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，与加速衰老和高吞咽水平有关 功能障碍(吞咽困难)。这是一个严重的问题，因为DS患者的存活率增加到了老年人 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，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研究中存在着重大的知识空白，即人类第21号的额外副本如何 已知的染色体是驱动DS表型的因素。拟议的研究将解决这些差距 通过两个在翻译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)和设计新的DS小鼠模型(Yu)。这个 拟议工作的首要目标是量化衰老对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 目的：(目的1)验证以下假设：在DS小鼠模型中，吞咽困难随着年龄的增长而加重。 量化不同年龄组小鼠吞咽功能、舌肌改变、脑干区改变 AGEs，并在分子和表型水平上进行额外分析；以及(目标2)量化 三体不同成分对DS患者关键行为和功能障碍吞咽功能的影响 生物变量。我们将通过生成和分析一些小说来追求目标2的目标 量身定制的鼠标模型。这项工作意义重大，因为它将定义燕子的年龄相关变化 使用一种也用于临床的生态有效分析方法(视频透视)在DS小鼠模型中发挥作用 在人类身上。此外，这项工作将介绍关于三体的关键因素对 通过使用新的小鼠模型获得DS相关的吞咽困难，从而使我们能够解开与 在这种情况下吞咽困难和优化翻译的精确度。目前只有有限的补偿性 治疗DS相关的吞咽困难，因此迫切需要提高我们的机械性 了解这一临床表现以支持未来治疗干预措施的合理发展。 这项建议是对NIH唐氏综合症研究项目NOT-OD-20-025的回应。

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.