Development of PNEC innervation and neuroplasticity after early life insult

早期生活损伤后 PNEC 神经支配和神经可塑性的发展

• 批准号: 10089028
• 负责人: Xingbin Ai
• 金额: $ 42.77万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089028
• 关键词: Address; Adoptive Transfer; Airway Disease; Allergens; Asthma; Biological Assay; Cell physiology; Cells; Chronic; Chronic lung disease; Complex; Connective Tissue; Data; Development; Developmental Process; Disease; Disease Progression; Dose; Efferent Neurons; Endocrine; Evaluation; Event; Exposure to; Foundations; Functional disorder; Glutamates; Goals; Goblet Cells; Growth; Human; Hyperplasia; Immune response; Infant; Inflammation; Injury; Knowledge; Lead; Life; Link; Longevity; Lung; Measures; Metabolism; Metaplastic Cell; Modeling; Mucous body substance; Mus; Neonatal; Nerve; Neuroendocrine Cell; Neuronal Plasticity; Neurons; Neurosecretory Systems; Neurotransmitters; Nodose Ganglion; Organ; Pathogenesis; Pathologic; Pattern; Phosphotransferases; Physiology; Population; Predisposition; Primates; Process; Reproduction; Role; Sampling; Sensory; Signal Transduction; Slice; Smoker; Source; Stress; Time; Tropomyosin; Work; afferent nerve; airway hyperresponsiveness; asthmatic; early life exposure; experimental study; gamma-Aminobutyric Acid; lung injury; mast cell; mouse allergen; mouse model; neonatal exposure; nerve supply; neuromechanism; neuroregulation; neurotrophic factor; neurotrophin 4; new therapeutic target; nonhuman primate; postnatal; postnatal development; receptor; respiratory smooth muscle; response; screening; targeted treatment; treatment strategy; Address; Adoptive Transfer; Airway Disease; Allergens; Asthma; Biological Assay; Cell physiology; Cells; Chronic; Chronic lung disease; Complex; Connective Tissue; Data; Development; Developmental Process; Disease; Disease Progression; Dose; Efferent Neurons; Endocrine; Evaluation; Event; Exposure to; Foundations; Functional disorder; Glutamates; Goals; Goblet Cells; Growth; Human; Hyperplasia; Immune response; Infant; Inflammation; Injury; Knowledge; Lead; Life; Link; Longevity; Lung; Measures; Metabolism; Metaplastic Cell; Modeling; Mucous body substance; Mus; Neonatal; Nerve; Neuroendocrine Cell; Neuronal Plasticity; Neurons; Neurosecretory Systems; Neurotransmitters; Nodose Ganglion; Organ; Pathogenesis; Pathologic; Pattern; Phosphotransferases; Physiology; Population; Predisposition; Primates; Process; Reproduction; Role; Sampling; Sensory; Signal Transduction; Slice; Smoker; Source; Stress; Time; Tropomyosin; Work; afferent nerve; airway hyperresponsiveness; asthmatic; early life exposure; experimental study; gamma-Aminobutyric Acid; lung injury; mast cell; mouse allergen; mouse model; neonatal exposure; nerve supply; neuromechanism; neuroregulation; neurotrophic factor; neurotrophin 4; new therapeutic target; nonhuman primate; postnatal; postnatal development; receptor; respiratory smooth muscle; response; screening; targeted treatment; treatment strategy

ABSTRACT How pulmonary neuroendocrine cells (PNECs) become innervated and to what extent nerves regulate PNEC function in development and diseases are open and basic questions for the field. The objective of this proposal is to address these fundamental issues and to assess the key role of neurotrophin 4 (NT4) in these events. Using a NT4-/- mouse line and a neonatal mouse model of allergen exposure, we generated preliminary data leading to 3 hypotheses that will be studied in this proposal: 1) NT4 is required for PNEC innervation during development and for the increases in PNEC innervation following early life insults; 2) early life allergen exposure alters the function of sensory afferents and efferent nerves that innervate PNECs thereby causing deregulated γ-aminobutyric acid (GABA) secretion and long-term goblet cell metaplasia; 3) pulmonary mast cells are a candidate source of elevated NT4 levels following early life allergen exposure. To summarize, we found that NT4 was expressed by PNECs during postnatal development and acted as a trophic factor for the innervating nerves to establish connection. Allergen exposure to developing, postnatal lungs aberrantly elevated the levels of NT4. Under this pathological condition, we discovered that PNEC innervation was increased associated with prolonged goblet cell metaplasia. Notably, PNECs were the only cell source of GABA in lungs, a signal essential for allergen-induced goblet cell metaplasia in mouse models and associated with mucous overproduction in human asthmatics and smokers. In addition, NT4 was required for PNEC hyperinnervation and deregulated GABA secretion, consistent with the established paradigm in other neuroendocrine systems that nerves regulate endocrine secretion. These preliminary findings point to an essential role for NT4 in PNEC innervation during development and neuroplasticity following early life injury, which will be extensively characterized by comparing the pattern and degree of PNEC innervation between wild type and NT4-/- mice with and without allergen exposure using markers for different types of nerves (Aim 1). To connect NT4-induced PNEC hyperinnervation to prolonged goblet cell metaplasia following early life allergen exposure, proposed experiments in Aim 2 will assess functional changes in sensory afferents and efferent signals that induce GABA secretion from PNECs and their relationships to NT4. Lastly, given the central role of NT4 in aberrant PNEC innervation under pathological conditions, we examined NT4 expression in injured lungs. We found an enlarged, activated mast cell population expresses NT4 during early life allergen exposure. Whether pulmonary mast cells contribute to PNEC hyperinnervation by producing NT4 will be evaluated (Aim 3). To further enhance disease relevance, we will validate key findings from the mouse work in infant primate models of injury and human lung samples. Together, this proposal investigates complex interactions between nerves, PNECs, and inflammation during postnatal development and injury. Our findings indicate that the pathogenesis of chronic airway diseases, such as asthma, may involve disrupted developmental processes following early episodes of insults. We expect that completion of the proposed studies will provide fundamental knowledge about how the pulmonary neuroendocrine system forms and functions. Identification of the mechanisms along the nerve-PNEC axis underlying mucous overproduction may lay the foundation for the discovery of new treatment strategies.

抽象的 肺神经内分泌细胞（PNEC）如何支配以及神经在多大程度上调节PNEC 发育和疾病的功能是该领域的开放和基本问题。这个目的 提案是解决这些基本问题，并评估神经营养蛋白4（NT4）的关键作用 事件。使用NT4 - / - 鼠标线和过敏原暴露的新生小鼠模型，我们生成了 在此提案中将研究的3个假设的初步数据：1）PNEC需要NT4 早期侮辱后的PNEC神经支配期间的神经支配； 2）早期 生命过敏原暴露改变了感官传入和有效神经的功能 从而导致失调的γ-氨基丁酸（GABA）分泌和长期的杯状细胞化生； 3） 肺肥大细胞是早期生命过敏原暴露后NT4水平升高的候选来源。到 总结，我们发现NT4在产后发育过程中由PNEC表达，并充当营养 神经神经建立联系的因素。过敏原暴露于发育后的产后肺 异常升高NT4的水平。在这种病理状态下，我们发现PNEC神经 值得注意的是，PNEC是唯一的细胞来源 肺中的GABA，这是过敏原诱导的杯状细胞化生和相关的信号 人类哮喘患者和吸烟者的粘液过量生产。此外，PNEC需要NT4 过度连接和放松管制的GABA分泌，与其他范式一致 神经调节内分泌分泌的神经内分泌系统。这些初步发现指出 NT4在生命早期损伤后发育和神经可塑性期间的PNEC神经上的重要作用， 它将通过比较PNEC神经的模式和程度来广泛特征 野生型和NT4 - / - 鼠标，有或没有过敏原暴露于不同类型神经的标记物（AIM 1）。将NT4诱导的PNEC过度连接连接到早期延长的杯状细胞化学 过敏原暴露，AIM 2中的拟议实验将评估感觉传入的功能变化和 会影响PNEC及其与NT4的关系的GABA分泌的发出信号。最后，给定 NT4在病理条件下异常PNEC神经支配中的中心作用，我们检查了NT4表达 在受伤的肺部。我们在早期过敏原中发现了扩大的，激活的肥大细胞群体表达NT4 接触。肺肥大细胞是否通过产生NT4有助于PNEC过度作用 评估（目标3）。为了进一步增强疾病的相关性，我们将验证小鼠工作中的关键发现 婴儿损伤和人类肺样本的私人模型。该提案一起调查了复杂 神经，PNEC和注射之间的相互作用在产后发育和受伤期间。我们的发现 表明慢性气道疾病（例如哮喘）的发病机理可能涉及破坏 早期伤害发作后的发育过程。我们预计提议的完成 研究将提供有关肺神经内分泌系统如何形成和 功能。识别沿着神经-PNEC轴的机理，粘液过度生产 可能为发现新的治疗策略奠定了基础。