A nonhuman primate model for the link between childhood asthma and obesity

描述（由申请人提供）：近年来，儿童哮喘和肥胖症的发病率都有惊人的增长。17%的儿童现在肥胖，35%的儿童超重。多项研究清楚地表明，肥胖增加了儿童哮喘的发病风险，但其潜在机制尚不清楚，预防肥胖增加哮喘风险的最佳策略也尚不清楚。这项探索性R21应用的目的是利用非人类灵长类动物模型来表征早发性肥胖和哮喘之间的联系，作为开发潜在治疗干预措施的第一步。该应用程序利用了俄勒冈国家灵长类动物研究中心开发的一种独特的非人类灵长类动物早发性肥胖模型，并与肺生物学家、免疫学家和内分泌学家合作。该模型使用长期喂食典型美国高脂肪（HF）饮食的年轻成年猴子。高脂肪饮食的后代显示出体脂增加，脂肪肝和细胞因子水平增加，所有这些都与人类儿童肥胖一致。在拟议的研究中，幼崽将在8个月大时对卵清蛋白敏感，然后在1岁时测试对卵清蛋白的反应性。这项应用的基本假设是，HF饲粮后代对卵清蛋白的攻击会表现出更高的支气管反应性，并有证据表明Th2活化和炎症细胞因子表达增加。将检查四个基本标准来表征模型：先天性气道高反应性，通过甲基胆碱挑战测量；用卵清蛋白激发法测定过敏性高反应性；全身和肺部免疫和细胞因子反应；气道结构和几何形状的变化。在本计划的第一年，将对HF和正常日粮动物的后代进行研究。在第二项研究中，我们将确定将HF饮食母亲转换回对照饮食是否可以防止其后代肺部变化的发展。此外，我们将确定断奶后将HF饮食改为对照饮食是否可以逆转肺部变化。饮食逆转研究对于确定饮食干预在打破肥胖和哮喘之间联系方面的有效性至关重要。在插管动物中测量支气管反应性，直接测量肺阻力的变化。气道几何将测量由新开发的微计算机断层扫描（微ct）程序。猴子和人类在肺发育、免疫系统、细胞因子表达和代谢调节方面的相似之处，将允许直接翻译这些研究，以制定应对肥胖流行病导致的哮喘增加的策略。公共卫生相关性：近年来，儿童哮喘和肥胖的发病率急剧上升，现在很清楚，肥胖增加了患哮喘的风险。哮喘是儿童最常见的慢性疾病，发病率持续上升。本应用程序的目的是确定儿童肥胖导致哮喘的机制，以协助制定新的策略来减少儿童哮喘的发病率。

DESCRIPTION (provided by applicant): The incidence of both childhood asthma and obesity has increased alarmingly in recent years. 17% of children are now obese and 35% are overweight. Multiple studies have clearly demonstrated that obesity increases the risk of developing childhood asthma but the underlying mechanisms are unknown and the optimum strategies to prevent the increased risk of asthma from obesity are also unknown. The purpose of this exploratory R21 application is to utilize a non-human primate model to characterize the link between early onset obesity and asthma as a first step in developing potential therapeutic interventions. This application takes advantage of a unique non-human primate model of early onset obesity developed at the Oregon National Primate Research Center and collaborations between lung biologists, immunologists and endocrinologists. This model uses young adult monkeys chronically fed a typical American high fat (HF) diet. The high fat diet offspring show increased body fat, fatty liver and increased cytokine levels, all of which are consistent with human childhood obesity. For the proposed study, the offspring will be sensitized to ovalbumin at 8 months of age, then reactivity to ovalbumin will be tested at 1 year of age. The basic hypothesis of this application is that the HF diet offspring will show increased bronchial reactivity to challenge with ovalbumin as well as evidence of increased Th2 activation and inflammatory cytokine expression. Four basic criteria will be examined to characterize the model: innate airway hyperreactivity as measured by methacholine challenge; allergic hyperreactivity as measured by ovalbumin challenge; systemic and lung immune and cytokine responses; and changes in airway structure and geometry. In the first year of this proposal, offspring of HF and normal diet animals will be studied. In the second we will determine if switching HF diet mothers back to a control diet can prevent the development of pulmonary changes in their offspring. Furthermore, we will determine if switching HF diet offspring to a control diet after weaning can reverse the pulmonary changes. The diet reversal studies will be critical for determining the effectiveness of dietary interventions in breaking the link between obesity and asthma. Bronchial reactivity will be measured in intubated animals to directly measure changes in lung resistance. Airway geometry will be measured by a newly developed micro-computed tomography (micro-CT) procedure. The similarities in lung development, immune systems, cytokine expression and metabolic regulation between monkeys and humans will allow direct translation of these studies to develop strategies to combat the increase in asthma driven by the obesity epidemic. PUBLIC HEALTH RELEVANCE: In recent years the incidence of childhood asthma and obesity has risen dramatically, and it is now clear that obesity increases the risk of developing asthma. Asthma is the most common chronic disease of childhood and the incidence of asthma continues to increase. The purpose of this application is determine the mechanism by which childhood obesity leads to asthma in order to assist in developing new strategies to decrease the incidence of childhood asthma.