Consequences of Neonatal Hypoxia

描述（由申请人提供）：越来越多的人认识到，50%的早产儿患有经常致命的复发性呼吸暂停。呼吸暂停与间歇性低氧血症有关。缺氧是由颈动脉体和随之而来的反射感觉是至关重要的维持体内平衡。然而，对于新生儿来说，颈动脉体和化学反射通路还不成熟。这项研究的总体目标是了解新生儿低氧血症对颈动脉体的影响以及对低氧的反应。基于我们的初步数据，我们假设：a）新生儿间歇性缺氧促进颈动脉体的发育成熟，这反过来又改善了对缺氧的反应，和B）IH诱导的颈动脉体的成熟变化涉及活性氧（ROS）的产生增加，导致兴奋性和/或[Ca 2 +] i稳态和/或血管球细胞中的递质机制的改变。我们建议在新生大鼠幼仔上测试这些假设，因为它们在神经元成熟度方面类似于未成熟的婴儿。将采用一种综合方法，使用一系列技术，从完整动物的呼吸测量到颈动脉体的感觉活动测量，再到离体血管球细胞的离子通道和递质测量。目的1中提出的实验定义了有助于IH诱导的颈动脉体对缺氧敏感性成熟的因素。目的2中的方案确定IH条件化大鼠幼仔的呼吸模式并评估颈动脉体的潜在贡献。目的3中的实验旨在评估IH诱导的颈动脉体功能发育成熟的细胞机制并确定ROS的潜在作用。了解新生儿IH的后果，可以深入了解由反复呼吸暂停引起的新生儿间歇性缺氧如何影响早产儿的通气。实验动物模型：大鼠幼仔。

DESCRIPTION (provided by applicant): It is being increasingly recognized that 50% of prematurely born infants suffer with recurrent apneas that can be often fatal. Apneas are associated with intermittent hypoxemia. Hypoxia is sensed by the carotid bodies and the ensuing reflexes are critical for maintaining homeostasis. However, in neonates, carotid bodies and chemoreflex pathway are immature. The overall goal of the proposed research is to understand the consequences of neonatal hypoxemia on carotid bodies and ventilatory response to hypoxia. Based on our preliminary data, we hypothesize that: a) neonatal intermittent hypoxia promotes the developmental maturity of carotid bodies, which in turn improves ventilatory response to hypoxia, and b) IH-induced maturational changes in the carotid body involve increased generation of reactive oxygen species (ROS) leading to alterations in excitability and/or [Ca2+]i homeostasis and/or transmitter mechanisms in the glomus cells. We propose to test these hypotheses on neonatal rat pups because they resemble immature infants in terms of neuronal maturity. An integrated approach will be employed using a repertoire of techniques ranging from ventilatory measurements in intact animals to sensory activity measurements from carotid body to ion channel and transmitter measurements in isolated glomus cells. Experiments proposed in Aim 1 define the factors that contribute to IH-induced maturity of the carotid body sensitivity to hypoxia. Protocols in Aim 2 determine ventilatory patterns in IH-conditioned rat pups and assess the potential contribution of carotid bodies. Experiments in Aim 3 are aimed at assessing the cellular mechanism(s) underlying IH-induced developmental maturation of carotid body function and determine potential role of ROS. Understanding the consequences of neonatal IH provide insights into how neonatal intermittent hypoxia caused by recurrent apneas affects the ventilation in premature infants. Experimental Animal Model: Rat Pups.