, and dysphagia (Connor/Glass) and in the engineering of novel DS mouse models (Yu). The overarching goals of the proposed work are to quantify effects of aging on DS-related dysphagia and to resolve a current major uncertainty concerning the mechanisms underlying phenotypes in DS. There are two proposed aims: (Aim 1) To test the hypothesis that dysphagia is exacerbated by aging in mouse models of DS by quantifying swallowing function, tongue muscle alterations, changes in brainstem regions in mice of different ages, and by performing additional analyses at the molecular and phenotypic levels; and (Aim 2) To quantify the impacts of various components of a trisomy on swallowing function in DS in crucial behavioral and biological variables. We will pursue the objective of Aim 2 by generating and analyzing a number of the novel tailor-designed mouse models. This work is significant because it will define age-related changes in swallow function in mouse models of DS using an ecologically valid assay (videofluoroscopy) that is also used clinically in humans. Further, this work will introduce clarity regarding the impact of the critical elements of a trisomy on DS-related dysphagia by using new mouse models thereby allowing us to unravel molecular contributors to dysphagia in this context and to optimize translational precision. There are currently only limited compensatory treatments for DS-associated dysphagia, and thus there is an urgent need to enhance our mechanistic understanding of this clinical manifestation to support rational development of future therapeutic interventions. This proposal is in response to NOT-OD-20-025, for the NIH INCLUDE Project on Down syndrome research.

抽象的 唐氏综合症 (DS) 是一种遗传性疾病，与加速衰老和高水平吞咽有关 损伤（吞咽困难）。鉴于 DS 患者到老年的生存率不断提高，这是一个至关重要的问题 年龄，以及吞咽困难、吸入性肺炎和死亡的关联。虽然吞咽困难是一个突出的 DS 的特征，但对其与年龄相关的进展或其背后的遗传机制知之甚少 病因学。 DS 研究中关于人类 21 世纪的额外副本如何 已知存在的染色体正在驱动 DS 表型。拟议的研究将解决这些差距 通过两个在转化动物模型方面拥有丰富专业知识的实验室之间的合作 衰老、DS 和吞咽困难 (Connor/Glass) 以及新型 DS 小鼠模型的工程 (Yu)。这 拟议工作的总体目标是量化衰老对 DS 相关吞咽困难的影响并解决 目前关于 DS 表型潜在机制的主要不确定性。有两个建议 目标：（目标 1）通过以下方法检验 DS 小鼠模型中吞咽困难会因衰老而加剧的假设： 量化不同小鼠的吞咽功能、舌肌改变、脑干区域的变化 年龄，并在分子和表型水平上进行额外的分析；和（目标 2）量化 三体性的各个组成部分对 DS 中关键行为和吞咽功能的影响 生物变量。我们将通过生成和分析一些小说来实现目标 2 量身设计的鼠标模型。这项工作意义重大，因为它将定义吞咽中与年龄相关的变化 使用生态有效的检测（视频荧光检查）在 DS 小鼠模型中发挥功能，该检测也已用于临床 在人类中。此外，这项工作将阐明三体性关键要素对 通过使用新的小鼠模型，我们能够解开与 DS 相关的吞咽困难的分子因素 在这种情况下吞咽困难并优化翻译精度。目前只有有限的补偿 DS 相关吞咽困难的治疗，因此迫切需要增强我们的机制 了解这种临床表现以支持未来治疗干预措施的合理发展。 该提案是针对 NIH INCLUDE 唐氏综合症研究项目的 NOT-OD-20-025 的回应。