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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。尽管几十年来交感神经元、卫星胶质细胞、交感神经节中主要胶质细胞的研究，仍然是该系统的一个神秘组成部分。卫星胶质细胞紧紧包裹着交感神经元细胞体。在最近的工作中，我们揭示了卫星胶质细胞的作用限制神经元活动，从而调节对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神经胶质细胞应该被视为协调形成和的结构和功能单元交感神经系统的功能。然而，卫星胶质细胞是一种远远不足的研究了神经系统中的细胞类型，但对其发育的了解有限，神经元-神经胶质细胞的通讯，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在发育过程中建立，以及如何建立这个过程中的扰动会影响神经元的连接和功能。基于我们的初步结果，我们假设靶源性神经营养素信号传导交感神经元指示与邻近卫星神经胶质细胞基于接触的相互作用在开发过程中。该应用程序的目标是检验该假设并定义这种双向神经元-卫星神经胶质细胞相互作用的分子基础遗传小鼠模型、神经元-胶质细胞共培养、生物化学和成像。我们的研究将建立关于这些研究不足的神经胶质细胞如何发挥作用的基础知识神经系统的连接和功能，并将为治疗新策略提供信息与交感神经功能障碍有关的疾病。