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基本方面。大脑关键取决于 葡萄糖，消耗大量的生化燃料，用于认知，记忆和行为。基本的 大脑代谢方面已经进行了广泛的研究，但有关的最新证据 神经系统疾病中的葡萄糖和糖原代谢最近开发了新的研究途径。 已深入研究了异常葡萄糖代谢的神经系统疾病是Lafora病 （LD）。 LD是一种常染色体隐性，致命的，糖原储存疾病（GSD），同样影响两性。 抗药性癫痫，共济失调，神经退行性和快速下降的症状在青春期出现 死亡前进入营养状态。使用多个模型的多个实验室的结果表明， 异常的细胞内糖原样聚集体，称为聚葡萄糖体（PGB），是LD的原因。 令人惊讶的是，我们和其他人已经确定了多种神经系统疾病中的PGB，我们假设 PGB是脑反影响GSD疾病进展的驱动力，PGB也发挥 在阿尔茨海默氏病（AD）中的关键作用。 我们已经对LD中的葡萄糖低代谢进行了基本发现，该发现定义了PGB 影响细胞过程，开发的尖端工具以确定潜在的细胞机制，并 建立了抑制和/或消除PGB的治疗平台。定义糖原的机制 LD中的代谢提供了有关PGB如何形成和影响大脑稳态的见解。因此，LD提供了 当此时，独特的窗口进入正常的脑葡萄糖代谢和更广泛的疾病意义 代谢受到干扰。 这种补充剂将使Trey Coburn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 在确定PGB在AD中的作用。他将研究分子水平的信号传导中的扰动， 阐明细胞生理的变化，并在生物水平上建立新的治疗方式。