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. !

大脑新陈代谢是生物学和人类疾病的一个基本方面。大脑严重依赖于 葡萄糖，消耗大量的葡萄糖作为认知、记忆和行为的生化燃料。基本原理 大脑新陈代谢的各个方面已经得到了广泛的研究，但最近关于脑代谢的关键作用的证据 神经疾病中的葡萄糖和糖原代谢最近开辟了新的研究途径。 深入研究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性、致命性糖原贮积症(GSD)，对两性都有影响。 症状出现在青春期，表现为抗药性癫痫、共济失调、神经变性和迅速下降。 在死前进入植物人状态。使用多种模型的几个实验室的结果表明， 细胞内异常的糖原样聚集体，称为多聚葡聚糖体(PGBs)，是LD的原因。 令人惊讶的是，我们和其他人已经在多种神经疾病中发现了pGb，我们假设 PGb是大脑受影响的GSD疾病进展的驱动力，pGb也扮演着 在阿尔茨海默病(AD)中的关键作用。 我们已经取得了关于LD的葡萄糖低代谢的基础性发现，定义了PGB是如何 影响细胞过程，开发尖端工具来确定潜在的细胞机制，以及 建立治疗平台，以抑制和/或消除前列腺癌。明确糖原的作用机制 LD中的新陈代谢提供了关于PGB如何形成和影响大脑动态平衡的见解。因此，LD提供了一个 这是了解正常大脑葡萄糖代谢和更广泛的疾病含义的独特窗口 新陈代谢受到干扰。 这款R35将结合我们由NINDS资助、以LD为中心的R01和P01，并将我们的专业知识扩展到Brain- 对GSD的影响和确定PGB在AD中的作用。展望未来，我们将进一步定义LD驱动 分子水平上的信号扰动，阐明细胞生理学的变化，并建立新的 在生物体层面上的治疗方式。令人兴奋的是，关于LD的工作可以作为如何 询问其他神经疾病中的大脑代谢紊乱情况，这些疾病涉及大脑皮质基底节。我们将应用这些 LD开发了强大的工具和见解来定义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如何 作为临床前治疗，移除会影响大脑新陈代谢。重要的是，我们有关键的预赛片段 来自小鼠模型和患者组织的LD、脑影响GSD和AD的数据。增加的 R35提供的稳定性、自由度和灵活性将使我们能够在大脑中做出开创性的发现 新陈代谢和确定PGB在多种疾病中的作用，同时执行发展的关键步骤 治疗和生物标记物的开发。 好了！