? ? This application is for a new Program Project Grant entitled """"""""INTEGRATIVE CONSEQUENCES OF HYPOXIA"""""""". Intermittent Hypoxia (IH) is a common and life threatening condition associated with many different diseases including sleep-disordered breathing with recurrent apneas. IH associated with recurrent apneas is a major cause of morbidity and mortality in the U.S. population, affecting an estimated 18 million adults and 50% of premature infants. The overall objective of the proposed study for the next five years is to examine the physiological consequences of chronic IH. Patients with recurrent apneas develop serious cardio-respiratory morbidities manifested as hypertension, augmented sympathetic activity, and abnormalities in breathing. An overarching hypothesis of the current proposal is that IH leads to an imbalance between facilitatory and inhibitory mechanisms that govern homeostasis of the cardio-respiratory systems resulting in morbidity. Using in vivo and in vitro models of IH, all four projects in the current program albeit to different degrees test this hypothesis. Chronic IH leads to up-regulation of peripheral chemoreceptor reflex and down-regulation of baroreceptor reflex resulting in unopposed elevation of sympathetic nerve activity. Therefore, Project 1 aims at identifying the cellular and molecular mechanisms associated with augmented carotid body chemoreceptor function, whereas Project 2 examines the cellular and molecular mechanism(s) underlying the down-regulation of baroreceptor reflex by chronic IH. Project 3 determines the impact of chronic IH on network and membrane properties of the neurons in pre-Boetzinger complex that regulate the respiratory rate and tidal neural activities, which may contribute to changes in breathing. IH alters the balance between pro- and anti-oxidants resulting in increased cellular reactive oxygen species (ROS), which amplify the brief hypoxic signals and translate them to systemic responses. Projects 1,2,3 examine the role of HIF-1 transcriptional activator on IH-evoked up-regulation of pro-oxidants, whereas Project 4 assesses the contribution of HIF-2 to chronic IH- evoked down-regulation of anti-oxidants in chemo and baro-reflex pathways. Core A fulfills an administrative and coordinating function. Core B provides central facilities for exposure of rodents to CIH, maintenance of genetically modified mice colony carrying out morphological, biochemical and molecular biological assays for all four projects. The conceptual frame work emerging from the proposed integrated approaches provide novel insights into the functional reorganization of the cardio-respiratory systems, which is of translational significance in understanding the consequences of IH associated with sleep-disordered breathing. The integrative and comprehensive nature of this Program offers maximal collaborative efforts and enhances the impact of knowledge that eventually emerges from this Program. We are confident that the total knowledge accrued from these studies will truly be greater than the sum of each project because of the tight thematic linkages across the projects.
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