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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL090554-05
Application #
8310206
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Laposky, Aaron D
Project Start
2008-09-23
Project End
2013-09-25
Budget Start
2012-08-01
Budget End
2013-09-25
Support Year
5
Fiscal Year
2012
Total Cost
$2,255,683
Indirect Cost
$752,222
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Peng, Ying-Jie; Makarenko, Vladislav V; Nanduri, Jayasri et al. (2014) Inherent variations in CO-H2S-mediated carotid body O2 sensing mediate hypertension and pulmonary edema. Proc Natl Acad Sci U S A 111:1174-9
Mariani, Christopher J; Vasanthakumar, Aparna; Madzo, Jozef et al. (2014) TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma. Cell Rep 7:1343-52
Limberg, Jacqueline K; Curry, Timothy B; Prabhakar, Nanduri R et al. (2014) Is insulin the new intermittent hypoxia? Med Hypotheses 82:730-5
Ramirez, Jan-Marino (2014) The integrative role of the sigh in psychology, physiology, pathology, and neurobiology. Prog Brain Res 209:91-129
Prabhakar, Nanduri R; Peers, Chris (2014) Gasotransmitter regulation of ion channels: a key step in O2 sensing by the carotid body. Physiology (Bethesda) 29:49-57
Zanella, S├ębastien; Doi, Atsushi; Garcia 3rd, Alfredo J et al. (2014) When norepinephrine becomes a driver of breathing irregularities: how intermittent hypoxia fundamentally alters the modulatory response of the respiratory network. J Neurosci 34:36-50
Makarenko, Vladislav V; Usatyuk, Peter V; Yuan, Guoxiang et al. (2014) Intermittent hypoxia-induced endothelial barrier dysfunction requires ROS-dependent MAP kinase activation. Am J Physiol Cell Physiol 306:C745-52
Peng, Ying-Jie; Yuan, Guoxiang; Khan, Shakil et al. (2014) Regulation of hypoxia-inducible factor-? isoforms and redox state by carotid body neural activity in rats. J Physiol 592:3841-58
Garcia 3rd, Alfredo J; Koschnitzky, Jenna E; Dashevskiy, Tatiana et al. (2013) Cardiorespiratory coupling in health and disease. Auton Neurosci 175:26-37
Nanduri, Jayasri; Prabhakar, Nanduri R (2013) Developmental programming of O(2) sensing by neonatal intermittent hypoxia via epigenetic mechanisms. Respir Physiol Neurobiol 185:105-9

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