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发生率很高，这可能对沟通效率、健康和生活质量产生毁灭性影响。在患有DS的人类和DS动物模型中进行的研究报告了头部和颈部神经和肌肉的独特属性，表明DS中的沟通和吞咽困难可能至少部分归因于外周神经肌肉病变。然而，很少有人知道这些病理在DS的生物学特性，他们如何表现和/或相互作用的解剖生长在出生后的发展和成熟，以及他们如何与功能缺陷。此外，尚不清楚DS患者的头部和颈部肌肉是否表现出对不断变化的需求的肌肉适应异常（神经肌肉可塑性）。这种知识的缺乏在转化研究途径中造成了相当大的障碍，通过转化研究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Ts 65 Dn（DS的三体小鼠模型）和Dp（16）1 Yey/+（DS中涉及许多基因重复的小鼠模型）中头部和颈部肌肉的神经肌肉损伤来填补这些知识空白。这项为期一年的研究有两个具体目标。目标1：为了解决Ts 65 Dn和Dp（16）1 Yey/+的出生后发育涉及肌肉适应变化或肌肉功能需求的异常这一假设，我们将在幼年小鼠与未受影响的同胞对照中，对断奶后食物稠度改变的咀嚼速率和肌肉肌球蛋白重链（MyHC）亚型谱的变化进行定量。我们进一步假设，与对照组相比，幼年Ts 65 Dn和Dp（16）1 Yey/+小鼠在食物稠度改变后，咀嚼率降低，与相关肌肉中的非典型MyHC 2b亚型分布变化一致。目标二：为了检验成年Ts 65 Dn和Dp（16）1 Yey/+小鼠在发声和咀嚼相关肌肉中具有神经肌肉差异的假设，我们将检查成年小鼠与未受影响的同胞对照小鼠的头颈部神经肌肉功能和病理学。为此，我们假设，成熟的Ts 65 Dn和Dp（16）1 Yey/+小鼠将表现出增加的神经肌肉接头断裂和减少的MyHC 2b水平在头部和颈部肌肉，同时在发声和咀嚼功能缺陷。研究结果将有助于了解发生在DS的头颈部肌肉表型的内在生物学属性，并将提供洞察表型，可能是动态的，通过出生后的发展。更好地了解神经肌肉可塑性和神经肌肉病理目前在DS将提供大量的动力，以确定新的治疗目标，独特的缺陷，这种综合征。预计这些知识将最终允许开发具有改善的临床结果的有效治疗。

 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.