Neurotrophin Regulation of the Airway Parasympathetic Nervous System

神经营养素对气道副交感神经系统的调节

基本信息

批准号：
7373093
负责人：
ALLEN C MYERS
金额：
$ 41万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7373093
关键词：
Acetylcholine Action Potentials Address Adrenergic Agents Adult Affect Affinity Air Anatomy Asthma Autacoids Brain-Derived Neurotrophic Factor Cells Cholinergic Agents Chronic Chronic Bronchitis Chronic Obstructive Airway Disease Chronic Obstructive Asthma Complex Coughing Development Disease Exposure to Family suidae FarGo Fibroblasts Functional disorder Gland Growth Growth Factor Human Hyperactive behavior Hypersensitivity Inflammation Light Lung Lung diseases Morphology Mucous body substance Mus Muscle Nerve Nerve Growth Factors Nervous system structure Neuraxis Neurons Neurotransmitters Neurotrophic Tyrosine Kinase Receptor Type 1 Nicotinic Receptors Numbers Parasympathetic Nervous System Peripheral Nervous System Phenotype Physiology Play Potassium Production Property Pulmonary Emphysema Receptor Activation Regulation Research Role Smooth Muscle Source Structure Structure of parasympathetic ganglion Sus scrofa Symptoms Synapses Synaptic Potentials Synaptic Transmission Techniques Testing Trachea and Bronchus adrenergic afferent nerve airway remodeling asthmatic airway axon growth cell type cholinergic inhibitory neuron mature animal neuronal excitability neurotransmitter release neurotrophic factor novel therapeutics receptor respiratory smooth muscle response

项目摘要

DESCRIPTION (provided by applicant): In the lower airways, the activity of airway smooth muscle, microvasculature, and glands and, consequently, air flow to the lungs, is regulated predominantly by the parasympathetic nervous system. Over the past decade, we have demonstrated that airway parasympathetic ganglionic neurons regulate input (preganglionic) from the central nervous system and how this is altered by neighboring nerves or by inflammation. In this proposal, we will address hypotheses related to how neurotrophins, especially nerve growth factor (NGF), regulate the function of adult airway parasympathetic neurons. Neurotrophins, such as NGF, are increased in the inflamed or infected airways and many symptoms of these diseases (hyperactivity, cough, mucous production) may be related to altered or aberrant functions of the airway nervous system as seen in asthma, chronic obstructive pulmonary disease (COPD), and chronic bronchitis. Neurotrophins function during development, particularly as survival factors, but also as factors involved in differentiation and axon growth. However, both the neurotrophins themselves (NGF, BDNF, NT-4/5 and NT-3) and their high affinity receptors (trkA, trkB and trkC) continue to be expressed post-natally indicating that their function goes far beyond their role in development. We propose to study their role in modulating the airway parasympathetic nervous system in adult animals (mice) and in humans. In Specific Aim 1, we will evaluate the mechanisms by which NGF increase synaptic efficacy at airway parasympathetic ganglia; in this aim, we will directly address hypotheses related to NGF-induced changes in synaptic transmission in mouse and human pig bronchial parasympathetic ganglia as well as hypotheses pertaining to the mechanisms by which neurotrophins modulate the action potential. In Aim 2, we'll determine how neurotrophins regulate the anatomy and neurotransmitter phenotype of airway neurons in mouse and human excitatory cholinergic and inhibitory neurons. In this Aim, we will address hypotheses relating to the changes in dendritic structure that occur with chronic exposure to NGF (and potentially, other neurotrophins), and address the hypothesis that neurotrophins can modulate the function of parasympathetic nerves by altering the neurotransmitter(s) they release. Results from these studies will shed new light on the complex pathophysiology of airway diseases such as asthma and COPD and may ultimately determine new therapeutic treatments for these complex diseases. PROJECT NARRATIVE: Air flows to the lungs through the trachea and bronchi and this airflow is predominately regulated by the parasympathetic nervous system. Certain molecules, call neurotrophins, especially nerve growth factor (NGF), are increased in the inflamed or infected airways and many symptoms of these diseases may be related to changes in parasympathetic nerves that then cause decreased airflow to the lungs as seen in asthma, chronic obstructive pulmonary disease (COPD), and chronic bronchitis. Our research will directly address how NGF and other neurotrophins change the airway parasympathetic nervous system.

描述（由申请人提供）：在下部气道中，气道平滑肌，微血管和腺体的活性以及随之而来的气流流向肺部，主要受副交感神经系统的调节。在过去的十年中，我们已经证明了气道副交感神经神经元从中枢神经系统调节输入（peganglionic），以及如何通过邻近神经或炎症改变这种情况。在此提案中，我们将解决与神经营养蛋白（尤其是神经生长因子（NGF））如何调节成人气道副交感神经元功能有关的假设。在发炎或感染的气道中，神经营养蛋白（例如NGF）增加，这些疾病的许多症状（多动症，咳嗽，粘液产生）可能与气道神经系统的改变或异常功能有关，如哮喘，慢性阻塞性肺部疾病（COPD）和慢性凝发炎所见。神经营养蛋白在发育过程中的功能，尤其是作为生存因子，也是涉及分化和轴突生长的因素。然而，神经营养蛋白本身（NGF，BDNF，NT-4/5和NT-3）及其高亲和力受体（TRKA，TRKB和TRKC）继续表达出来后，表明其功能远远超出了其在发育中的作用。我们建议研究它们在调节成年动物（小鼠）和人类中的气道副交感神经系统中的作用。在特定的目标1中，我们将评估NGF在气道副交感神经上提高突触功效的机制。在此目标中，我们将直接解决与NGF诱导的小鼠和人支气管支气管副交感神经的突触变化有关的假设，以及与神经营养蛋白调节动作电位的机制有关的假设。在AIM 2中，我们将确定神经营养蛋白如何调节小鼠和人兴奋性胆碱能和抑制性神经元中气道神经元的解剖学和神经递质表型。在此目标中，我们将解决与长期暴露于NGF（以及可能是其他神经营养蛋白）发生的树突状结构变化有关的假设，并解决了神经营养蛋白可以通过改变神经性释放的神经性神经来调节副交感神经的功能的假设。这些研究的结果将为哮喘和COPD等气道疾病的复杂病理生理学提供新的启示，并最终可能确定这些复杂疾病的新治疗方法。项目叙述：空气通过气管和支气管流向肺部，该气流主要由副交感神经系统调节。在发炎或感染的气道中，某些分子，称为神经营养蛋白，尤其是神经生长因子（NGF），这些疾病的许多症状可能与副交感神经的变化有关，这些疾病的变化会导致流动流量减少到肺中，如哮喘，慢性阻塞性肺部疾病（COPD）和慢性慢性炎。我们的研究将直接解决NGF和其他神经营养蛋白如何改变气道副交感神经系统。