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

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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.