The overall purpose of this proposal is to investigate the control of respiratory smooth and skeletal muscles. Our view is that this regulatory system consists of controlling and controlled elements, organized hierarchically and coupled to other physiological systems. The objectives of this program project grant are to characterize linkages (anatomical, biochemical and function) among components of the respiratory system and between the respiratory and other systems, to delineate the features of the controlled and controlling units, and to study the maturation of these units. We will approach these aims using focused systems, cellular, and molecular approaches in a closely related program consisting of seven projects and three cores. Project 1 combines mathematical analysis with experiments in vertebrate and invertebrates to investigate the responses of the respiratory system to disturbances. It tests the idea that these responses are likely to be the result of coupling between neural network controllers and nonlinear controlled elements. Project 2 examines CNS responses to hypoxia in vivo to elucidate its effects on respiratory and vasomotor activity while Project 3 uses in vitro brain slice preparations to study the neural and synaptic effects of hypoxia. Project 4 assesses the anatomical and functional pathways mediating the responses of the carotid body to hypoxia. Project 5 examines the maturation of airway smooth muscle regulation in animals, and in humans with health and disease. Project 6 assesses surface forces affecting long-term upper airway patency and rheological characteristics of fluids lining the upper airways. Project 7 evaluates the role of muscle afferents in respiratory behavior in humans and in animals, particularly the contribution of phrenic afferents to development of central fatigue of the respiratory muscles. Core facilities are designed to facilitate the increased emphasis in this proposal on cellular and subcellular mechanisms. Besides Core A which serves an administrative and coordinating function, Core B will integrate research which employs immunocyto-chemical and anatomical techniques to study cell structure and histochemistry and Core C will serve as a facility for molecular pharmacology and biochemical methods to examine cell-to-cell communication. Each project in this renewal proposal arises directly or indirectly from ongoing work and each attempts to relate questions of system behavior to studies at the cellular level.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL025830-14
Application #
2215897
Study Section
Heart, Lung, and Blood Research Review Committee A (HLBA)
Project Start
1981-04-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
14
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Prabhakar, Nanduri R; Semenza, Gregg L (2012) Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev 92:967-1003
Kline, David D (2010) Chronic intermittent hypoxia affects integration of sensory input by neurons in the nucleus tractus solitarii. Respir Physiol Neurobiol 174:29-36
Peng, Y-J; Nanduri, J; Yuan, G et al. (2009) NADPH oxidase is required for the sensory plasticity of the carotid body by chronic intermittent hypoxia. J Neurosci 29:4903-10
Kline, David D; Hendricks, Gabriel; Hermann, Gerlinda et al. (2009) Dopamine inhibits N-type channels in visceral afferents to reduce synaptic transmitter release under normoxic and chronic intermittent hypoxic conditions. J Neurophysiol 101:2270-8
Prabhakar, Nanduri R; Kumar, Ganesh K; Nanduri, Jayasri (2009) Intermittent hypoxia-mediated plasticity of acute O2 sensing requires altered red-ox regulation by HIF-1 and HIF-2. Ann N Y Acad Sci 1177:162-8
Braga, Valdir A; Prabhakar, Nanduri R (2009) Refinement of telemetry for measuring blood pressure in conscious rats. J Am Assoc Lab Anim Sci 48:268-71
Kline, David D (2008) Plasticity in glutamatergic NTS neurotransmission. Respir Physiol Neurobiol 164:105-11
Buniel, Maria; Glazebrook, Patricia A; Ramirez-Navarro, Angelina et al. (2008) Distribution of voltage-gated potassium and hyperpolarization-activated channels in sensory afferent fibers in the rat carotid body. J Comp Neurol 510:367-77
Pawar, Anita; Peng, Ying-Jie; Jacono, Frank J et al. (2008) Comparative analysis of neonatal and adult rat carotid body responses to chronic intermittent hypoxia. J Appl Physiol 104:1287-94
Hsieh, Yee-Hsee; Dick, Thomas E; Siegel, Ruth E (2008) Adaptation to hypobaric hypoxia involves GABA A receptors in the pons. Am J Physiol Regul Integr Comp Physiol 294:R549-57

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