PHYSIOLOGICAL ACCLIMATIZATION TO CHRONIC HYPOXIA
Currently, our laboratory is focused on determining the molecular mechanisms of neural plasticity and ventilatory acclimatization to chronic hypoxia using humans and awake, behaving animal models. Chronic hypoxia occurs with chronic lung disease and at high altitude (sustained hypoxia) and with sleep apnea (intermittent hypoxia). We especially focus on mechanisms of susceptibility and tolerance to chronic hypoxia in the central nervous system (CNS) circuits that control breathing.
Our recent experiments study:
- • The effects of HIF-1α versus HIF-2α in neurons versus glia for plasticity in the CSN with chronic hypoxia.
- • The role of inflammatory signals in acclimatization to chronic hypoxia.
- • Identifying therapeutic targets for manipulating neural plasticity in respiratory centers arising from chronic sustained versus intermittent hypoxia.
- • Genetic determinants of individual variation in the hypoxic ventilatory response, including adaptions in human populations native to high altitude.
- • Plasticity in the control of breathing in patients with chronic hypoxemia from lung disease.
We study the problem at multiple levels, translating from genetic and molecular mechanisms to the whole animal physiology.
Experimental approaches include:
- • Ventilatory responses, respiratory gas exchange and functional MRI in healthy humans during acclimatization to hypoxia at high altitude, and in patients with sleep apnea receiving various treatments,
- • Measuring ventilatory responses, metabolism and respiratory muscle activity in conscious, freely moving, instrumented rats and transgenic mice,
- • Temporally and spatially specific gene deletion using loxP-Cre strategies in transgenic mice,
- • Neurophysiological studies of chemoreceptor reflexes in anesthetized rats and mice,
- • In vivo and confocal fluorescent imaging, immunohistochemistry and molecular biological measures of signals for neural plasticity.
Our laboratory also continues to make in gas exchange measurements in humans and various animal models. These studies are generally focused on gas exchange limitations (diffusion limitation, ventilation-perfusion heterogeneity), breath testing (e.g. alcohol) and blood sampling (non-invasive measures of gas levels in blood), and comparative physiology (animal models of human gas exchange and lung disease).