Brain Glycogen - Metabolism, Mechanisms, and Therapeutic Potential

这是针对NOT-NS-21-040提出的行政补充请求，内容为 促进ADRD中的睡眠/昼夜节律研究“为R35NS116824题为”脑糖原代谢， 机制和治疗潜力。“申请的资金将用于进行代谢组学、组织学和 R35NS116824对阿尔茨海默病小鼠的RNA测序实验 模型中添加了包括睡眠中断的方法。家长助学金的重点是定义 被称为多聚葡糖体(PGB)的异常细胞内糖原样聚集体(PGBs)如何影响 神经退行性变。这项工作的中心是阿尔茨海默氏症和儿童痴呆症Lafora 疾病，努力定义新陈代谢的扰动如何影响疾病的进展，并测试前 临床治疗的选择，以消融大脑皮质，并测试生物学结果。我们假设睡眠 碎片化将增加PGB的形成，我们的初步数据强烈表明，增加的PGB 会对大脑新陈代谢产生负面影响。这份补充材料的一个显著优点是它将两个 具有互不重叠和互补专业知识且未合作的主要调查员 一起度过了过去的时光。该附录还将利用英国提供的丰富的专业知识和资源。 阿尔茨海默病中心(ADC)。在本补充资料中，我们将利用我们在PGB方面的广泛专业知识： 目的1：确定睡眠中断时的PGBs、代谢谱、基因表达和AD特征。 目的2：评估使用Val-0417治疗的AD动物睡眠中断时的AD特征。

This is an Administrative Supplement request in response to NOT-NS-21-040 for “Collaborative Activities to Promote Sleep/Circadian Research in ADRD” for R35NS116824 entitled “Brain Glycogen – Metabolism, Mechanisms, and Therapeutic Potential.” The requested funds are to perform metabolomics, histology, and RNA-sequencing experiments proposed within the scope of R35NS116824 on Alzheimer's disease mouse models with the addition of including sleep disruption to the methods. The parent grant focuses on defining how aberrant intracellular glycogen-like aggregates, known as polyglucosan bodies (PGBs), impact neurodegeneration. The work is centered on both Alzheimer's disease and the childhood dementia Lafora disease with efforts to define how perturbations in metabolism impact disease progression and test a pre- clinical therapeutic option to ablate PGBs and test the biological outcome. We hypothesize that sleep fragmentation will increase PGB formations and our preliminary data strongly suggests that increased PGBs will negatively impact brain metabolism. A significant strength of this supplement is that it brings together two principle investigators that have non-overlapping and complementary expertise and who have not collaborated together in the past. The supplement will also utilize the wealth of expertise and resources provided by the UK Alzheimer's Disease Center (ADC). In this supplement, we will utilize our extensive expertise with PGBs to: Aim 1: Define PGBs, metabolic profiles, gene expression, and AD hallmarks during disrupted sleep. Aim 2: Assess AD hallmarks during disrupted sleep in AD animals treated with VAL-0417.