Defining the Role of Lactate in Axon Degeneration

定义乳酸在轴突变性中的作用

• 批准号: 10750375
• 负责人: Hadas Tal
• 金额: $ 3.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750375
• 关键词: Acidosis; Animals; Automobile Driving; Auxins; Axon; Back; Bacteria; Behavior; Binding; Biological Assay; Biology; Caenorhabditis elegans; Cell Death; Cells; Cellular biology; Coupling; Custom; Data; Disease; Early Intervention; Elderly; Environment; Enzymes; Exhibits; Fellowship; Fluorescence Resonance Energy Transfer; Genetic Research; Glycolysis; Glycolysis Inhibition; Health; Homologous Gene; Human; Individual; Intervention; Kinesin; Lactate Transporter; Lactic acid; Link; Locomotion; Metabolism; Microscope; Mitochondria; Modeling; Molecular; Morphology; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Pathology; Pharmaceutical Preparations; Phenotype; Prevention; Prevention therapy; Process; Production; Pyruvate Metabolism Pathway; Research; Role; System; Testing; Training; Work; academic preparation; age related; axonal degeneration; career; combat; driving force; experimental study; improved; in vivo; inhibitor; insight; lactate dehydrogenase 1; lactate dehydrogenase A; mutant; neuronal metabolism; novel strategies; optogenetics; overexpression; prevent; sensor; skills; tool; trafficking

Project Summary/Abstract Axon degeneration is a conserved and tightly regulated process and is a driving force of later pathologies in many neurodegenerative diseases. There is a lack of treatments for neurodegeneration that results from disease, and axon degeneration is a target for early intervention and prevention. Elucidating the specific mechanisms that initiate axon degeneration could assist in identifying ways to protect axons in disease and ultimately treat neurodegeneration. C. elegans Mitochondrial Trafficking Mutants (MTMs) have no axonal mitochondria, resulting in axon degeneration. In preliminary experiments the applicant made a surprising discovery: inhibiting glycolysis in MTMs suppresses axon degeneration. Following this finding the applicant showed that degrading the enzyme responsible for lactate production rescues degeneration of axons, suggesting that lactate accumulation may drive axon degeneration. However, the molecular mechanism by which this occurs is unknown. This observation prompted the hypothesis that the product of glycolysis, lactate, accumulates in the absence of mitochondria and by creating a more acidic axonal environment instigates degeneration. Completion of this proposed work will elucidate the role of lactate and related metabolites on axon degeneration (Aim 1). Further, it will shed light on the consequences of loss of axonal mitochondria for neurons —a key feature of neurodegenerative diseases. Finally, these experiments may identify novel approaches for preventing morphological and functional axon degeneration (Aim 2). Work proposed here will establish the role of lactate in axon degeneration and further our understanding of the coupling between neuronal activity and lactate in health and disease. Upon completion of this fellowship the trainee will have received extensive training in an environment well equipped to support collaborative and cutting-edge research. The trainee will gain technical and analytical skills, and professional independence in preparation for an academic career in cellular and molecular neuroscience.

项目摘要/摘要 轴突变性是一个保守且严格调节的过程，是后来病理的驱动力 许多神经退行性疾病。缺乏对神经退行性的治疗，这是由 疾病和轴突变性是早期干预和预防的目标。阐明特定 启动轴突变性的机制可以帮助确定保护疾病中轴突的方法 最终处理神经变性。 秀丽隐杆线虫线粒体运输突变体（MTMS）没有轴突线粒体，导致轴突 退化。在初步实验中，申请人令人惊讶的发现：抑制糖酵解 MTM抑制轴突变性。在此发现之后，适用的表明降解酶 负责导致轴突变性的生产响应，这表明撕裂的积累可能 驱动轴突变性。但是，发生这种情况的分子机制尚不清楚。这 观察促使一个假设，即糖酵解，乳酸的产物在没有的情况下积累 线粒体并通过创建更酸性的轴突环境促进变性。 这项建议的工作的完成将阐明鞋底和相关代谢物在轴突上的作用 变性（目标1）。此外，它将阐明轴突线粒体损失的后果 神经元 - 神经退行性疾病的关键特征。最后，这些实验可以识别出新颖 预防形态和功能性轴突变性的方法（AIM 2）。 这里提出的工作将确定乳酸在轴突变性中的作用，并进一步了解我们对 神经元活动与健康和疾病中的耦合。 该奖学金完成后，学员将在环境中接受广泛的培训 配备了协作和尖端研究。学员将获得技术和分析 技能和专业独立性，为细胞和分子的学术生涯做准备 神经科学。