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

描述（由申请人提供）：患有哮喘的人患焦虑或抑郁的可能性是未患哮喘的人的两倍，这种合并症早在青春期就可能发生。鉴于利率不断上升，这一点尤其令人关切 哮喘在美国不幸的是，哮喘和内化障碍之间的联系的机制尚不清楚，因此，不能开发适当的干预措施，以尽量减少哮喘患者的焦虑和抑郁的发生率，特别是在不断增长的年轻哮喘患者中。为了阐明哮喘和焦虑/抑郁症之间的相关机制，我们建议使用一个青春期小鼠模型来测试两种可能的机制。其机制基于过敏性哮喘的两个特定方面：（1）可能危及生命的呼吸窘迫伴严重呼吸困难的高度应激体验，以及（2）气道中慢性升高的炎症反应。哮喘青少年在神经系统快速发育和参与情绪调节的神经递质系统成熟的时期经历这些症状。青春期前后的严重压力和慢性炎症可能对应激激素（糖皮质激素）的调节产生长期影响，并最终导致糖皮质激素失调-这是一种众所周知的内化障碍相关因素。因此，我们建议使用小鼠模型，以实验确定独立的影响，青少年期呼吸困难和气道炎症对成人糖皮质激素的调节，探索和享乐行为，和5-羟色胺转运蛋白基因的表达-三个重要的人类焦虑和抑郁症和小鼠模型，这些疾病的相关性。在进行纵向和实验研究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相互作用时，经验证的小鼠模型是必不可少的第一步。辨别这些机制中的每一个对焦虑和抑郁的发展的相对作用将为评估未来的干预措施提供关键信息，以最大限度地减少青少年哮喘患者内化障碍的风险。 公共卫生相关性：哮喘是美国儿童和青少年最常见的慢性疾病，目前的患病率为9%，约有500万青年。哮喘通常与焦虑和抑郁并存，这一事实加剧了公众对健康的担忧-哮喘患者患焦虑和抑郁的比率是非哮喘患者的两倍。这种并发症的生理过程尚不清楚，因此，适当的干预方法，以尽量减少这些内化的哮喘青少年的疾病率必然是有限的。我们提出的研究将使用青春期小鼠模型来比较两种哮喘症状（呼吸困难，气道炎症）对焦虑和抑郁相关行为和神经内分泌过程发展的影响。这两种症状中的每一种在内化障碍发展中的相对作用是开发未来干预措施以最大限度地减少哮喘患者焦虑和抑郁的关键。

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. PUBLIC HEALTH RELEVANCE: Asthma is the most common chronic condition for children and adolescents in the U.S., with a current prevalence of 9 percent, or approximately 5 million youth. Public health concerns are compounded by the fact that asthma is often co-morbid with anxiety and depression - asthma patients suffer from anxiety and depression at twice the rate as persons without asthma. The physiological processes underlying this co-morbidity are not clear, and thus appropriate intervention methods to minimize rates of these internalizing disorders in asthmatic adolescents are necessarily limited. Our proposed research will use a periadolescent mouse model to compare the influence of two asthma symptoms (labored breathing, airway inflammation) on the development of anxiety- and depression-related behavior and neuroendocrine processes. The relative role of each of these two symptoms in the development of internalizing disorders is key to developing future interventions to minimize anxiety and depression in patients with asthma.