Title of project: Neural plasticity during acclimatization to hypoxia. Chronic hypoxia increases the hypoxic ventilatory response (HVR) by increasing the CV sensitivity of carotid body chemoreceptors and the sensitivity of respiratory centers in the CNS to sensory input from carotid bodies. These changes in the HVR involve O2-sensitive gene expression and other molecular signals in carotid bodies and the CNS. Ventilatory drive in normoxia is also increased by chronic hypoxia but the mechanisms for this are unknown. However, central chemoreceptors may be involved because arterial PCO2 is regulated at a lower level after acclimatization. Recently, we discovered that the increased HVR and increased normoxic ventilatory drive after chronic hypoxia could be blocked by microinjecting glutamate receptor antagonists into the nucleus tractus solitarius (NTS). The NTS is important for respiratory control as the site of the primary synapse from carotid body chemoreceptors, and as 1 of many CO2-sensitive central chemoreceptor sites. We hypothesize that (1) chronic hypoxia increases sensitivity to carotid body sensory input and increases normoxic ventilatory drive by changes in NMDA and non-NMDA glutamate receptors in the NTS, (2) such neural plasticity is caused by O2-sensitive (e.g. HIF-1a, reactive O2 species) and O2-independent mechanisms (e.g. increased glutamate), and (3) central chemoreceptors in the NTS play a unique role in ventilatory acclimatization to hypoxia compared to CO2-sensitive chemoreceptors at other sites in the brainstem. We will test these hypotheses by (1) microinjecting NMDA and AMPA receptor agonists and antagonists in awake and anesthetized rats while measuring respiratory motor output, (2) measuring effects of chronic hypoxia and neural stimulation on mRNA and protein levels for glutamate receptors in the NTS, (3) studying central chemoreceptors in rat medullary slices in vitro, and (4) using transgenic mouse models of conditional HIF-1a deletion in the CNS. Experiments are designed to elucidate general principles of signaling for adaptive changes to chronic hypoxia in the brain, and ultimately how changes in ventilatory control may contribute to hypoxemia in patients with chronic lung disease.
| 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 |
| Gupta, Ankit; Quan, Stuart F; Oldenburg, Olaf et al. (2018) Sleep-disordered breathing in hospitalized patients with congestive heart failure: a concise review and proposed algorithm. Heart Fail Rev 23:701-709 |
| Hepokoski, Mark L; Malhotra, Atul; Singh, Prabhleen et al. (2018) Ventilator-Induced Kidney Injury: Are Novel Biomarkers the Key to Prevention? Nephron 140:90-93 |
| Hepokoski, Mark L; Odish, Mazen; Malhotra, Atul (2018) Prone positioning in acute respiratory distress syndrome: why aren't we using it more? J Thorac Dis 10:S1020-S1024 |
| 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 |
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