Mechanisms behind asthma-internalizing disorder co-morbidity: novel mouse model

描述(申请人提供)：患有哮喘的人患焦虑或抑郁的可能性是没有哮喘的人的两倍，这种共同的发病率可能早在青春期就会发生。鉴于利率上升，这一点尤其令人担忧 哮喘在美国的发病率。不幸的是，哮喘和内化障碍之间联系的潜在机制尚不清楚，因此无法制定适当的干预措施，将哮喘患者的焦虑和抑郁率降至最低，特别是在日益增长的哮喘青年人口中。为了阐明哮喘和焦虑/抑郁之间联系的潜在机制，我们建议使用青春期前后的小鼠模型来测试两种可能的机制。这些机制基于过敏性哮喘的两个特定方面：(1)潜在危及生命的呼吸窘迫的高度应激经历，以及(2)呼吸道慢性炎症反应的增加。哮喘青少年在神经快速发育和参与情绪调节的神经递质系统成熟的时期会出现这些症状。青春期期间的严重压力和慢性炎症会对应激激素(糖皮质激素)的调节产生长期影响，并最终导致糖皮质激素调节失调--众所周知，糖皮质激素失调与内化紊乱有关。因此，我们建议使用小鼠模型来实验确定青春期劳累呼吸和呼吸道炎症对成人糖皮质激素调节、探索性和享乐性行为以及5-羟色胺转运体基因表达的独立影响-这三个重要因素与人类焦虑和抑郁以及这些疾病的小鼠模型相关。一个有效的小鼠模型是进行纵向和实验研究的必要的第一步，以确定呼吸困难和慢性炎症对这些症状的独立影响，并模拟内化行为和哮喘的双向交互作用。辨别这些机制中的每一种在焦虑和抑郁的发展中的相对作用将为评估未来的干预措施提供关键信息，以最大限度地减少哮喘青少年内在性障碍的风险。

DESCRIPTION (provided by applicant): Persons that have had asthma are twice as likely to develop anxiety or depression compared to those that have not had asthma, and this co-morbidity can occur as early as adolescence. This is of particular concern in light of rising rates of asthma in the US. Unfortunately, the mechanisms underlying the association between asthma and internalizing disorders are not clear, and thus proper interventions to minimize rates of anxiety and depression in asthma patients cannot be developed, particularly in the growing population of young people with asthma. To elucidate mechanisms underlying the association between asthma and anxiety/depression, we propose to use a periadolescent mouse model to test two possible mechanisms. The mechanisms are based on two specific aspects of allergic asthma: (1) the highly stressful experiences of potentially life-threatening respiratory distress with severely labored breathing, and (2) chronically-elevated inflammatory responses in the airways. Asthmatic adolescents experience these symptoms during a period of rapid neurological development and maturation of neurotransmitter systems involved in emotion regulation. Severe stress and chronic inflammation during periadolescence can have long-term influences on the regulation of stress hormones (glucocorticoids) and can eventually lead to glucocorticoid dysregulation - a well-known correlate of internalizing disorders. Thus, we propose to use a mouse model to experimentally determine the independent influence of periadolescent labored breathing and airway inflammation on adult glucocorticoid regulation, exploratory and hedonic behavior, and serotonin transporter gene expression - three important correlates of human anxiety and depression and mouse models of these disorders. A validated mouse model is an essential first step in conducting longitudinal and experimental studies to determine the independent effects of labored breathing and chronic inflammation on these symptoms and to model the bidirectional interactions of internalizing behavior and asthma. Discerning the relative role of each of these mechanisms on the development of anxiety and depression would provide key information for evaluating future interventions to minimize the risk of internalizing disorders in adolescents with asthma.