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

基本信息

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
项目类别：
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

项目摘要

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：该提案的总体目标是了解糖酵解终产物的功能作用神经系统。星形胶质细胞是最丰富的CNS细胞类型，是乳酸最重要的生产者在中枢神经系统中。中枢神经系统中代谢物通量的主要假设假设星形胶质细胞转移乳酸它们会产生神经元用作燃料，但这种假设仍然存在争议。重要的是，变化中枢神经系统牙齿水平与许多病理状态和致命疾病有关。但是，确切的星形胶质细胞产生的鞋底在中枢神经系统中的作用尚不清楚，严重限制了我们对这些的解释观察以及我们对健康和疾病中脑能量代谢调节的基本理解。这里，我们假设星形胶质细胞裂解的生产支持各种CNS功能，并且是必需的维持星形胶质细胞和神经元的生存力和正常功能。为了研究这一点，我们提出了三个免费的目的，利用人类和啮齿动物在体外神经元和星形胶质细胞系统中以及一种新颖体内研究的小鼠模型。在AIM 1中，我们将衡量抑制乳酸产生对星形胶质生存力，代谢和体外功能。在AIM 2中，我们将测量沉默星形胶质细胞的效果乳酸在体外神经元生存力和代谢上产生。在AIM 3中，我们将衡量擦洗的效果在体内运动，认知和感觉功能上的星形胶质乳酸产生。我们提出了几本小说研究此问题的方法：直接测量星形胶质细胞神经元通过稳定 - 隔室化细胞培养中的同位素标记技术，结合代谢组和代谢组具有纵向细胞特异性功能和活力研究的测量以及新型小鼠模型的使用该靶向乳酸操纵专门针对星形胶质细胞。我们假设星形胶质细胞乳酸维持星形胶质细胞和神经元的生存能力和正常功能需要生产各种CNS功能。该应用程序寻求全面的奖学金培训计划，该计划将培训纳入新技术在实验室内，尖端的壁外研讨会的技术培训，通过参加并介绍了多个时刻系列，通过正式课程和职业的道德培训通过科学的半手和研讨会的发展培训集中在独立途径上。这拟议项目是一个由申请人设计的全新项目，该项目称赞赞助商的广泛的研究计划，旨在促进独立，同时得到赞助商在与该项目有关的领域方面的广泛专业知识。威尔·康奈尔（Weill Cornell）的研究环境医学院始终被排名该国榜首，并提供所有必要的设施，该提案成功所需的资源和职业发展支持。