The proposed research seeks to define the role of neuronal growth factors in development of chemoafferent neurons and peripheral chemoreflexes in rats and mice. Chemoafferent neurons in the petrosal are the afferent link between the carotid body and central autonomic pathways and thereby play a pivotal role in regulating chemoreceptor control of cardiorespiratory function. Until recently, relatively little was known about mechanisms that underlie development of the chemoafferent pathway, despite evidence that derangements of chemoreflex maturation may contribute to developmental disorders of cardiorespiratory control, including Sudden Infant Death Syndrome and hypoventilation and apneic syndromes in neonates and infants. This continuation proposal is based on our recent discovery that Brain-Derived Neurotrophic Factor (BDNF), a member of the neurotrophin family of neuronal growth factors, is expressed in the fetal carotid body and is required for survival of chemoafferent neurons and development of peripheral chemoreflexes. The proposed studies are designed to further define the role of BDNF in development of chemoreflex function and to elucidate the role of Glial Cell Line-Derived Neurotrophic Factor (GDNF), a newly discovered growth factor in the developing chemoafferent pathway. To approach these issues, the proposed research seeks to define growth factor influences on chemoafferent development and chemoreflex maturation, using rat fetuses and neonates, as well as genetically engineered mice lacking functional growth factor alleles. Specifically, we plan to define 1) Growth factor regulation of chemoafferent survival and differentiation, in vivo and in vitro, 2) Growth factor regulation of chemoreflex development, using plethysmographic recording in intact animals, 3) Regulation of chemoafferent survival by oxygen availability in vivo, and 4) The role of endogenous BDNF in chemoafferent neurons. By defining growth factor regulation of chemoafferent pathway development, the proposed research aims to shed light on cellular and molecular mechanisms relevant to understanding and improved management of hypoventilation and apnea syndromes in neonates and infants. Already, molecular genetic studies have identified bdnf and gdnf as candidate genes for at least one developmental disorder of breathing, Congenital Central Hypoventilation Syndrome. In addition, by elucidating how oxygen availability regulates chemoafferent survival after birth, these studies are designed to provide insight into potential links between supplemental oxygen therapy and delayed maturation of peripheral chemoreflexes in preterm infants. Moreover, it is hoped that defining development of this system will, in turn, create a model of growth factor function and regulation that is applicable to the nervous system as a whole.
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