Cellular and molecular mechanisms of central chemosensory control of breathing. Central chemosensitivity and the reaction theory revisited. (360G-Wellcome-079040_Z_06_Z)

Breathing is the vital rhythmic activity which supports life of an individual by maintaining appropriate rates of oxygen uptake and CO2 elimination. This project addresses one of the most fundamental processes in respiratory physiology - central respiratory CO2 chemosensitivity, which is essential to adjust breathing to the needs of metabolism. Despite significant progress in this field the specific mechanisms of central respiratory chemosensitivity remain largely unknown. In order to pinpoint these mechanisms I propose to usea unique combination of experimental models ranging from cell culture to in vivo animal preparations. Cutting-edge optical imaging and electrophysiological recording techniques will be used to re-evaluate the relative roles of CO2, H+, and HCO3- as potential stimuli for central respiratory chemoreceptors. I shall then identify within the brainstem the populations of cells which respond first to physiologically relevant chemosensory stimulation in physiologically appropriate experimental conditions. To determine how the chemosensory stimulus is transduced I shall use pharmacological approaches to screen through potential intracellular and membrane targets to identify the mechanisms responsible for cellular chemosensitivity. When the candidate central respiratory chemoreceptors and putative chemosensory transduction mechanisms are identified, their physiological roles in mediating respiratory responses to CO2 will be tested using in vivo models.