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乳酸在神经系统中星形胶质细胞是最丰富的中枢神经系统细胞类型，是最重要的乳酸产生者。关于中枢神经系统代谢流的主要假设假设星形胶质细胞转移乳酸。它们产生神经元用作燃料，但这一假设仍然存在争议。中枢神经系统乳酸水平与许多病理状态和致命疾病有关。星形胶质细胞产生的乳酸在中枢神经系统中的作用仍不清楚，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大脑能量代谢调节的基本了解。我们追求星形胶质细胞乳酸的产生支持多种中枢神经系统功能，并且是维持星形胶质细胞和神经元的活力和正常功能为了研究这一点，我们提出了三种方法。互补的目标，利用人类和啮齿动物的体外神经元和星形胶质细胞系统以及一种新颖的在目标 1 中，我们将测量抑制乳酸生成对小鼠模型的影响。在目标 2 中，我们将测量星形胶质细胞沉默的效果。在目标 3 中，我们将测量消融的影响。我们提出了几种新颖的星形胶质细胞乳酸产生对体内运动、认知和感觉功能的影响。研究这个问题的方法：通过稳定的星形胶质细胞-神经元乳酸转移的直接测量区室细胞培养中的同位素标记技术，结合代谢和代谢组学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它专门针对星形胶质细胞进行乳酸操作，我们捕获了星形胶质细胞的乳酸。维持星形胶质细胞和神经元的活力和正常功能需要产生中枢神经系统功能多样。该申请寻求一个全面的奖学金培训计划，其中包含新技术培训在实验室内、在尖端的校外研讨会上进行技术培训、通过参加并出席多个研讨会系列、通过正式课程进行道德培训以及职业通过科学研讨会和讲习班开展发展培训，重点关注独立之路。拟议项目是申请人设计的一个全新项目，它补充了赞助商的广泛的研究计划，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。医学院一直在全国名列前茅，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。