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Neuron-satellite glia interactions in the sympathetic nervous system

交感神经系统中神经元-卫星胶质细胞的相互作用

基本信息

批准号：
10719545
负责人：
Rejji Kuruvilla
金额：
$ 56.69万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10719545
关键词：
Ablation Address Adhesives Axon BAX gene Biochemical Biochemistry Brain Candidate Disease Gene Cell Communication Cell physiology Cell-Cell Adhesion Cellular Morphology Cellular biology Coculture Techniques Communication Congestive Heart Failure Cues Defect Dendrites Dependence Development Diabetes Mellitus Disease EGF gene Environment Functional disorder Ganglia Genetic Glial Cell Proliferation Goals Growth Heart failure Homeostasis Human Hypertension Image In Vitro Individual Insulin Resistance Integral Membrane Protein Knockout Mice Knowledge Link Mediating Membrane Proteins Modeling Molecular Morphogenesis Morphology Mus Mutant Strains Mice NGFR Protein Nerve Regeneration Nervous System Neuroglia Neurons Neurotrophic Tyrosine Kinase Receptor Type 1 Organ Output Parkinson Disease Pathway interactions Peripheral Peripheral Nervous System Diseases Physiology Process Reporting Research Role Signal Transduction Structure Sympathetic Ganglia Sympathetic Nervous System Synapses Synaptic Transmission System Testing Tissues Work cell type chronic pain conditional knockout defined contribution fighting glial cell development in vivo mouse genetics mouse model nerve supply neural circuit neuron development neuron loss neuronal cell body neuronal survival neurotrophic factor notch protein prevent receptor receptor binding response satellite cell single cell sequencing single-cell RNA sequencing

项目摘要

The sympathetic nervous system is a key regulator of whole body physiology. A dysfunctional sympathetic nervous system is linked to a growing list of human disorders including chronic heart failure, hypertension, and insulin resistance. Despite decades of research on sympathetic neurons, satellite glia, the major glial cells in sympathetic ganglia, have remained an enigmatic component of the system. Satellite glia tightly ensheathe sympathetic neuron cell bodies. In recent work, we revealed a role for satellite glial cells in restricting neuron activity to thereby modulate sympathetic output to peripheral organs. Our findings suggest that sympathetic neurons and their surrounding satellite glia should be considered as structural and functional units that orchestrate the formation and functioning of the sympathetic nervous system. However, satellite glia are a vastly under- studied cell type in the nervous system, with limited understanding of their development, neuron-glia communication, and how they contribute to neural circuits. This application addresses this knowledge gap by seeking to define how sympathetic neuron-satellite glia units are established during development, and how perturbations in this process impact neuronal connectivity and function. Based on our preliminary results, we hypothesize that target-derived neurotrophin signaling in sympathetic neurons instructs contact-based interactions with neighboring satellite glia during development. The goal of this application is to test this hypothesis and define the molecular underpinnings of this bi-directional neuron-satellite glia interactions using genetic mouse models, neuron-glia co-cultures, biochemistry, and imaging. Our studies will establish a fundamental knowledge of how these poorly studied glial cells contribute to nervous system connectivity and function and will inform new strategies for treating disorders linked to sympathetic dysfunction.

交感神经系统是全身生理的关键调节器。一交感神经系统功能失调与越来越多的人类疾病有关包括慢性心力衰竭、高血压和胰岛素抵抗。尽管经过数十年的研究交感神经元，卫星胶质细胞，交感神经节中的主要胶质细胞，一直是这个系统中神秘的一部分卫星胶质细胞紧密包裹交感神经元细胞体。在最近的工作中，我们揭示了卫星神经胶质细胞的作用，限制神经元活动，从而调节到外周器官的交感神经输出。我们的研究结果表明，交感神经元及其周围的卫星胶质细胞应该被认为是协调形成的结构和功能单元，交感神经系统的功能。然而，卫星神经胶质细胞是一个大大低于- 研究神经系统中的细胞类型，对它们的发育了解有限，神经元-神经胶质细胞通讯，以及它们如何对神经回路做出贡献。该应用程序通过寻求定义如何解决这一知识差距交感神经元卫星神经胶质细胞单位是在发育过程中建立的，以及如何该过程中的扰动影响神经元连接和功能。基于我们初步结果，我们假设，靶源性神经营养因子信号转导，交感神经元指导与邻近卫星胶质细胞的接触式相互作用在发展过程中。本应用程序的目标是测试此假设并定义这种双向神经元-卫星神经胶质相互作用的分子基础，遗传小鼠模型、神经元-神经胶质细胞共培养物、生物化学和成像。我们的研究将建立一个基本的知识，这些缺乏研究的神经胶质细胞如何贡献神经系统的连接和功能，并将为治疗与交感神经功能障碍有关的疾病