Brain Glycogen - Metabolism, Mechanisms, and Therapeutic Potential

脑糖原 - 代谢、机制和治疗潜力

• 批准号: 10159325
• 负责人: Matthew S. Gentry
• 金额: $ 114.75万
• 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/10159325
• 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; Data; Diagnosis; Disease; Disease Progression; Event; Excision; Foundations; Freedom; Funding; Glucose; Glycogen; Glycogen Storage Disease; Homeostasis; Intractable Epilepsy; Knowledge; Lafora Disease; Memory; Metabolic; Metabolism; Modality; Modeling; Molecular; Mutation; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Patients; Play; Research; Role; Seminal; Signal Transduction; Symptoms; Therapeutic; Tissues; Translating; Vegetative States; Work; biomarker development; brain metabolism; driving force; flexibility; glucose metabolism; glycogen metabolism; human disease; insight; mouse model; nervous system disorder; novel therapeutics; polyglucosan; pre-clinical; sex; therapy development; 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 R35 will combine our NINDS-funded, LD-centric R01 and P01, and extend our expertise to brain- impacted GSDs and determining the role of PGBs in AD. Moving forward, we will further define LD-driven perturbations in signaling at the molecular level, elucidate changes in cellular physiology, and establish novel therapeutic modalities at the organismal level. Excitingly, the work on LD serves as a model for how to interrogate brain metabolic perturbations in other neurological diseases involving PGBs. We will apply these powerful LD-developed tools and insights to define how PGBs impact multiple neurological diseases, determine the glycogen-centric molecular mechanisms impacting disease progression, and define how PGB removal affects brain metabolism as a pre-clinical therapeutic. Importantly, we have key pieces of preliminary data for LD, brain-impacted GSDs, and AD from both mouse models and patient tissue. The increased stability, freedom, and flexibility provided by the R35 would allow us to make seminal discoveries in brain metabolism and define the role of PGBs in multiple diseases while carrying out key steps in the development of therapies and biomarker development. !

大脑代谢是生物学和人类疾病的基本方面。 葡萄糖，消耗大量的生化燃料，用于认知，记忆和行为。 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）。 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 死亡前的植物状态。 异常的细胞内糖原样聚集（称为聚葡萄糖体（PGB））是LD的停止。 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的疾病进展的推动力，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，开发的最先进的工具设置的基础细胞机制，以及 建立的治疗平台以吸入/或消除PGB。 LD中的代谢提供了有关PGB的形成和影响大脑稳态的见解。 正常的脑葡萄糖代谢和更广泛的疾病含义的独特窗口，而 代谢受到干扰。 这款R35将结合我们的Ninds资助，以LD为中心的R01和P01，并将我们的专业知识扩展到大脑 受影响的GSD并确定PGB在AD中的作用，我们将进一步定义LD驱动 在分子水平的信号传导中扰动，阐明细胞生理的变化，并建立新颖的 令人兴奋的是，LD上的工作是如何进行的。 询问其他涉及PGB的神经系统疾病中的大脑代谢扰动。 强大的LD开发工具和见解，以定义PGB如何影响多种神经疾病， 确定影响疾病进展的以糖原为中心的分子机制，并定义PGB 去除会影响大脑代谢作为一种临床前治疗。 LD，脑影响的GSD和AD的数据来自小鼠模型和患者组织 R35提供的稳定性，自由和灵活性将使我们能够在Brain中进行开创性发现 代谢并定义了PGB在多种疾病中的作用，同时在开发中执行关键步骤 疗法和生物标志物开发。 呢