Brain Glycogen - Metabolism, Mechanisms, and Therapeutic Potential

脑糖原 - 代谢、机制和治疗潜力

• 批准号: 10285469
• 负责人: Matthew S. Gentry
• 金额: $ 0.19万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10285469
• 关键词: Adolescence; Affect; Alzheimer' s Disease; Ataxia; Behavior; Biochemical; Biology; Brain; Carbohydrates; Cell physiology; Cellular Metabolic Process; Cessation of life; Cognition; Complex; Comprehension; Consumption; Diagnosis; Disease; Disease Progression; Event; Foundations; Glucose; Glycogen; Glycogen Storage Disease; Homeostasis; Intractable Epilepsy; Knowledge; Lafora Disease; Memory; Metabolism; Modality; Modeling; Molecular; Nerve Degeneration; Neurosciences; Play; Research; Role; Signal Transduction; Symptoms; Therapeutic; Translating; Vegetative States; Work; brain metabolism; driving force; glucose metabolism; glycogen metabolism; human disease; insight; nervous system disorder; novel therapeutics; polyglucosan; sex; skills; tool

Brain metabolism is a fundamental aspect of biology and human disease. The brain critically depends on glucose, consuming large quantities as the biochemical fuel for cognition, memory, and behavior. Fundamental aspects of brain metabolism have been extensively studied, but recent evidence regarding the key role of glucose and glycogen metabolism in neurological diseases has recently opened up new avenues of research. The neurological disease where aberrant glucose metabolism has been investigated in-depth is Lafora disease (LD). LD is an autosomal recessive, fatal, glycogen storage disease (GSD) that equally affects both sexes. Symptoms emerge in adolescence with drug-resistant epilepsy, ataxia, neurodegeneration, and a rapid decline into a vegetative state before death. Results from several labs using multiple models have demonstrated that aberrant intracellular glycogen-like aggregates, known as polyglucosan bodies (PGBs), are the cause of LD. Strikingly, we and others have identified PGBs in multiple neurological diseases and we hypothesize that PGBs are a driving force in disease progression for brain-impacted GSDs, and that PGBs also play a critical role in Alzheimer's disease (AD). We have made foundational discoveries regarding glucose hypometabolism in LD, defined how PGBs impact cellular processes, developed cutting-edge tools to determine the underlying cellular mechanisms, and established therapeutic platforms to inhibit and/or eliminate PGBs. Defining the mechanisms of glycogen metabolism in LD provides insights into how PGBs form and impact brain homeostasis. Thus, LD offers a unique window into both normal brain glucose metabolism and broader disease implications when this metabolism is perturbed. This supplement will allow Mr. Trey Coburn to further hone his skills in neuroscience. His results will assist in determining the role of PGBs in AD. He will look at perturbations in signaling at the molecular level, elucidate changes in cellular physiology, and establish novel therapeutic modalities at the organismal level.

脑代谢是生物学和人类疾病的一个基本方面。大脑关键取决于 葡萄糖，消耗大量作为认知、记忆和行为的生化燃料。基本的 大脑代谢的各个方面已被广泛研究，但最近的证据表明大脑代谢的关键作用 神经系统疾病中的葡萄糖和糖原代谢最近开辟了新的研究途径。 已深入研究葡萄糖代谢异常的神经系统疾病是拉福拉病 （LD）。 LD 是一种常染色体隐性遗传、致命的糖原累积病 (GSD)，对两性都有同样的影响。 青春期出现耐药性癫痫、共济失调、神经退行性变等症状，且病情迅速衰退 死前进入植物人状态。多个实验室使用多种模型的结果表明 异常的细胞内糖原样聚集体，称为聚葡聚糖体 (PGB)，是 LD 的原因。 引人注目的是，我们和其他人已经在多种神经系统疾病中发现了 PGB，并且我们假设 PGB 是脑部影响的 GSD 疾病进展的驱动力，并且 PGB 还发挥着重要作用 在阿尔茨海默病（AD）中发挥着重要作用。 我们在 LD 中的葡萄糖代谢减退方面取得了基础性发现，定义了 PGB 如何 影响细胞过程，开发尖端工具来确定潜在的细胞机制，以及 建立了抑制和/或消除 PGB 的治疗平台。定义糖原的机制 LD 中的新陈代谢提供了关于 PGB 如何形成和影响大脑稳态的见解。因此，LD 提供了 了解正常大脑葡萄糖代谢和更广泛的疾病影响的独特窗口 新陈代谢受到干扰。 该补充品将使特雷·科伯恩先生能够进一步磨练他在神经科学方面的技能。他的结果将有助于 确定 PGB 在 AD 中的作用。他将在分子水平上研究信号传导的扰动， 阐明细胞生理学的变化，并在有机体水平上建立新的治疗方式。