Title AMP-activated protein kinase and oxygen-sensing Abstract The carotid bodies are small organs located on the carotid arteries. They serve an essential biological function by detecting and relaying information regarding blood gas composition to the breathing centers of the brain. Thus, a deficit in blood oxygen (hypoxia) is 'sensed'by the carotid body, resulting in an increased firing frequency of the carotid sinus nerve and ultimately a change in the pattern of breathing. Recent research suggests that the exact molecular mechanism by which hypoxia is transduced into increased carotid sinus nerve activity is close to being resolved. Evidence indicates that activation of the energy- sensing enzyme AMP-activated protein kinase (AMPK) may be critical for the transduction of an acute hypoxic stimulus by the carotid bodies. The novel experimental protocols detailed in the current proposal will provide functional insights into the role of AMPK in acute oxygen-sensing.
Specific Aim 1 will define the importance of AMPK in the generation of the carotid body mediated acute hypoxic ventilatory response in whole animals.
Specific Aim 2 will address the importance of AMPK in the response of isolated oxygen-sensing cells from the carotid body to hypoxia.
Specific Aim 3 will address the importance of regulators of AMPK in the generation of a hypoxic response by oxygen-sensing cells in the carotid body. This project will use genetically modified mice, plethysmography, immunocytochemistry, electrophysiology and calcium imaging to define the role of AMPK in mediating hypoxic transduction at the level of the whole animal and the oxygen-sensing cells of the carotid bodies. Meeting the aims of the current proposal will provide clinically relevant information pertaining to the basic physiology of the carotid bodies and to the generation of the ventilatory increase observed during hypoxia. Furthermore the conceptually novel hypothesis that AMPK is involved in oxygen-sensing by the carotid body raises the possibility of new therapeutic strategies for disorders such as sleep apnea and sudden infant death.
The carotid bodies are vital organs which detect a fall in blood oxygen and increase the drive to breathe in order to restore oxygen levels to normal. The mechanisms that underpin the response of these organs to changes in blood gases are not well understood. This research will test the hypothesis that that the energy- sensing enzyme AMP-activated protein kinase is required for the generation of a complete ventilatory response to low oxygen.