Temperament as a risk factor in a monkey model of asthma susceptibility

描述（由申请人提供）：长期以来，哮喘被认为具有重要的心理社会因素。有相当多的证据表明，社会心理因素，如焦虑、抑郁和压抑的气质，与哮喘有关。虽然许多研究使用这些结构对比了哮喘和非哮喘患者，但这种方法无法确定这些因素是否易患哮喘。然而，一些前瞻性研究确实表明，在早期拥有这些特征的人将来患哮喘的风险更大。在发育早期和哮喘症状发生之前识别高危个体的能力将具有巨大的益处，因为可以识别易感的遗传、免疫和神经机制，并开发可能预先预防哮喘发展的干预措施。这种方法最近被认为具有很大的价值，尽管用人类进行这种研究非常困难和昂贵，并且需要数年才能完成。一项对参加哮喘项目的恒河猴的初步回顾性研究表明，在婴儿期评估的抑制性气质和皮质醇反应迟钝的指标，可以预测哪些动物会在青少年时期发展为气道高反应性，哪些不会。在拟议的研究中，我们将前瞻性地对比两组幼年动物的各种哮喘相关措施。在婴儿期对短暂的母亲分离表现出压抑的气质和迟钝的皮质醇反应的动物将构成我们的“风险”样本。第二组将是未显示这些特征的对照动物。我们的具体目标是：1）前瞻性地证实我们的回顾性发现，即皮质醇反应迟钝和行为方式抑制的幼猴在幼年时表现出气道高反应性; 2）确定气质差异是否与哮喘相关的免疫指标有关; 3）确定气质差异是否与下丘脑-垂体-肾上腺活动改变有关; 4）研究婴儿气质与幼年动物行为功能的当前测量值之间的关系，并确定当前功能的测量值是否增加了预测哪些动物显示哮喘相关结果的能力。公共卫生相关性：哮喘的患病率在全世界，特别是在发达国家大大增加。使用与人类哮喘密切相似的实验动物模型，拟议的项目旨在确定可能有患哮喘风险的个体。这一系列研究的最终目标是确定可以在生命早期实施的有效干预措施，这些干预措施可能会预先阻止这种疾病的发展。

DESCRIPTION (provided by applicant): Asthma has long been recognized as having a significant psychosocial component. Considerable evidence exists that psychosocial factors, such as anxiety, depression, and inhibited temperament, are associated with asthma. While many studies have contrasted asthmatic and non-asthmatic people using these constructs, such an approach cannot determine whether these factors are predisposing to development of asthma. A handful of prospective studies, however, do suggest that individuals possessing some of these characteristics at an early age are more at-risk for developing asthma in the future. The ability to identify at-risk individuals early in development and prior to development of asthmatic symptoms would be of enormous benefit, in that predisposing genetic, immunologic, and neurologic mechanisms could be identified, and interventions developed that might pre-empt the development of asthma. Such an approach has recently been suggested as having great value, although conducting such research with humans is very difficult and expensive, and would take years to accomplish. A preliminary, retrospective study of rhesus monkeys enrolled in an asthma project demonstrated that indicators of inhibited temperament and blunted cortisol responsiveness, assessed in infancy, predicted which animals would develop airways hyper-responsiveness as juveniles, and which would not. In the proposed study, we will contrast prospectively two sets of juvenile animals on a variety of asthma-relevant measures. Animals that showed inhibited temperament and blunted cortisol responsiveness to brief maternal separation in infancy will comprise our "at-risk" sample. The second set will be control animals that did not show those characteristics. Our specific aims are to: 1) confirm prospectively our retrospective finding that infant monkeys with a blunted cortisol response and an inhibited behavioral style show airways hyper-responsiveness as juveniles; 2) determine whether differences in temperament are associated with asthma-relevant immune measures; 3) determine whether differences in temperament are associated with altered hypothalamic-pituitary-adrenal activity; 4) examine how infant temperament relates to current measures of behavioral functioning in juvenile animals, and determine whether measures of current functioning increase the ability to predict which animals display asthma-related outcomes. PUBLIC HEALTH RELEVANCE: The prevalence of asthma is increasing greatly throughout the world, especially in developed countries. Using an experimental animal model that has close parallels to asthma in humans, the proposed project is aimed at identifying individuals that might be at-risk for developing asthma. The eventual goal of this line of research is to identify effective interventions that could be implemented early in life that might pre-empt development of this disease.