Mechanism of perinatal-hyperoxic suppression of chemoreceptor function

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DESCRIPTION (provided by applicant): Carotid body chemoreceptors are the primary sensors of the respiratory/cardiovascular system for the rapid detection of hypoxia (low blood oxygen). Their stimulation initiates a number of protective reflexes, including an increase in drive to breathe, arousal from sleep and increased blood pressure. Previous, published results demonstrated that exposure to hyperoxia (high blood oxygen) during critical periods in the time immediately after birth results in an impaired ventilatory response to acute hypoxia, an impairment that lasts throughout life, despite a return to normal levels of oxygen. The purpose of our proposed study is to identify the mechanism by which hyperoxia exposure results in impaired chemoreceptor function. Work from our laboratories demonstrate that hyperoxia exposure results in a large decrease in afferent nerve activity during normoxia and during acute hypoxia exposure. The impaired oxygen sensing appears due to alterations in the function of glomus cells - cells presynaptic to the afferent nerve endings and which are generally believed to be the site of transduction of hypoxia. Gene chip analysis (and confirmation by real-time, semi-quantitative PCR) demonstrate that hyperoxia reduces expression of multiple genes involved in the synthesis of secretory granules and reduces expression of some ion channels which are proposed to be involved in hypoxia-mediated depolarization of glomus cells, specifically TASK-1 and TASK-3. Furthermore, the depolarization and secretory responses of glomus cells to acute hypoxia are reduced by hyperoxia exposure. The proposed studies will examine the time course of genetic changes and correlate this with changes in organ function as assessed by secretion (voltammetry), organ function (spiking activity on single axons) and biophysical responses to hypoxia of glomus cells (depolarization, calcium responses). Identification of genes critical for organ function and which are altered by hyperoxia will be assessed by gene chip analyses and confirmation by PCR and quantitative immunohistochemistry. Confirmation of function will be undertaken using siRNA suppression of candidate genes. The anticipated results will identify critical elements within peripheral chemoreceptors which are altered by perinatal hyperoxia. Since hyperoxia is extensively used clinically in newborn and, especially in premature infants, these results are important in understanding physiologic alterations caused by this intervention.