Sleep-disordered breathing is characterized primarily by partial or total upper airway obstruction during sleep. The most common form of sleep-disordered breathing is obstructive sleep apnea due to recurrent collapse of the upper airway with the onset of sleep state. The major risk factors associated with the development of sleep apnea are obesity, male gender, and older age. Currently, our overall hypothesis is that obesity alters both mechanical properties and compensatory neuromuscular responses leading to upper airway obstruction. Based on our most recent findings, we demonstrate that obesity is associated with alterations in the mechanical properties (passive Pcrit) of the upper airway that are counterbalanced by compensatory upper airway neural responses (active Pcrit). Loss of the compensatory neuromuscular responses leads to obstructive-sleep apnea. In Specific Aim 1, we will explore the effects of gender, obesity and age in patients with obstructive sleep apnea and normal individuals. Our preliminary data suggest that female gender, peripheral adiposity, increased leptin and younger age are associated with increased compensatory neuromuscular responses, while male gender, central adiposity, decreased leptin and older age are associated with blunted compensatory responses. In Specific Aim 2, we will determine the role of the genioglossus muscle and whether co-activation of other muscles is required for the maintenance of upper airway patency. In Specific Aim 3, we hypothesize that weight reduction will lower the passive Pcrit and/or restore the compensatory neuromuscular responses in both men and women with obstructive sleep apnea. The proposed studies are designed to elucidate the pathophysiologic basis for the development of obstructive sleep apnea. Novel physiologic techniques have been developed during sleep and allow partitioning of the mechanical and neural regulation of upper airway control. The studies also provide insights into the neurohumoral regulation of upper airway function, and thus potentially new approaches to the treatment for sleep-disordered breathing. [unreadable] [unreadable]