Brain Glycogen - Metabolism, Mechanisms, and Therapeutic Potential

脑糖原 - 代谢、机制和治疗潜力

• 批准号: 10401225
• 负责人: Matthew S. Gentry
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10401225
• 关键词: Administrative Supplement; Alzheimer' s Disease; Alzheimer' s disease related dementia; Animals; Biological Testing; Brain; Carbohydrates; Cellular Metabolic Process; Childhood; Complex; Comprehension; Data; Dementia; Diagnosis; Disease; Disease Progression; Event; Funding; Gene Expression; Glycogen; Histology; Knowledge; Lafora Disease; Metabolism; Methods; Mus; Nerve Degeneration; Outcome; Research; Research Personnel; Resources; Sleep; Sleep Fragmentations; Sleep disturbances; Testing; Therapeutic; Translating; Work; brain metabolism; circadian; experimental study; glycogen metabolism; insight; metabolic profile; metabolomics; mouse model; parent grant; polyglucosan; pre-clinical; response; transcriptome sequencing

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.

这是对NOT-NS-21-040“合作活动， 促进ADRD中的睡眠/昼夜节律研究”，针对R35 NS 116824，标题为“脑糖原-代谢， 机制和治疗潜力。”所要求的资金是进行代谢组学，组织学， 在R35 NS 116824范围内对阿尔茨海默病小鼠进行的RNA测序实验 模型中添加了睡眠中断的方法。父母补助金的重点是定义 异常的细胞内糖原样聚集体（称为葡聚糖体（PGB））如何影响 神经变性这项工作的重点是阿尔茨海默病和儿童痴呆症Lafora 疾病，努力确定代谢紊乱如何影响疾病进展，并测试预 消融PGB并测试生物学结局的临床治疗选择。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，PGB的增加 会对大脑新陈代谢产生负面影响这一补充的一个显着优势是，它汇集了两个 具有非重叠和互补专业知识且未合作的主要研究者 一起在过去。该补充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）。在本补充文件中，我们将利用我们在PGB方面的广泛专业知识： 目的1：定义PGB，代谢谱，基因表达和AD标志在睡眠中断。 目的2：评估瓦尔-0417给药AD动物睡眠中断期间的AD标志。