David Cool (Committee Member), Lynn Hartzler (Committee Member), Robert Putman (Committee Co-chair), Mark Rich (Committee Member), Christopher Wyatt (Advisor)
Doctor of Philosophy (PhD)
The carotid bodies are small sensory organs located along the bifurcation of the carotid arteries. They detect changes in blood gases and relay this information to the brain to allow for initiation of appropriate respiratory and cardiovascular responses. A decrease in oxygen (hypoxia) sensed by the carotid body results in an increase in firing of the carotid sinus nerve and ultimately a change in one's breathing pattern. An inability to respond to an acute hypoxic (low oxygen) episode via increased ventilation may result in death or lead to pathological or chronic conditions such as stroke and hypertension (Prabhakar et.al., 2005). The carotid bodies are therefore responsible for initiating the acute hypoxic ventilatory response (HVR) and blunting or attenuation of the HVR has been implicated in sudden infant death syndrome (SIDS) in 'at risk' infant groups (Calder et al., 1994; Horne et al., 2005; Gauda et. al., 2007).
The exact mechanism(s) responsible for hypoxic chemotransduction by the carotid body remains controversial and are the subject of intense investigation. There is evidence indicating the energy-sensing enzyme AMP-activated protein kinase (AMPK) may play a critical role in the transduction of an acute hypoxic stimulus by the carotid bodies (Evans et. al., 2005; Wyatt et.al., 2007). Global AMPK α1 and AMPK α2 subunit knockout mice were used to gain further insight into the role AMPK has in acute oxygen-sensing in whole animal and in isolated oxygen-sensing cells of mice carotid bodies. A two-chamber plethysmography system was used to measure baseline breathing during normoxia (21% O2) and the hypoxic ventilatory response to 8% oxygen. AMPK α1 subunit knockout mice had a significant attenuation in percent change in breathing frequency during hypoxic exposure and AMPK α2 knockouts also showed a significant decrease in percent change in minute ventilation. The plethysmography data shows AMPKα subunits may be involved in baseline breathing and generation of acute hypoxic ventilatory responses. Isolated type I cells from global knockout mice were also used in calcium imaging experiments. Hypoxia induced Ca2+ signaling was inhibited by 85% in cells from AMPK α2 knockout mice whereas AMPK α1 KO mice showed a mixed response to hypoxia. The cellular data seem to show that a decrease in response to hypoxia may be due to an effect at the level of the carotid body. These findings provide further support for the hypothesis that AMPK regulates acute hypoxic chemotransduction and thereby energy supply at the whole body level.
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