Brain Glycogen - Metabolism, Mechanisms, and Therapeutic Potential

脑糖原 - 代谢、机制和治疗潜力

• 批准号: 10610572
• 负责人: Matthew S. Gentry
• 金额: $ 2.36万
• 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 2022-08-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10610572
• 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一个基本方面。 葡萄糖，消耗大量作为认知、记忆和行为的生化燃料。 人们主要研究了脑代谢的各个方面，但最近的证据表明， 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) 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 多个实验室使用多种模型的结果表明，在死亡前进入植物状态。 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，并且我们捕捉到了这一点 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/消除 PGB 的治疗平台，定义了糖原的机制。 LD 中的代谢提供了关于 PGB 如何形成和影响大脑稳态的见解。 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。 这个 R35 将结合我们 NINDS 资助的、以 LD 为中心的 R01 和 P01，并将我们的专业知识扩展到脑- 影响 GSD 并确定 PGB 在 AD 中的作用展望未来，我们将进一步定义 LD 驱动的。 分子水平上信号传导的扰动，阐明细胞生理学的变化，并建立新的 令人兴奋的是，关于 LD 的工作为如何 研究涉及 PGB 的其他神经系统疾病中的大脑代谢扰动我们将应用这些。 LD 开发的强大工具和见解可定义 PGB 如何影响多种神经系统疾病， 确定影响疾病进展的以糖原为中心的分子机制，并定义 PGB 如何 重要的是，作为临床前治疗，去除会影响大脑代谢。 来自小鼠模型和患者组织的 LD、脑影响 GSD 和 AD 数据。 R35 提供的稳定性、自由度和灵活性将使我们能够在大脑方面做出开创性的发现 代谢并定义 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。 ！