REGULATION OF CAROTID BODY AFFERENT DEVELOPMENT

这项拟议的研究试图确定神经生长因子在大鼠和小鼠化学传入神经元和外周化学反射发育中的作用。岩骨中的化学传入神经元是连接颈动脉小体和中枢自主神经通路的传入纽带，在调节化学感受器对心肺功能的调控中起着关键作用。直到最近，尽管有证据表明化学反射成熟的紊乱可能导致心肺控制的发育障碍，包括婴儿猝死综合征、新生儿和婴儿呼吸不足和呼吸暂停综合征，但人们对化学传入途径发展的机制知之甚少。这一延续建议是基于我们最近的发现，脑源性神经营养因子(BDNF)是神经生长因子家族神经营养因子家族的成员，在胎儿颈动脉体中表达，是化学传入神经元生存和外周化学反射发育所必需的。这些研究旨在进一步明确BDNF在化学反射功能发育中的作用，并阐明新发现的生长因子胶质细胞系衍生神经营养因子(GDNF)在化学传入通路发育中的作用。为了解决这些问题，这项拟议的研究试图确定生长因子对化学传入发育和化学反射成熟的影响，使用的是大鼠胚胎和新生儿，以及缺乏功能性生长因子等位基因的基因工程小鼠。具体地说，我们计划定义1)生长因子对体内和体外化学传入存活和分化的调控，2)生长因子对化学反射发育的调控，利用完整动物的体积描记，3)体内氧气供应对化学传入存活的调节，以及4)内源性BDNF在化学传入神经元中的作用。通过定义生长因子对化学传入通路发育的调控，该研究旨在阐明与理解和改善新生儿和婴儿低通气性和呼吸暂停综合征的治疗相关的细胞和分子机制。分子遗传学研究已经确定BDNF和GDNF是至少一种呼吸发育障碍的候选基因，即先天性中枢低通气综合征。此外，通过阐明氧气供应如何调节出生后的化学传入存活，这些研究旨在深入了解补充氧气治疗和早产儿外周化学反射延迟成熟之间的潜在联系。此外，人们希望，定义这一系统的发展将反过来创建一个适用于整个神经系统的生长因子功能和调节模型。

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.