Molecular pathways underlying organ-specific targeting by the vagus nerve

迷走神经器官特异性靶向的分子途径

• 批准号: 9767520
• 负责人: Ga Young Lee
• 金额: $ 6.74万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767520
• 关键词: Address; Afferent Neurons; Anatomy; Animals; Autonomic nervous system disorders; Axon; Blood Pressure; Blood Vessels; Brain; Brain Stem; Breathing; Candidate Disease Gene; Cell physiology; Cells; Chromosome Mapping; Communication; Congenital Megacolon; Cranial Nerves; Cues; Data; Development; Diabetes Mellitus; Digestion; Digestive System Disorders; Disease; Enteral; Event; Foundations; Ganglia; Gastrointestinal tract structure; Gastroparesis; Gene Expression; Genes; Genetic; Goals; Health; Heart; Heart Rate; Homeostasis; Image Analysis; Imaging Techniques; Individual; Ingestion; Knock-in Mouse; Knockout Mice; Knowledge; Label; Location; Lung; Maps; Measures; Mechanics; Metabolic; Metabolic Diseases; Metabolism; Microscopy; Molecular; Molecular Genetics; Motor; Mutate; Neck; Nerve; Neural Crest; Neurobiology; Neurons; Nutrient; Organ; Other Genetics; Outcome; Pathway interactions; Pattern; Peripheral; Physiological; Play; Population; Reagent; Regulation; Research Personnel; Resolution; Role; Sensory; Shapes; Side; Signal Transduction; Signaling Molecule; Site; Stereotyping; Stomach; System; Techniques; Testing; TimeLine; Tissues; Vagus nerve structure; Viscera; Visualization; cell motility; cell type; ganglion cell; genetic approach; hindbrain; microscopic imaging; migration; mouse genetics; mouse model; nerve supply; neurobiological mechanism; neuronal cell body; neuroregulation; neurovascular; novel; receptor; tool

PROJECT SUMMARY / ABSTRACT The long-term goal of this project is to reveal basic neurobiological mechanisms about how vagal sensory neurons find, innervate, and interact with specific end-organs and tissues during development. Sensory neurons of the vagus nerve detect and transmit diverse signals from internal organs, including ingested nutrients, changes in blood pressure, and mechanical distension of the stomach. Anatomically, it is a uniquely long cranial nerve that emanates from a single pair of ganglia near the hindbrain yet courses through the entire body and innervates a myriad of target tissues. From these ganglia, each vagal sensory neuron sprouts a single pseudounipolar axon that targets a specific internal organ peripherally and a dedicated brainstem circuit centrally. Faithfully establishing this connectivity is essential for neural control of physiological functions such as breathing, heart rate and digestion. Despite its vital role and the emerging importance of brain-viscera communication, it remains largely unknown how the intricate anatomical structure of the vagus nerve forms during development, and whether miswiring of the vagus nerve may contribute to diseases of the autonomic nervous system. This project proposes to leverage novel genetic and advanced imaging techniques to begin addressing the long-term goal by combining anatomical (Aim 1), cellular (Aim 2), and molecular (Aim 3) approaches. Aim 1 will establish a comprehensive, high-resolution map of vagus nerve development in the context of the whole animal, by utilizing genetic labeling, tissue clearing, and high- resolution microscopy. Aim 2 will elucidate the interplay between enteric neuron migration and vagal afferent outgrowth, by utilizing cutting- edge mouse genetics tools to selectively manipulate different cell types. Aim 3 will identify molecular determinants of vagus nerve pathfinding, by combining publicly available data and mouse genetics tools to label and perturb candidate gene expression in vagal sensory neurons. It is becoming increasingly apparent that vagus nerve connectivity plays a role in metabolism and energy homeostasis, with implications in related disorders. Therefore, results of this project will open new lines of inquiry on how viscera-to-brain communication is established and maintained in health and disease.!

项目摘要 /摘要 该项目的长期目标是揭示有关迷走性感觉的基本神经生物学机制 神经元在发育过程中发现，神经支配并与特定的末端和组织相互作用。感官 迷走神经的神经元检测并传输来自内部器官的多种信号，包括摄取 营养，血压的变化和胃的机械延伸。从解剖学上，这是一个独特的 长颅神经是从后部脑附近一对神经节中散发出来的，但整个过程中的课程 身体并支配无数的目标组织。从这些神经节中，每个迷走性感觉神经元萌芽a 单个伪极轴突靶向特定的内脏外周和专用脑干电路 集中。忠实建立这种连通性对于生理功能的神经控制至关重要 作为呼吸，心率和消化。尽管它具有至关重要的作用，并且是脑维来的新兴重要性 交流，它在很大程度上仍然未知迷走神经的复杂解剖结构如何 在发展过程中，以及迷走神经的错误偏离可能导致自主神经的疾病 神经系统。该项目建议利用新颖的遗传和先进的成像技术开始 通过结合解剖学（AIM 1），细胞（AIM 2）和分子（AIM 3）来解决长期目标 方法。 AIM 1将建立一个全面的高分辨率神经发展图 通过利用遗传标记，组织清除和高分辨率显微镜，整个动物的背景。目的 2将通过使用剪裁来阐明肠神经元迁移与迷走神经传入的生长之间的相互作用 边缘鼠标遗传学工具可有选择地操纵不同的细胞类型。 AIM 3将识别分子 通过将公开可用的数据和鼠标遗传学工具结合到迷走神经探路的决定因素 迷走性感觉神经元中的标记和烧伤候选基因表达。它变得越来越明显 迷走神经连通性在代谢和能量稳态中起作用，对 相关疾病。因此，该项目的结果将开启有关内脏到脑的新调查。 沟通是在健康和疾病中建立和维持的。