This is a competing renewal application of the Program Project Grant entitled """"""""INTEGRATIVE CONSEQUENCES OF HYPOXIA"""""""". The overall focus of the Program continues to examine the effects of systemic, cellular and molecular responses to chronic intermittent hypoxia (CIH). The overarching hypotheses of the competing renewal application are: a) ROS affect chemo reflex function by recruiting distinct cellular mechanisms in the individual components of the chemo reflex pathway (sensor, controller, and end organ);and b) Long-term exposure to CIH leads to stable changes in ROS as well as cardio respiratory functions and involves epigenetic regulation of redox homeostasis in the chemo reflex pathway. PROJECT 1 will test the hypothesis that the effects of CIH on the carotid body are due to ROS-mediated imbalance between inhibitory (carbon monoxide;CO) and excitatory (hydrogen sulfide;H2S) gaseous messengers. PROJECT 2 tests the hypothesis that chemo reflex triggered sympathetic activation by CIH evokes oxidative stress in the adrenal medulla, a major sympathetic end organ resulting in augmented catecholamine secretion by hypoxia, which contributes to ClH-induced hypertension. PROJECT 3 tests the hypothesis that the ClH-induced irregular breathing is mediated by carotid body-dependent ROS generation and reconfiguration of the respiratory neural network in the PreBotC. PROJECT 4 tests the hypothesis that epigenetic regulation of genes encoding redox regulatory enzymes in the chemo reflex pathway contributes to persistent oxidative stress, and the cardio-respiratory responses to long-term CIH. CORE A fulfills an administrative and coordinating function. CORE B provides centralized facilities for exposure of rodents to CIH, maintenance of genetically modified mice, morphological, biochemical and molecular biological assays for all four projects. Because of the tight thematic linkages across the projects, the total knowledge gained from the overall program will truly be greater than the sum derived from each project.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL090554-07
Application #
8743247
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Laposky, Aaron D
Project Start
2007-12-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Garcia 3rd, Alfredo J; Dashevskiy, Tatiana; Khuu, Maggie A et al. (2017) Chronic Intermittent Hypoxia Differentially Impacts Different States of Inspiratory Activity at the Level of the preBötzinger Complex. Front Physiol 8:571
Samanta, Debangshu; Prabhakar, Nanduri R; Semenza, Gregg L (2017) Systems biology of oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med 9:
Peng, Ying-Jie; Zhang, Xiuli; Gridina, Anna et al. (2017) Complementary roles of gasotransmitters CO and H2S in sleep apnea. Proc Natl Acad Sci U S A 114:1413-1418
Semenza, Gregg L (2017) A compendium of proteins that interact with HIF-1?. Exp Cell Res 356:128-135
Anderson, Tatiana M; Ramirez, Jan-Marino (2017) Respiratory rhythm generation: triple oscillator hypothesis. F1000Res 6:139
Garcia 3rd, Alfredo J; Zanella, Sebastien; Dashevskiy, Tatiana et al. (2016) Chronic Intermittent Hypoxia Alters Local Respiratory Circuit Function at the Level of the preBötzinger Complex. Front Neurosci 10:4
Wang, N; Kang, H S; Ahmmed, G et al. (2016) Calpain activation by ROS mediates human ether-a-go-go-related gene protein degradation by intermittent hypoxia. Am J Physiol Cell Physiol 310:C329-36
Ramirez, Jan-Marino; Dashevskiy, Tatiana; Marlin, Ibis Agosto et al. (2016) Microcircuits in respiratory rhythm generation: commonalities with other rhythm generating networks and evolutionary perspectives. Curr Opin Neurobiol 41:53-61
Anderson, Tatiana M; Garcia 3rd, Alfredo J; Baertsch, Nathan A et al. (2016) A novel excitatory network for the control of breathing. Nature 536:76-80

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