The mammalian respiratory control system continues to mature after birth. Newborns deprived of peripheral chemoreceptors show hypoventilation, apnea, and sudden death during the neonatal period. Although the peripheral chemoreceptors mediate critically important breathing responses to hypoxia and carbon dioxide, chemoreceptor maturation has received little direct study. This grant application is designed to characterize development of carotid chemoreceptor function and possible mechanisms, using neurophysiological, neuropharmacological, and morphological approaches.
The specific aims are: 1) To characterize maturation of peripheral chemoreceptor sensitivity to O2 and CO2 including dynamic responses, and O2CO2 interaction; 2) To correlate functional changes during maturation with postnatal changes in carotid body levels of neurotransmitters or modulators such as dopamine, norepinephrine, serotonin, and acetylcholine, which may play a prominent role in chemotransduction. 3) Determine the role of dopamine in carotid chemoreceptor responses to natural stimuli; 4) Examine the role of acetylcholine and postnatal development of chemoreceptor function, and 5) Characterize development of carotid body morphology, specifically vascular development with increasing postnatal age. As principal investigator, Dr. Carroll brings to this project an M.D. and 3 years of research training focused on neonatal respiratory physiology; specifically, newborn breathing control. Between the awarding of the M.D. degree and the present, time will have passed in the pursuit of pediatric residency training (3 years), pursuing other interests (1 year), research training in neonatal breathing control (3 years), and becoming established in a faculty position (2.5 years, 1 year without research experience). Since this proposal represents a major departure from techniques learned during Dr. Carroll's fellowship (i.e., training will be necessary in two new areas - neurophysiology and neuropharmacology), this application is for a clinical investigator award. Dr. Robert Fitzgerald (primary sponsor) brings to this application a long history of notable work in the area of carotid body neurophysiology, recently turning his attention to mechanisms in chemotransduction. He is an internationally recognized authority on the peripheral chemoreceptors, having extensively investigated carotid body function over the past 20 years. Dr. Fitzgerald also plays a major role, now and for the last 15 years, in the educational programs of the Department of Environmental Health Sciences. In addition to research pursuits, coordinating courses in physiology, and teaching, he served as associate department chairman from 1978-1988.
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