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

描述(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，肥胖会增加儿童哮喘的风险，但潜在的机制尚不清楚，预防肥胖导致哮喘风险增加的最佳策略也是未知的。这一探索性的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。这项应用利用了俄勒冈州国家灵长类研究中心开发的一种独特的早发性肥胖的非人类灵长类动物模型，以及肺部生物学家、免疫学家和内分泌学家之间的合作。这个模型使用的是长期以典型的美国高脂肪(HF)饮食喂养的成年幼猴。高脂肪饮食的后代表现出体脂增加、脂肪肝和细胞因子水平增加，所有这些都与人类童年肥胖的情况一致。在拟议的研究中，后代将在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能力。这一应用的基本假设是，HF饮食后代将表现出对卵清蛋白挑战的支气管反应性增加，以及Th2激活和炎性细胞因子表达增加的证据。将检查四个基本标准来描述该模型：通过乙酰甲胆碱挑战衡量的先天气道高反应性；通过卵蛋白挑战衡量的过敏性高反应性；全身和肺免疫和细胞因子反应；以及呼吸道结构和几何形状的变化。在这项提议的第一年，将对HF和正常饮食动物的后代进行研究。在第二项研究中，我们将确定将HF母亲的饮食改回对照饮食是否能防止其后代肺部病变的发生。此外，我们将确定断奶后将HF后代的饮食转换为对照饮食是否可以逆转肺部的变化。饮食逆转研究对于确定饮食干预在打破肥胖和哮喘之间的联系方面的有效性至关重要。将在插管动物身上测量支气管反应性，以直接测量肺阻力的变化。新开发的微型计算机断层扫描(Micro-CT)程序将测量呼吸道几何形状。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。与公共卫生相关：近年来，儿童哮喘和肥胖症的发病率急剧上升，现在很明显，肥胖症增加了患哮喘的风险。哮喘是儿童最常见的慢性病，哮喘的发病率还在持续增加。这项应用的目的是确定儿童肥胖导致哮喘的机制，以帮助制定减少儿童哮喘发病率的新策略。

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.