Project Summary Obesity-related asthma is a significant comorbidity exacerbated by the accelerating global obesity public health crisis. Obese individuals are more than twice as likely to be diagnosed with asthma, and make up the majority of asthmatic patients with severe or difficult-to-treat asthma. These individuals often respond poorly to typical asthma medications, such as corticosteroids, which leads to higher healthcare costs and a substantially reduced quality of life. Although obesity is known to increase the incidence and severity of asthma, the mechanisms driving obesity-related asthma are still not fully defined. There have been a limited number of investigations into mechanisms involving insulin and excessive nerve-mediated bronchoconstriction of the airways, a defining feature of asthma, in obesity-related asthma. Understanding the role of insulin and its effect on the development of obesity-related asthma is critical to targeting preventative interventions and treatments. The goal of this proposal is to elucidate the functional and structural consequences of insulin-mediated changes on reflex bronchoconstriction and airway sensory nerves in the setting of obesity and hyperinsulinemia. The overall hypothesis is that hyperinsulinemia in obesity potentiates airway nerve- mediated reflex bronchoconstriction through increased sensory innervation of the airway epithelium and increased neuronal expression of substance P. This hypothesis will be tested using a mouse model of diet- induced obesity. In vivo lung physiology measurements and novel quantitative imaging techniques will be used to explore the effects of hyperinsulinemia on airway physiology and nerve growth, morphology, and specific neuropeptide expression in obese animals. The specific aims of this proposal are to: (1) Test whether increased insulin potentiates reflex bronchoconstriction in obese mice; and (2) Test whether increased insulin mediates changes in airway sensory nerve structure and neuropeptide expression in obese mice. Achieving these goals will provide insight into how insulin may promote airway nerve-mediated bronchoconstriction and sensory nerve changes in obesity-related asthma and explain why obese individuals are more likely to have asthma. Investigating the mechanisms behind severeand poorly controlled obesity-related asthma will greatly impactthis currently unmet clinical need.