Cholinergic hyperinnernation in early life regulates long-term airway reactivity

项目总结： 哮喘是一种慢性呼吸道疾病，影响着2500多万人，其中包括700万儿童 在美国，并给患者、他们的家人和 社区。虽然哮喘可能会影响到所有年龄段的人，但它最常始于儿童时期。临床 观察显示，早年的环境侮辱与慢性呼吸道疾病的风险增加有关 包括哮喘在内的阻塞性疾病。此外，人们越来越多地认识到，在整个过程中，肺功能 在出生后肺发育期间发生的呼吸事件对生命有深远的影响。 这些发现强调了更充分地了解与年龄相关的特定的气道适应性的重要性。 早期生活中暴露在环境中的变化。 我们正在进行的一项早期小鼠哮喘模型的工作揭示了神经的关键作用 在维持气道高反应性(AHR)中，气道平滑肌(ASM)调节失调。我们发现 早期接触变应原通过胆碱能神经支配诱导ASM收缩功能的独特上调。 ASM的这种收缩可塑性在出生后呼吸道发育的时间窗口中发挥了关键作用 保留长期的AHR。相反，神经调节的改变和随后的长期增强 在成人哮喘的小鼠模型中没有发现呼吸道收缩。此外，ASM的微阵列分析 CD38和-actinin1(ACTN1)基因在P21ASM中的表达选择性上调 接触过敏原。这些基因已经确立了在ASM收缩调节中的作用。因此，我们 假设在出生后发育过程中胆碱能刺激异常激活钙离子和ACTN1- ASM中的中介通路，进而导致持续性AHR。我们建议通过1)来检验这一假设 确定ASM易受异常胆碱能调节影响的关键时间窗口；2) 探讨胆碱能刺激引起ASM收缩亢进的两种可能机制 CD38介导的钙信号通路和ACTN1介导的细胞内机械转导； 评价抗胆碱能药物预防早期持续性AHR的疗效 接触过敏原。 在我的导师艾兴斌博士和布鲁斯·利维博士的指导下，我们制定了为期五年的培训 该计划包括量身定制的教学和技术培训，以发展学习更多的技能 ASM在健康和疾病中的调节。重要的是，这个项目将由一个科学的职业咨询来监督 具有与此提案的关键领域相关的专业知识的委员会，包括ASM生理学、分子和 发育肺生物学和动物疾病模型。拟议的职业发展计划将确定 科学基础，并提供必要的额外培训，以实现我成为一名 美国国立卫生研究院资助的独立内科医生兼科学家，研究肺平滑肌生物学和肺功能失调 肺部疾病。

Project Summary: Asthma is a chronic respiratory disease affecting more than 25 million people including 7 million children in the United States and imposing a substantial health and economic burden on patients, their families and the communities. Although asthma may affect all age groups, it most often starts during childhood. Clinical observations have revealed early life environmental insults are associated with increased risk of chronic airway obstructive diseases including asthma. In addition, there is increasing recognition that lung function throughout life is profoundly impacted by respiratory events that occur during the time period of postnatal lung development. These findings highlight the significance of more fully understanding age-related specific airway adaptive changes from environmental exposures in early life. Our work in progress with an early life mouse asthma model has revealed a key role of neural dysregulation of airway smooth muscle (ASM) in the maintenance of airway hyperreactivity (AHR). We found early life allergen exposure induced a unique upregulation of ASM contractility via cholinergic hyperinnervation. This contractile plasticity of ASM in the time window of postnatal airway development played a key role in retaining long term AHR. In contrast, alteration in neural regulation and subsequent long term enhancement of airway contractility was not seen in a murine model of adult asthma. Moreover, microarray analysis of ASM revealed gene expression of CD38 and -actinin1 (ACTN1) was selectively upregulated in P21 ASM following allergen exposure. These genes have established role in the contractile regulation of ASM. We therefore hypothesize that cholinergic stimulation during postnatal development aberrantly activates Ca2+ and ACTN1- mediated pathways in ASM, which in turn causes persistent AHR. We propose to test this hypothesis by 1) identifying the critical time window during which ASM is vulnerable to the aberrant cholinergic regulation; 2) investigating two potential mechanisms underlying cholinergic stimulation induced ASM hypercontractility, ie CD38 mediated Ca2+ signaling pathway and ACTN1 mediated intracellular mechanotransduction; and 3) evaluating the efficacy of anti-cholinergic medication in the prevention of persistent AHR following early life allergen exposure. With the guidance of my mentors, Drs. Xingbin Ai and Bruce Levy, we have developed a five-year training program that includes both tailored didactic and technical training to develop additional skills for study of the regulation of ASM in health and disease. Importantly, this project will be overseen by a scientific career advisory committee with expertise related to key areas of this proposal, including ASM physiology, molecular and developmental lung biology and animal disease models. The proposed career development plan will establish scientific foundations and provide the additional training necessary to achieve my ultimate goal of becoming an independent, NIH-funded physician-scientist studying pulmonary smooth muscle biology and dysregulation in lung diseases.