Physiological Acclimatization to Chronic Hypoxia
Our laboratory’s primary objective is to determine the mechanisms of neural plasticity and ventilatory acclimatization with chronic hypoxia. 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 susceptibilty and tolerance to chronic hypoxia in the central nervous system (CNS) circuits that control breathing.
Our recent experiments study:
- The importance of genes, which have been shown to be important for hypoxic tolerance in Drosophila selected for low O2 (e.g. Notch pathway genes), in mice.
- The role of signaling pathways, which are known to be important for plasticity in intermittent hypoxia (e.g. ROS, TrkB), in plasticity with chronic sustained hypoxia.
- The effects of HIF-1a versus HIF-2a in neurons versus glia for plasticity in the CSN with chronic hypoxia.
- Interactions between HIF, FIH and Notch in chronic hypoxia.
- The role of inflammatory signals in acclimatization to chronic hypoxia.
- Neural plasticity with chronic hypoxia in animal models of lung disease (vs. environmental hypoxia).
We study the problem at multiple levels, translating from genetic and molecular mechanisms to the whole animal physiology. Experimental approaches include:
- measuring ventilatory responses 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,
- ventilatory responses and functional MRI in healthy humans during acclimatization to hypoxia at high altitude, and in patients with sleep apnea receiving various treatments.
