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Postnatal Resetting of Carotid Chemoreceptor Sensitivity

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The carotid body (CB) chemoreceptors are the main arterial oxygen sensors in mammals. Hypoxic stimulation of O2-sensing CB glomus cells leads depolarization, release of neurotransmitters and increased activity of the carotid sinus nerve (CSN). This initiates corrective responses to ameliorate the reduction in PaO2 including increased drive to breathe, arousal from sleep, increased blood pressure and sympathetic activation. Despite their importance, the carotid chemoreceptors exhibit low sensitivity to hypoxia at birth and become more sensitive over the first few weeks of life. Glomus cell depolarization is an essential step in CB O2 sensing and we previously showed that the magnitude of hypoxia-induced glomus cell depolarization is small just after birth and increases with age. The central developmental hypothesis of this proposal is that postnatal development of the CB glomus cell response to hypoxia is due to an age-related change in the balance of a) ionic forces leading to cell membrane depolarization in response to hypoxia and b) ionic forces that reduce cell membrane excitability and "brake" or limit the magnitude of depolarization. Candidates for K+ channels that initiate/drive hypoxia-induced depolarization are TASK-1, TASK-3 and THIK-1, of which one or more should show increased expression and/or O2-sensitivity with age. TREK-1, TREK-2, BK and HERG-like K+ channels are likely candidates to serve the function of reducing glomus cell excitability in the newborn. BK channels are inhibited by hypoxia in an age-dependent manner and are therefore likely to play a role in CB glomus cell functional maturation. The specific roles of each of these channels in shaping the glomus cell hypoxia response and its postnatal development will be addressed by the 3 aims of this proposal. We believe that successful completion these studies holds the potential to extend our understanding of developmental changes in CB function and provide the basis for greater understanding of how alterations in CB development may lead to cardiorespiratory control disorders and abnormalities. Project Narrative: The proposed studies will elucidate the mechanism by which carotid body glomus cell O2 sensing increases during postnatal maturation. The results will provide a foundation for parallel and future studies to understand how glomus cell depolarization is modulated and how maturation may be affected by environment and disease. The ultimate goal of these studies is to increase our understanding of the pathophysiology of abnormal peripheral chemoreceptor O2 sensing maturation and to provide the basis for pharmacological treatment of disorders involving carotid body O2 sensing.

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