Defining the functional role of astrocyte-derived lactate

定义星形胶质细胞衍生的乳酸的功能作用

• 批准号: 10394035
• 负责人: Kevin McAvoy
• 金额: $ 3.42万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394035
• 关键词: Ablation; Affect; Affinity; Anxiety; Area; Astrocytes; Auditory; Behavior; Behavioral; Bioenergetics; Biological Assay; Body Weight; Brain; Cell Culture Techniques; Cells; Citric Acid; Coculture Techniques; Cognitive; Complex; Conditioned Culture Media; Country; Coupled; Coupling; Development; Disease; Educational workshop; Electrons; Energy Metabolism; Energy Supply; Environment; Enzymes; Ethics; Excision; Exposure to; Extramural Activities; Fellowship; Fluorescence Microscopy; Fostering; Genes; Genetic; Genetic Transcription; Glutamates; Glycolysis; Goals; Health; Homeostasis; Human; In Vitro; Injury; Isoenzymes; Knock-out; Label; Lactate Dehydrogenase; Learning; Longevity; Mass Spectrum Analysis; Measurement; Measures; Mediating; Membrane Potentials; Memory; Metabolic; Metabolic Pathway; Metabolism; Morphology; Motor; Mus; NADH; Nerve Degeneration; Nervous system structure; Neuroglia; Neurons; Oxygen Consumption; Pathologic; Pathway interactions; Performance; Pharmacology; Process; Production; Pyruvate; Pyruvate Dehydrogenase Complex; Regulation; Research; Resource Development; Rest; Rodent; Role; Sensory; Series; Signal Transduction; Sleep Deprivation; Spinal Cord; Stable Isotope Labeling; System; Techniques; Testing; Time; Touch sensation; Training; Variant; Vision; age related; behavior test; career development; cell type; design; extracellular; genetic approach; in vivo; in vivo Model; induced pluripotent stem cell; knock-down; lactate dehydrogenase A; medical schools; metabolomics; mitochondrial membrane; mouse model; neurotransmission; novel; novel strategies; postnatal development; prevent; programs; success; uptake

Project Summary/Abstract: The overarching goal of this proposal is to understand the functional role of the glycolytic end-product lactate in the nervous system. Astrocytes, the most abundant CNS cell-type, are the most significant producers of lactate in the CNS. A leading hypothesis on metabolite fluxes in the CNS postulates that astrocytes transfer the lactate they produce to neurons for use as fuel, but this hypothesis remains controversial. Importantly, variations in CNS lactate levels are associated with a number of pathological states and fatal diseases. However, the exact role of astrocyte-produced lactate in the CNS remains unclear, severely limiting our interpretation of these observations and our basic understanding of brain energy metabolism regulation in health and disease. Here, we hypothesize that astrocytic lactate production supports diverse CNS functions and is required for maintaining viability and normal function of both astrocytes and neurons. To study this, we propose three complimentary aims, making use of human and rodent in vitro neuron and astrocyte systems as well as a novel mouse model for in vivo studies. In Aim 1 we will measure the effect of inhibiting lactate production on astrocytic viability, metabolism, and function in vitro. In Aim 2 we will measure the effect of silencing astrocytic lactate production on neuronal viability and metabolism in vitro. In Aim 3 we will measure the effect of ablating astrocytic lactate production on motor, cognitive, and sensory functions in vivo. We propose several novel approaches to studying this question: direct measurements of astrocyte-neuron lactate transfer through stable- isotope labeling techniques in compartmentalized cell-cultures, combining metabolic and metabolomic measurements with longitudinal cell-specific function and viability studies, and the use of a novel mouse model which targets lactate manipulations specifically to astrocytes. We hypothesize that astrocytic lactate production is required for maintaining viability and normal function of both astrocytes and neurons in diverse CNS functions. This application seeks a comprehensive fellowship training plan which incorporates training in new techniques within the lab, technical training at cutting-edge extramural workshops, intellectual development through attending and presenting at multiple seminar series, ethical training through formal coursework, and career development training through scientific seminars and workshops focused on pathways to independence. The proposed project is an entirely new project devised by the applicant which compliments the sponsor’s extensive research program, such designed to foster independence while being supported by the sponsor’s extensive expertise in areas related to the project. The research environment at Weill Cornell Medical College is consistently ranked among the top in the country and provides all the necessary facilities, resources, and career development support required for the success of this proposal.

项目摘要/摘要： 这项建议的首要目标是了解糖酵解最终产物乳酸在 神经系统。星形胶质细胞是最丰富的中枢神经系统细胞类型，是乳酸最重要的产生者 在中枢神经系统。中枢神经系统代谢产物流量的主要假说假设星形胶质细胞转移乳酸 它们为神经元制造燃料，但这一假设仍然存在争议。重要的是， 中枢神经系统乳酸水平与多种病理状态和致命性疾病有关。然而，准确的 星形胶质细胞产生的乳酸在中枢神经系统中的作用尚不清楚，这严重限制了我们对这些的解释 观察和我们对健康和疾病中大脑能量代谢调节的基本认识。这里, 我们假设星形细胞乳酸的产生支持不同的中枢神经系统功能，是 维持星形胶质细胞和神经元的活性和正常功能。为了研究这一点，我们提出了三个 利用人和啮齿动物体外神经元和星形胶质细胞系统以及一种新的 用于活体研究的小鼠模型。在目标1中，我们将测量抑制乳酸生成对 体外培养星形胶质细胞的活力、代谢和功能。在目标2中，我们将测量沉默星形细胞的效果 乳酸的产生对体外培养的神经元活性和代谢的影响。在目标3中，我们将测量消融的效果 体内星形细胞乳酸的产生对运动、认知和感觉功能的影响。我们提出了几部小说 研究这个问题的方法：直接测量星形胶质细胞-神经元乳酸转移通过稳定- 新陈代谢与代谢组学相结合的隔室细胞培养中的同位素标记技术 纵向细胞特异性功能和活性研究的测量，以及新的小鼠模型的使用 它专门针对星形胶质细胞进行乳酸操纵。我们假设星形细胞乳酸盐 维持星形胶质细胞和神经元的活性和正常功能所需的产物 中枢神经系统功能多样。 本申请寻求一项全面的奖学金培训计划，其中包括新技术培训 在实验室内，在尖端校外研讨会进行技术培训，通过 参加并在多个系列研讨会上演讲，通过正规课程进行道德培训，以及职业生涯 通过科学研讨会和讲习班开展发展培训，重点是实现独立的途径。这个 建议项目是由申请人设计的一个全新的项目，它是对发起人的 广泛的研究计划，这种计划旨在培养独立性，同时得到 赞助商在项目相关领域的广泛专业知识。威尔·康奈尔大学的研究环境 医学院一直位居全国前列，提供所有必要的设施， 这项提议的成功所需的资源和职业发展支助。