The objective of this project is to determine the cellular signals for plasticity in central nervous system components of ventilatory chemoreflexes during Chronic Sustained Hypoxia (CSH). The significance of this research is that it addresses a fundamental but unanswered question in pulmonary medicine: What are the neural mechanisms that increase ventilatory drive and enhance the reflex control of arterial O2 and CO2 during chronic hypoxemia from pulmonary disease? More specifically, we will test the hypothesis that some of the same molecular signals and cellular mechanisms described by others to explain Long Term Facilitation (LTF) with intermittent hypoxia (IH) also contribute to plasticity in ventilatory chemoreflexes during CSH. There has been tremendous progress on mechanisms of LTF recently, which allows us to efficiently test evaluate the model in CSH. Comparing and contrasting plasticity in CSH and IH is significant by allowing us to systematically evaluate potential therapeutic targets for the most important causes of chronic hypoxemia, namely COPD causing CSH and sleep disordered breathing causing IH. First we will establish that the molecular signals for enhanced glutamatergic neurotransmission reported for phrenic LTF in anesthetized rats occur with ventilatory LTF after IH in conscious mice. Then we will measure those molecular signals in mice after CSH and use pharmacology and conditional gene deletion to test their physiological significance for ventilatory acclimatization to CSH. Drugs or Cre-recombinase expressed by adeno-associated virus will be microinjected intrathecally to the spinal cord or stereotaxically in the brainstem of wildtype or transgenic mice to manipulate putative signals for plasticity in different populations of respiratory neurons. Experiments are designed to compare and contrast plasticity with IH vs. CSH. For example, we hypothesize that TrkB phosphorylation is a signal for plasticity in both IH and CSH but BDNF is only a signal in IH. Also, we hypothesize that increases in Reactive Oxygen Species (ROS) with both IH and CSH are an important signal for plasticity and we will measure the time course of ROS changes with different patterns of hypoxia and alter them to test physiological significance. Finally, we will test the hypothesis that CSH causes similar molecular signals for plasticity in a transgenic mouse model of emphysema (conditional deletion of the vascular endothelial growth factor gene in the lung). This is our first step towards addressing the important question of whether the neural plasticity studied in healthy animals acclimatized to environmental hypoxia occurs in diseases with chronic hypoxemia, or if chronic lung disease also involves abnormal plasticity.

Public Health Relevance

This project studies changes in the reflex control of breathing caused by two different patterns of decreased blood oxygen: chronic intermittent hypoxia, which occurs with sleep disordered breathing and apnea, and chronic sustained hypoxia, which occurs with chronic obstructive pulmonary disease. We will use pharmacology and genetic engineering to determine similarities and differences in molecular signals for changes in the neural control of breathing with different patterns of hypoxia in conscious mice. Also, we will use a mouse model of chronic lung disease to distinguish the independent effects of low oxygen from other effects of lung disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Grandner, Michael A; Malhotra, Atul (2017) Connecting insomnia, sleep apnoea and depression. Respirology 22:1249-1250
Sands, Scott A; Mebrate, Yoseph; Edwards, Bradley A et al. (2017) Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure. Am J Respir Crit Care Med 195:237-246
Hocker, Austin D; Stokes, Jennifer A; Powell, Frank L et al. (2017) The impact of inflammation on respiratory plasticity. Exp Neurol 287:243-253
Landry, Shane A; Joosten, Simon A; Sands, Scott A et al. (2017) Response to a combination of oxygen and a hypnotic as treatment for obstructive sleep apnoea is predicted by a patient's therapeutic CPAP requirement. Respirology 22:1219-1224
Orr, Jeremy E; Malhotra, Atul; Sands, Scott A (2017) Pathogenesis of central and complex sleep apnoea. Respirology 22:43-52
Rukhadze, Irma; Carballo, Nancy J; Bandaru, Sathyajit S et al. (2017) Catecholaminergic A1/C1 neurons contribute to the maintenance of upper airway muscle tone but may not participate in NREM sleep-related depression of these muscles. Respir Physiol Neurobiol 244:41-50
Mbanze, Irina; Moschovis, Peter P; Malhotra, Atul (2016) The American Thoracic Society Global Scholars Program. J Thorac Dis 8:S586-7
Malhotra, Atul; Liang, Ni-Cheng (2016) Introduction: American Thoracic Society International Meeting 2016. J Thorac Dis 8:S528-9
Hepokoski, Mark; Owens, Robert L; Malhotra, Atul et al. (2016) Mechanical ventilation in acute respiratory distress syndrome at ATS 2016: the search for a patient-specific strategy. J Thorac Dis 8:S550-2
Pamenter, Mathhew E; Powell, Frank L (2016) Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis. Compr Physiol 6:1345-85

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