权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A function of the neuroendocrine system in mucous hyperplasia

神经内分泌系统在粘液增生中的功能

基本信息

批准号：
9330208
负责人：
Juliana Beverly Barrios
金额：
$ 2.15万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330208
关键词：
Address Adult Affect Aftercare Agonist Air Allergens Allergic inflammation Asthma Baclofen Binding Binding Sites Biological Assay Bronchoconstriction CREB1 gene Cause of Death Cell Line Cells Child Childhood Asthma Chloride Channels Chronic Chronic Disease Clinical Communication Cyclic AMP Endocrine Epidermal Growth Factor Epithelial Epithelial Cells Epithelium Exposure to GABA Agonists GABA Antagonists GTP-Binding Protein alpha Subunits, Gs Gene Expression Gene Expression Regulation Goblet Cells Histology Hyperplasia Immunohistochemistry In Vitro Inflammation Inflammatory Interleukin-13 Investigation LPAR4 gene Lead Life Link Liquid substance Luciferases Lung MUC5AC gene Measures Mediating Metaplasia Molecular Mucins Mucous body substance Mus Muscimol Mutagenesis Neonatal Nerve Nervous system structure Neurosecretory Systems Neurotransmitters Organ Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Poison Process Proteins Quantitative Reverse Transcriptase PCR Risk Factors Role SP1 gene Signal Transduction Source System Testing Viral Respiratory Tract Infection airway hyperresponsiveness airway inflammation airway obstruction asthmatic airway asthmatic patient chromatin immunoprecipitation cigarette smoking cytokine gamma-Aminobutyric Acid in vivo mortality mouse model nerve supply neuroregulation neurotrophin 4 new therapeutic target novel pathogen pollutant promoter public health relevance pup receptor transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): Childhood asthma is steadily increasing worldwide. Risk factors include early-life airway insults by pollutants, cigarette smoke, respiratory viral infection, and allergen exposure. Clinical hallmarks of asthma include TH2 inflammation, airway hyper-reactivity and mucous hyperplasia. Mucous hyperplasia is a major contributor to cause of death in patients suffering from asthma. Currently, there is no cure for asthma-with available drugs only alleviating airway inflammation and bronchoconstriction but no treatment directly targeting mucous hyperplasia. To develop better therapies for asthma, the mechanism behind mucous overproduction needs to be fully understood. Mucus serves as a first line of defense to protect and clear the lung from potential pathogens or toxic substances. In asthma, however, mucous hyperplasia results in airway obstruction contributing to mortality. Mucin proteins, such as MUC5AC, are predominantly synthesized by goblet cells that line the epithelium. In asthma, inflammatory signals including epidermal growth factor (EGF) and IL-13, are known to induce trans-differentiation of club cells and ciliated cells to mucin-producing goblet cells. In additionto these inflammatory signals, mucous hyperplasia in mouse models of asthma requires GABA, a central neurotransmitter. Consistently, GABA signaling is aberrantly upregulated in the airway of asthmatic patients and by cigarette smoke. This supports a role for deregulated GABA signaling in mucous hyperplasia, but how GABA signaling contributes to mucous hyperplasia is poorly understood. Our preliminary studies show that neuroendocrine bodies (NEBs) are the only source of GABA in the airway. In addition, my lab found that the neurotrophin 4 (NT4)-dependent innervation of NEBs is required for GABA signaling in early-life allergen-induced mucous hyperplasia. Built upon a paradigm that the neuroendocrine system mediates the communication between the nervous system and endocrine secretion to control important body functions, these preliminary findings implicate an unrecognized role of NEBs in mediating neural control of endocrine GABA secretion in the airway. Here, I hypothesize that the GABAa and GABAß pathways have distinct roles in lung epithelial metaplasia and Muc5ac gene expression after early-life allergen exposure. To address this hypothesis I will: 1) Determine the roles of th GABAa and GABAß pathways in mucous hyperplasia in vivo, 2) Investigate the role of GABA signaling in lung epithelial trans-differentiation ex vivo, and 3) Evaluate the GABAß pathway in Muc5ac gene expression regulation. This proposal will be addressed using specific agonists and antagonists of the GABA pathways in vivo and in vitro. Results of my proposed study may identify new drug targets for the treatment of mucous hyperplasia in asthma.

描述（由申请人提供）：儿童哮喘在全球范围内稳步增加。风险因素包括早期呼吸道污染物、香烟烟雾、呼吸道病毒感染和过敏原暴露。哮喘的临床特征包括TH 2炎症、气道高反应性和粘膜增生。粘膜增生是哮喘患者死亡的主要原因。目前，哮喘还没有治愈方法，可用的药物只能缓解气道炎症和支气管收缩，但没有直接针对粘膜增生的治疗方法。为了开发更好的哮喘治疗方法，需要充分了解粘液过度产生背后的机制。粘液是保护和清除肺部潜在病原体或有毒物质的第一道防线。然而，在哮喘中，粘膜增生导致气道阻塞，导致死亡。粘蛋白，如MUC 5AC，主要由衬在上皮上的杯状细胞合成。在哮喘中，已知包括表皮生长因子（EGF）和IL-13的炎症信号诱导俱乐部细胞和纤毛细胞转分化为产生粘蛋白的杯状细胞。除了这些炎症信号，哮喘小鼠模型中的粘膜增生需要GABA，一种中枢神经递质。因此，GABA信号在哮喘患者的气道和香烟烟雾中异常上调。这支持了GABA信号失调在粘膜增生中的作用，但GABA信号如何促进粘膜增生尚不清楚。我们的初步研究表明，神经内分泌体（NEBs）是气道中GABA的唯一来源。此外，我的实验室发现NEB的神经营养因子4（NT 4）依赖性神经支配是早期过敏原诱导的粘膜增生中GABA信号传导所必需的。基于神经内分泌系统介导神经系统和内分泌之间的通信以控制重要的身体功能的范例，这些初步发现暗示了NEB在介导气道内分泌GABA的神经控制中的未被认识的作用。在这里，我假设GABA α和GABA β通路在早期过敏原暴露后肺上皮化生和Muc 5ac基因表达中具有不同的作用。为了解决这一假设，我将：1）确定GABA α和GABA β通路在体内粘膜增生中的作用，2）研究GABA信号传导在离体肺上皮转分化中的作用，和3）评价GABA β通路在Muc 5ac基因表达调控中的作用。这一建议将解决使用特定的激动剂和拮抗剂的GABA途径在体内和体外。我的研究结果可能会发现新的药物靶点，用于治疗哮喘中的粘膜增生。