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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。一个交感神经系统功能障碍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。尽管几十年来交感神经节中主要的神经胶质细胞--交感神经元、卫星胶质细胞，一直是这一体系中一个神秘的组成部分。卫星神经胶质细胞紧密包裹在交感神经元胞体。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的活动，从而调节交感神经输出到外周器官。我们的发现表明，交感神经元及其周围的卫星胶质细胞应该被认为是编队和编队的结构和功能单位交感神经系统的功能。然而，卫星神经胶质细胞远远低于- 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。这个应用程序通过寻求定义如何交感神经元-卫星胶质细胞单位是在发育过程中建立的，以及如何这一过程中的干扰会影响神经元的连接和功能。基于我们的初步结果，我们假设靶向衍生神经营养因子信号在交感神经元指示与邻近卫星神经胶质细胞的接触性相互作用在开发过程中。这个应用程序的目标是测试这一假设并定义这种双向神经元-卫星胶质细胞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、生物化学和成像。我们的研究将建立一个关于这些研究很少的神经胶质细胞如何发挥作用的基础知识神经系统的连通性和功能，并将提供新的治疗策略与交感神经功能障碍有关的疾病。