Mechanisms of Down syndrome-associated swallowing dysfunction in mouse models

摘要 唐氏综合症（DS）是一种遗传性疾病，与加速衰老和高水平的吞咽有关 功能障碍（吞咽困难）。这是一个关键的问题，因为DS患者的生存率增加到老年 年龄，以及吞咽困难、吸入性肺炎和死亡的相关性。虽然吞咽困难是一个突出的 尽管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。 病因学在DS研究中，关于人类21世纪的额外拷贝如何与人类21世纪的DNA结合， 已知存在的染色体驱动DS表型。拟议的研究将解决这些差距 通过两个实验室之间的合作，在翻译动物模型方面具有丰富的专业知识， 衰老、DS和吞咽困难（康纳/格拉斯）以及新型DS小鼠模型的工程化（Yu）。的 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表型基础机制的主要不确定性。有两个建议 目的：（目的1）在DS小鼠模型中，通过以下方法检验吞咽困难因衰老而加重的假设： 定量不同剂量的小鼠的吞咽功能、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（目的2）量化 三体性的各种成分对DS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的目标 量身定制的鼠标模型。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。 在DS小鼠模型中使用生态学有效的试验（视频荧光透视），该试验也用于临床 在人类身上。此外，这项工作将介绍清晰的三体性的关键因素的影响， 通过使用新的小鼠模型研究DS相关的吞咽困难，从而使我们能够解开 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 治疗DS相关吞咽困难，因此迫切需要加强我们的机制 了解这种临床表现，以支持未来治疗干预的合理发展。 该提案是对NOT-OD-20-025的回应，用于NIH纳入唐氏综合征研究项目。

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.