Elevated mitochondrial fusion and function in Down syndrome - Revision - 2

唐氏综合征（DS）患者与骨骼肌和运动功能的缺陷作斗争， 其根本原因是未知的，并且比中枢神经系统的原因研究得更少。 张力减退是出生时DS的普遍特征。在以后的生活中，患有DS的成年人会经历皮肤的过早老化。 神经肌肉接头（NMJ），骨骼肌功能降低（肌肉减少症）。调解机制 DS人群中的肌肉减少症尚不清楚，但对DS患者的健康有重大影响 在他们的生命周期中。此外，人们越来越认识到， 健身和保存认知功能在老龄化过程中在一般人群中，因此，我们认为， 维持和改善DS患者NMJ的完整性将有利于他们的身体和 神经轨迹本行政补编下拟议的工作将深入了解 分子机制，有助于改变发展和老化的NMJ在DS和铺路 一种新的基于知识的治疗方法，旨在改善和保护肌肉功能。母 R 01-HD 101544是一项有效的INCLUDE（对整个生命周期内共发疾病的调查， 了解唐氏综合征）项目，该项目的资助将持续到2024年6月底。拟议的研究是 完全符合父母奖的基本目标，但增加了一个重要的新目标， 特别是关于NMJ来源于DS和同基因个体的诱导多能干细胞（iPSC） 对照iPSC将分化为运动神经元，并与骨骼肌肌管（衍生的）共培养。 来自iPSC或原代小鼠成肌细胞）以建立功能性NMJ（遵循既定方案）。 将评估iPSC衍生的NMJ（hiNMJ）的细胞学和电生理学特征， 比较DS hiNMJ与对照组的发育、功能和退行性轨迹。一个 hiNMJ模型的一个重要优点是它允许我们研究一个定义明确的突触， 两种非常不同的细胞类型（运动神经元和肌肉纤维）的贡献，从而使我们能够分离 三体对突触前过程的影响与其对突触后过程的影响不同。这些研究 通过开发一个易于处理的DS NMJ模型来增强父母奖励的目标，在这个模型中，我们可以测试我们的 潜在的假设，即代谢活性和ROS产生增加，加上能力下降， 清除受损的线粒体，随着时间的推移，增加了DS患者的累积氧化损伤。

Individuals with Down syndrome (DS) contend with deficits in skeletal muscle and motor function, the underlying causes of which are unknown and much less well studied than those of the central nervous system. Hypotonia is a universal feature of DS at birth. Later in life, adults with DS experience premature aging of the neuromuscular junction (NMJ) with reduced skeletal muscle function (sarcopenia). The mechanisms mediating sarcopenia in the DS population are not known but have a major impact on well-being of individuals with DS across their lifespan. Furthermore, there is a growing appreciation for the critical connection between physical fitness and preservation of cognitive function during aging in the general population at large, thus, we posit that maintaining and improving the integrity of the NMJ in individuals with DS will benefit both their physical and neurological trajectories. The work proposed under this Administrative Supplement will provide insights into the molecular mechanisms that contribute to altered development and aging of the NMJ in DS and pave the way for new knowledge-based therapies designed to improve and preserve muscle function. The Parent award, R01-HD101544, is an active INCLUDE (Investigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) project that is funded through the end of June 2024. The proposed studies are completely in line with the underlying goals of the parent award but add an important new objective focused specifically on the NMJ. Induced pluripotent stem cells (iPSCs) derived from individuals with DS and isogenic control iPSCs will be differentiated to motor neurons and cocultured with skeletal muscle myotubes (derived either from iPSCs or primary mouse myoblasts) to establish functional NMJs (following established protocols). The cytological and electrophysiological features of the iPSC-derived NMJ (hiNMJs) will be assessed to compare the developmental, functional, and degenerative trajectories of DS hiNMJs with controls. An important strength of the hiNMJ model is that it allows us to study a well-defined synapse that requires the contribution of two very different cell types (motor neurons and muscle fibers) thereby allowing us to separate the impact of trisomy on pre-synaptic processes from its impact on those in the post-synapse. These studies enhance the goals of the parent award by developing a tractable model of DS NMJs in which we can test our underlying hypothesis that elevated metabolic activity and ROS production, coupled with a decreased capacity to remove damaged mitochondria, increases cumulative, oxidative damage over time in individuals with DS.