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.

项目总结/摘要 轴突变性是一个保守的和严格调控的过程，并且是神经系统中晚期病理的驱动力。 许多神经退行性疾病。缺乏治疗神经变性的方法， 疾病，轴突变性是早期干预和预防的目标。阐明具体的 引发轴突变性的机制可以帮助确定在疾病中保护轴突的方法， 最终治疗神经变性。 C.线虫线粒体运输突变体（MTM）没有轴突线粒体，导致轴突 退化在初步实验中，申请人有了一个令人惊讶的发现：抑制糖酵解。 MTM抑制轴突变性。根据这一发现，申请人表明，降解酶 负责乳酸产生的神经元可以挽救轴突的变性，这表明乳酸的积累可能 导致轴突退化然而，这种情况发生的分子机制尚不清楚。这 这一观察提示了一个假设，即糖酵解的产物乳酸盐在缺乏糖酵解的情况下积累。 线粒体并通过创造更酸性的轴突环境而引起变性。 这项工作的完成将阐明乳酸和相关代谢物对轴突的作用 变性（目的1）。此外，它将阐明轴突线粒体丢失的后果， 神经元-神经退行性疾病的关键特征。最后，这些实验可以识别新的 预防形态和功能性轴突变性的方法（目的2）。 本文提出的工作将建立乳酸在轴突变性中的作用，并进一步了解轴突变性的机制。 健康和疾病中神经元活动和乳酸之间的耦合。 在完成这项研究后，受训者将在良好的环境中接受广泛的培训。 配备了支持协作和尖端研究的设备。受训者将获得技术和分析能力 技能和专业独立性，为细胞和分子领域的学术生涯做准备 神经科学