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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL081823-05A1
Application #
8186273
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
2005-08-15
Project End
2015-06-30
Budget Start
2011-07-14
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$369,900
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Malhotra, Atul; Morrell, Mary J; Eastwood, Peter R (2018) Update in respiratory sleep disorders: Epilogue to a modern review series. Respirology 23:16-17
Sands, Scott A; Edwards, Bradley A; Terrill, Philip I et al. (2018) Identifying obstructive sleep apnoea patients responsive to supplemental oxygen therapy. Eur Respir J 52:
Malhotra, Atul; Crocker, Maureen E; Willes, Leslee et al. (2018) Patient Engagement Using New Technology to Improve Adherence to Positive Airway Pressure Therapy: A Retrospective Analysis. Chest 153:843-850
Orr, Jeremy E; Sands, Scott A; Edwards, Bradley A et al. (2018) Measuring Loop Gain via Home Sleep Testing in Patients with Obstructive Sleep Apnea. Am J Respir Crit Care Med 197:1353-1355
Zhang, Jiao; Dong, Jianjie; Martin, Marcy et al. (2018) AMP-activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension. Am J Respir Crit Care Med 198:509-520
Moya, Esteban A; Powell, Frank L (2018) Serotonin and Adenosine G-protein Coupled Receptor Signaling for Ventilatory Acclimatization to Sustained Hypoxia. Front Physiol 9:860
De La Zerda, D J; Stokes, J A; Do, J et al. (2018) Ibuprofen does not reverse ventilatory acclimatization to chronic hypoxia. Respir Physiol Neurobiol 256:29-35
Deacon-Diaz, Naomi; Malhotra, Atul (2018) Inherent vs. Induced Loop Gain Abnormalities in Obstructive Sleep Apnea. Front Neurol 9:896
Light, Matthew; McCowen, Karen; Malhotra, Atul et al. (2018) Sleep apnea, metabolic disease, and the cutting edge of therapy. Metabolism 84:94-98
Hepokoski, Mark L; Bellinghausen, Amy L; Bojanowski, Christine M et al. (2018) Can We DAMPen the Cross-Talk between the Lung and Kidney in the ICU? Am J Respir Crit Care Med 198:1220-1222

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