Not all those who wander are lost: Specification of lung innervating sensory neurons

并非所有徘徊者都迷失了：肺支配感觉神经元的规范

• 批准号: 10224651
• 负责人: Justinn Barr
• 金额: $ 6.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224651
• 关键词: 3-Dimensional; Address; Adult; Aerosols; Afferent Neurons; Allergens; Antibodies; Architecture; Axon; Blood Pressure; Blood Vessels; Brain Stem; Brain region; Breathing; Cardiac; Cell Nucleus; Cell Size; Cells; Characteristics; Chemicals; Chronic; Communication; Cues; Data; Development; Embryo; Embryonic Development; Foundations; Ganglia; Gene Expression; Heart; Heterogeneity; Intestines; Knowledge; Label; Ligands; Literature; Lung; Lung diseases; Maps; Mechanics; Molecular Profiling; Morphology; Motor; Motor Neurons; Nerve; Nerve Endings; Nerve Fibers; Nervous system structure; Neural Crest; Neural Crest Cell; Neurons; Neurotransmitters; Nodose Ganglion; Organ; Output; Paracrine Communication; Pattern; Peripheral Nervous System; Play; Process; Publishing; Receptor Protein-Tyrosine Kinases; Regulation; Research Proposals; Sensory; Specific qualifier value; Specificity; Speed; Stains; Stimulus; Stretching; Structure of parenchyma of lung; Suggestion; Testing; Three-Dimensional Imaging; Tissues; To specify; Trachea; Transgenic Organisms; Vagus nerve structure; base; cell fate specification; gastrointestinal system; insight; lung development; mature animal; nerve supply; neural circuit; neurodevelopment; neuroregulation; receptor; receptor function; relating to nervous system; respiratory; response; single cell analysis; transcriptome; transcriptome sequencing

PROJECT SUMMARY Multiple lines of evidence demonstrate the importance of the peripheral nervous system in the control of organ function. For the lung, neural innervation plays a key role in breathing, pulmonary blood pressure, and the ability to sense and respond to aerosol inputs such as allergen. Sensory innervation of the lung originates from neurons in the vagal ganglia with axonal projections along the vagus (which means “wandering” in Latin) nerve. The vagus nerve projects to multiple organs, including the trachea, lung, heart and intestine. Most studies on vagal sensory neurons have focused on adult animals, and little has been done to understand the development of target organ innervation. Vagal sensory neurons have distinct embryonic origins; jugular neurons are derived from neural crest while nodose neurons are derived from epibranchial placode. Because of the many targets of the vagal ganglia, neurons are specified to allow for the diverse functions of vagal sensory neurons. Increasing evidence shows that there are multiple subtypes of vagal sensory neurons. For example, there is heterogeneity in cell sizes, nerve conducting speed, embryonic origin, and gene expression. How the diversity of sensory neurons is established during development is not understood. Whether cells are specified before or after target organ innervation is a key question. A suggestion that developmental cues may bias the pattern of innervation comes from findings that the majority of lung innervating sensory neurons are from the nodose, while the trachea is mainly innervated by jugular sensory neurons. I aim to test the hypothesis that “not all those who wander are lost”, and determine if vagal sensory neurons are specified prior to sending projections to target organs. To accomplish this, I will first characterize when vagal ganglia projections reach target organs such as the trachea and lung, and whether they follow cues from blood vessels or existing motor nerves (Aim 1). I will determine if heterogeneity exists among vagal sensory neurons prior to lung innervation, based on an analysis of single-cell transcriptome of embryonic vagal ganglia before and after target organ innervation (Aim 2). Specifically, I will determine the expression patterns of Trk receptors within jugular and nodose sensory neurons prior to and after lung innervation, and determine if vagal sensory neuron specification depends on neurotrophic ligand expression before or after organ innervation (Aim 2). This project will investigate the co-development of the trachea/lung and their innervating nerves, and uncover the foundational knowledge of how the neural control of organ function is established.

项目摘要 多种证据表明，周围神经系统在控制 器官功能对于肺来说，神经支配在呼吸、肺血压和肺功能中起着关键作用。 感知和响应气溶胶输入（如过敏原）能力。肺的感觉神经支配起源于 来自迷走神经节中的神经元，其轴突投射沿着迷走神经（在拉丁语中是“游荡”的意思） 神经。迷走神经投射到多个器官，包括气管、肺、心脏和肠。最 对迷走神经感觉神经元的研究集中在成年动物上，很少有人了解迷走神经感觉神经元的功能。 靶器官神经支配的发展。 迷走神经感觉神经元有不同的胚胎起源;颈静脉神经元来自神经嵴 而结状神经元来源于上鳃基板。由于迷走神经的靶点众多， 在神经节中，神经元被指定为允许迷走神经感觉神经元的多种功能。越来越多的证据 表明迷走神经感觉神经元有多种亚型。例如，细胞中存在异质性， 大小、神经传导速度、胚胎起源和基因表达。感觉神经元的多样性 在发展过程中，我们不了解。在靶器官之前或之后指定细胞 神经支配是一个关键问题。 发展线索可能会影响神经支配模式的建议来自以下发现： 支配肺的感觉神经元大多数来自结状体，而气管主要由 颈静脉感觉神经元我的目标是检验“并非所有徘徊的人都迷路了”的假设，并确定是否 迷走神经感觉神经元在将投射发送到靶器官之前被指定。为了做到这一点，我将首先 表征迷走神经节投射何时到达靶器官如气管和肺，以及是否 它们遵循来自血管或现有运动神经的线索（目标1）。我将确定是否存在异质性 在迷走神经感觉神经元之间的肺神经支配，基于单细胞转录组的分析， 靶器官神经支配前后的胚胎迷走神经节（Aim 2）。具体来说，我将确定 肺损伤前后颈静脉和结状体感觉神经元Trk受体的表达 神经支配，并确定迷走感觉神经元特化是否依赖于神经营养配体表达 在器官神经支配之前或之后（目标2）。本项目将研究气管/肺的共同发展 以及它们的支配神经，并揭示神经控制器官的基本知识。 功能已建立。