The prevalence of Obstructive Sleep Apnea (OSA) is increasing dramatically in the U.S. representing a serious health risk. The primary consequence of airway obstruction during sleep is to cause hypoxemia which stimulates the carotid body, leading to increased respiratory drive until arousal from sleep restores upper airway patency. This project proposes to determine the mechanisms by which the carotid body senses and responds to the repetitive intermittent periods of hypoxemia in OSA. Based on the critically important role of acetylcholine as an excitatory neurotransmitter in the carotid body's chemotransduction of hypoxia, it is hypothesized 1) that the repetitive intermittent hypoxia of OSA alters cholinergic transduction pathways in the carotid body, and 2) that the sensitivity of the carotid body is determined genetically.
Specific Aim 1 will examine the impact of repetitive intermittent hypoxia during sleep on carotid body function in a novel, murine model of sleep disordered breathing.
Specific Aim 2 will investigate the pattern of acetylcholine and other neurotransmitter release from the carotid body, as well as recording carotid sinus nerve activity, in response to repetitive intermittent hypoxia.
Specific Aim 3 will use immunohistochemical and patch clamp analyses to determine if neuronal nicotinic acetylcholine receptors (nAChRs) can account for differential hypoxic responsiveness between mouse strains with differential hypoxic responsiveness and determine whether repetitive intermittent hypoxia upregulates expression of subtypes of nAChRs.
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