PROJECT SUMMARY/ABSTRACT Over 40 million children and adults in the US suffer from chronic pulmonary diseases including asthma, chronic bronchitis and obstructive pulmonary disease. Asthma alone accounts for 25 million cases, with prevalence increasing by 10% each decade. Combination inhaled corticosteroids (ICs) are the treatment of choice for the long-term management of breathing symptoms. Regrettably, ICs are also associated with voice disorders in up to 50% of cases. These disorders become chronic, impair communication, and have significant adverse occupational, financial, and psychosocial consequences. Given the prevalence of voice disorders associated with combination ICs since chlorofluorocarbon-propelled inhalers were banned in 2008, compelling clinical evidence necessitates a new research initiative to address this critical threat to public health. The long-term goal of this research program is to prevent and cure voice disorders associated with combination ICs across the lifespan. Children placed on inhalers face lifelong, possibly permanent communication impairment. Determining the pathophysiology of IC-related voice disorders is the critical next step to developing new voice-sparing asthma drugs. It is essential to determine the pathophysiology of voice disorders associated with combination ICs, to treat, reverse, and prevent these voice changes. This project accomplishes these objectives in 3 hypothesis-driven aims. Aim 1 determines structural laryngeal biomarkers of IC use associated with voice disorders in children and adults with the 2 most common phenotypes of asthma (high TH2 allergic and low TH2 primarily eosinophilic). Aim 2 quantifies voice disorder onset and reversibility for ICs versus sham using an in vivo animal model. Aim 3 examines the pathogenesis of IC-related voice disorders via examination of cytokines associated with inflammation (IL-1β, IL-6, TNF-α) from animal true vocal folds and human false vocal folds. Collectively, these aims define the pathophysiology associated with IC-related voice disorders, laying the foundation for voice disorder cure and prevention in this population. This translational project will have immediate and significant clinical implications, making a powerful and sustained impact in the field of communication disorders.