Unravelling lung interoception and its functional consequence in the developing ovine lung

解开肺内感受及其在发育中的绵羊肺中的功能后果

基本信息

批准号：
10320593
负责人：
Arlin B Blood
金额：
$ 62.14万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10320593
关键词：
Acute Address Adult Affect Allergic Alveolar Animals Apnea Asthma Autonomic nervous system Behavioral Bilateral Birth Blood Blood Vessels Brain Brain Stem Breathing Bronchopulmonary Dysplasia C Fiber Cell Nucleus Cerebral cortex Cesarean section Chemicals Chronic Communication Computer software Custom Data Denervation Development Dyes Efferent Neurons Electrodes Embryo Environment Epithelial Esthesia Exercise Feedback Fetal Development Fetal Lung Fetal Sheep Fetus Foundations Future Gases Goals Growth Growth and Development function Human Hypoxia Immune response Implant Interoception Irritants Knowledge Life Link Location Lung Lung diseases Maintenance Maps Measures Mechanics Mechanoreceptors Modeling Modernization Monitor Morphology Myography Nature Nerve Neuraxis Neurobiology Neuroendocrine Cell Neuroimmune Neurons Newborn Infant Nodose Ganglion Operative Surgical Procedures Organ Outcome Study Pattern Perinatal Periodicity Phase Phenotype Physiology Play Population Pregnancy Prevalence Pulmonary Gas Exchange Pulmonary artery structure Research Respiration Respiratory physiology Role Sensory Series Sheep Signal Transduction Stress Structure Sudden infant death syndrome Synapses Techniques Testing The Sun Thinness Time Tissues Tracer Vagus nerve structure Viral Work afferent nerve airway epithelium course development environmental stressor experience fetal fetus hypoxia human model instrument loss of function lung development methacholine microbial nerve supply nervous system development neural circuit neural network neurotransmission novel pathogen postnatal premature pulmonary function receptor relating to nervous system respiratory response sheep model transcriptome sequencing

项目摘要

Project Summary The interoceptive link between the lung and CNS carries mechanical and irritant information to its first-order synapse in the brainstem. This information is critical in the newborn and adult for maintenance of pulmonary gas exchange in the face of behavioral changes and environmental stressors, and in orchestrating immune responses to viral, bacterial, and allergic pathogens. Although the fetal lung is richly innervated during development, the connectivity to the central nervous system (CNS), the extent to which these neurons help orchestrate lung and CNS formation over the course of development, and the role they play in function at birth remain largely unknown. This R01 application proposes to address this knowledge gap using a novel fetal sheep model. We hypothesize that intrinsic and extrinsic lung interoceptive units play a role in the normal development of the lung and central respiratory control centers. We will test this in the following aims: Aim 1: Traditional dye and novel viral track tracer techniques will be used in fetal sheep at various stages of lung development to delineate the location and connectivity of the interoceptive units within the lung, as well as first- and second-order central circuitry to and above the brainstem. The effect of surgical denervation on lung developmental morphology and the prevalence of various neural populations involved in chemo- and irritant sensation, including A- and C-fiber neurons involved in breathing control, and pulmonary neuroendocrine cells involved in pulmonary mechano- and chemosensation. Finally, single neuron RNAseq will be used to phenotypically characterize neurons within the fetal jugular and nodose ganglia at various stages of development. Aim 2: To test the necessity of interroception on fetal lung development and respiratory function after birth, fetuses in the canalicular stage will be subjected to either bilateral denervation of the lungs or periodic hyperstimulation of mechanoreceptors via overinflation for the remainder of gestation. Pulmonary vascular function, airway mechanics, and gas exchange will then be monitored following c-section delivery and in response to acute hypoxia and methacholine challenges, and responses will be compared to both sham and naive controls. Aim 3: Vagal ascending and descending nerve traffic will be recorded in fetuses instrumented with state-of-the-art cuff electrodes throughout fetal development and at birth. Custom time-series and spectral analysis software will be used to quantify changes in afferent/efferent vagal nerve signaling in response to pulmonary denervation, birth, and mechano- and chemosensory stimulations. The outcomes of these studies will fill in critical knowledge gaps of the role of interoception in lung development and function in a sheep model that has been a historically signature model of human perinatal lung development and physiology. Our proposed foundational work will inform future efforts focused on a variety of lung diseases in humans that originate during development, such as bronchopulmonary dysplasia, apnea of prematurity, sudden infant death syndrome, and asthma.

项目概要肺和中枢神经系统之间的内感受联系将机械和刺激信息传递到脑干中的一级突触。这些信息对于新生儿和成人在面对行为变化和环境压力源时维持肺部气体交换以及协调对病毒、细菌和过敏性病原体的免疫反应至关重要。尽管胎儿肺在发育过程中受到丰富的神经支配，但与中枢神经系统 (CNS) 的连接、这些神经元在发育过程中帮助协调肺和 CNS 形成的程度以及它们在出生时发挥的功能在很大程度上仍然存在未知。该 R01 应用建议使用新型胎羊模型来解决这一知识差距。我们假设内在和外在的肺内感受单位在肺和中枢呼吸控制中心的正常发育中发挥作用。我们将在以下目标中对此进行测试：目标 1：传统染料和新型病毒追踪示踪技术将用于肺发育各个阶段的胎羊，以描绘肺内内感受单元的位置和连接性，以及首先- 以及脑干及其上方的二阶中央电路。手术去神经支配对肺发育形态的影响以及参与化学和刺激感觉的各种神经群的患病率，包括参与呼吸控制的 A 纤维和 C 纤维神经元，以及参与肺机械感觉和化学感觉的肺神经内分泌细胞。最后，单神经元 RNAseq 将用于表征不同发育阶段胎儿颈静脉和结状神经节内神经元的表型特征。目标 2：为了测试出生后拦截对胎儿肺部发育和呼吸功能的必要性，小管阶段的胎儿将在妊娠剩余时间内接受双侧肺部去神经支配或通过过度充气对机械感受器进行周期性过度刺激。然后，在剖腹产后以及对急性缺氧和乙酰甲胆碱挑战的反应中，将监测肺血管功能、气道力学和气体交换，并将反应与假手术和初始对照组进行比较。目标 3：在整个胎儿发育和出生时，将使用最先进的袖带电极记录胎儿的迷走神经上升和下降神经流量。定制的时间序列和频谱分析软件将用于量化传入/传出迷走神经信号的变化，以响应肺去神经、出生以及机械和化学感觉刺激。这些研究的结果将填补绵羊模型中内感受在肺部发育和功能中的作用的关键知识空白，绵羊模型一直是人类围产期肺部发育和生理学的历史标志模型。我们提出的基础工作将为未来关注人类发育过程中产生的各种肺部疾病（例如支气管肺发育不良、早产儿呼吸暂停、婴儿猝死综合症和哮喘）的努力提供信息。