Study of Head and Neck Muscular Disruption in Mouse Models of Down Syndrome

 描述(由申请人提供)：唐氏综合症(DS)患者的言语和吞咽障碍的发生率很高，这可能会对沟通效率、健康和生活质量产生破坏性影响。对患有DS的人类和DS动物模型的研究报告了头部和颈部神经和肌肉的独特属性，表明DS患者的沟通和吞咽困难可能至少部分归因于外周神经肌肉病理。然而，对于DS中这些病理的生物学特征，它们在出生后发育和成熟过程中如何表现和/或与解剖生长相互作用，以及它们与功能缺陷的关系，人们知之甚少。此外，目前尚不清楚DS患者的头和颈部肌肉是否表现出肌肉对不断变化的需求(神经肌肉可塑性)的异常适应。这种知识的缺乏在翻译研究的道路上造成了相当大的障碍，通过这种途径可以开发有效的沟通和吞咽困难的治疗方法。这项拟议的研究将通过评估Ts65Dn和DP(16)1Yey/+的三体小鼠模型中头部和颈部肌肉的神经肌肉损伤来填补这些知识空白；Dp(16)1Yey/+是一种复制了与DS相关的许多基因的小鼠模型。这项为期一年的研究有两个具体目标。目的1：为了解释Ts65Dn和DP(16)1Yey/+基因的出生后发育涉及肌肉适应不断变化的运动功能需求的异常这一假设，我们将量化仔鼠断奶后的咀嚼速率和肌肉肌球蛋白重链(MyHC)亚型的变化，以响应断奶后食物一致性的改变，与未受影响的同胞对照组相比。我们进一步假设，与对照组相比，幼年Ts65Dn和DP(16)1Yey/+小鼠的咀嚼速度都会降低，这与食物一致性修改后相关肌肉中非典型的MyHC 2b亚型变化一致。目的：为了验证成年Ts65Dn和Dp(16)1Yey/+小鼠在发声和咀嚼相关肌肉中存在神经肌肉差异的假设，我们将检测成年小鼠和未受影响的同胞对照组小鼠的头和颈部神经肌肉功能和病理学。为此，我们假设成熟的Ts65Dn和DP(16)1Yey/+小鼠将表现出神经肌肉连接断裂增加和头部和颈部肌肉MyHC 2b水平降低，与发声和咀嚼功能缺陷相吻合。这些发现将有助于理解DS患者头部和颈部肌肉表型的内在生物学属性，并将提供对可能在出生后发育过程中动态变化的表型的洞察。更好地了解DS的神经肌肉可塑性和神经肌肉病理机制将为识别这种综合征特有的缺陷的新的治疗靶点提供实质性的动力。预计这些知识最终将允许开发有效的治疗方法，改善临床结果。

 DESCRIPTION (provided by applicant): Individuals with Down syndrome (DS) have a high incidence of speech and swallowing impairments that can have devastating impacts on communicative effectiveness, health, and quality of life. Studies in humans with DS and animal models of DS have reported unique attributes of head and neck nerves and muscles, suggesting that difficulties in communication and swallowing in DS may be due at least in part to peripheral neuromuscular pathologies. However, very little is known about the biological characteristics of these pathologies in DS, how they may manifest and/or interact with anatomic growth during postnatal development and maturation, and how they relate to functional deficits. Additionally, it is unknown if head and neck muscles in DS manifest abnormalities in muscular adaptation to changing demands (neuromuscular plasticity). This lack of knowledge poses considerable barriers in a translational research pathway through which effective treatments for communication and swallowing difficulties may be developed. This proposed research will fill these gaps in knowledge by assessing neuromuscular impairments in head and neck muscles in both Ts65Dn; a trisomic mouse model of DS, and Dp(16)1Yey/+; a mouse model with a duplication of many genes involved in DS. This one-year study has two specific aims. Aim 1: To address the hypothesis that post-natal development in Ts65Dn and Dp(16)1Yey/+ involves abnormalities in muscular adaptations to changing oromotor functional demands, we will quantify mastication rates and changes in muscle myosin heavy chain (MyHC) isoform profiles in response to food consistency modifications after weaning, in juvenile mice versus unaffected sibling controls. We further hypothesize that compared to controls, both juvenile Ts65Dn and Dp(16)1Yey/+ mice will show reduced mastication rates coinciding with atypical MyHC 2b isoform profile shifts in pertinent muscles after food consistency modifications. Aim 2: To test the hypothesis that adult Ts65Dn and Dp(16)1Yey/+ mice have neuromuscular differences within muscles involved in vocalization and mastication, we will examine head and neck neuromuscular function and pathology in the mature mice versus unaffected sibling controls. For this aim we hypothesize that mature Ts65Dn and Dp(16)1Yey/+ mice will show increased neuromuscular junction fragmentation and reduced MyHC 2b levels in head and neck muscles, coinciding with functional deficits in vocalization and mastication. Findings will help provide an understanding of the intrinsic biological attributes of head and neck muscle phenotypes that occur in DS, and will provide insight into phenotypes that may be dynamic through post-natal development. A better understanding of the neuromuscular plasticity and neuromuscular pathologies present in DS will provide substantial momentum to the identification of novel therapeutic targets for deficits unique to this syndrome. It is expected that such knowledge will ultimately permit the development of effective treatments with improved clinical outcomes.