A function of the neuroendocrine system in mucous hyperplasia

 描述(申请人提供)：儿童哮喘在全球范围内稳步增加。风险因素包括早期受到污染物的呼吸道侮辱、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TH2炎症、呼吸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--可用的药物只缓解呼吸道炎症和支气管收缩，而没有直接针对粘液增生的治疗方法。为了开发更好的哮喘治疗方法，需要充分了解粘液过度生产背后的机制。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，粘液增生会导致呼吸道阻塞，从而导致死亡。粘蛋白蛋白，如MUC5AC，主要由排列在上皮细胞内的杯状细胞合成。在哮喘中，包括表皮生长因子(EGF)和IL-13在内的炎症信号被认为可以诱导棒状细胞和纤毛细胞向产生粘蛋白的杯状细胞的转分化。除了这些炎症信号外，哮喘小鼠模型的粘膜增生还需要中枢神经递质GABA。一直以来，GABA信号在哮喘患者的呼吸道和香烟烟雾中异常上调。这支持了去调节的GABA信号在粘膜增生中的作用，但GABA信号如何在粘膜增生中起作用还知之甚少。我们的初步研究表明，神经内分泌体(NEB)是呼吸道中GABA的唯一来源。此外，我的实验室发现，在早期过敏原诱导的粘膜增生中，GABA信号转导需要神经营养因子4(NT4)依赖的NEBs的神经支配。建立在神经内分泌系统调节神经系统和内分泌之间的通信以控制重要身体功能的范式基础上，这些初步发现暗示了NEBs在介导呼吸道内分泌GABA分泌的神经控制中的未知作用。在这里，我假设GABAA和GABA？通路在早期过敏原暴露后肺上皮化生和Muc5ac基因表达中具有不同的作用。为了解决这一假说，我将：1)确定TH-GABAA和GABA？通路在体内粘膜增生中的作用；2)研究GABA信号在体外肺上皮细胞转分化中的作用；3)评价GABA？通路在Muc5ac基因表达调控中的作用。这一建议将使用体内和体外GABA途径的特定激动剂和拮抗剂来解决。我提出的研究结果可能会确定治疗哮喘粘膜增生的新药物靶点。

 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.