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.

这是针对 NOT-NS-21-040“合作活动 促进 ADRD 中的睡眠/昼夜节律研究”，R35NS116824，题为“脑糖原 – 代谢， 机制和治疗潜力。”请求的资金用于进行代谢组学、组织学和 R35NS116824 范围内提出的针对阿尔茨海默病小鼠的 RNA 测序实验 模型中还添加了睡眠干扰的方法。家长补助金的重点是定义 异常的细胞内糖原样聚集体（称为聚葡聚糖体 (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，努力定义代谢扰动如何影响疾病进展并测试预 消除 PGB 并测试生物学结果的临床治疗选择。我们假设睡眠 碎片化会增加 PGB 的形成，我们的初步数据强烈表明，增加的 PGB 会对大脑的新陈代谢产生负面影响。该补充品的一个重要优势在于它汇集了两种 主要研究人员具有不重叠和互补的专业知识并且没有合作 过去一起。该增刊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)。在本增刊中，我们将利用我们在 PGB 方面的丰富专业知识来： 目标 1：定义睡眠中断期间的 PG​​B、代谢特征、基因表达和 AD 标志。 目标 2：评估接受 VAL-0417 治疗的 AD 动物睡眠中断期间的 AD 标志。