Consequences of Neonatal Hypoxia

描述(由申请人提供)：越来越多的人认识到，50%的早产儿患有复发性呼吸暂停，往往是致命的。呼吸暂停与间歇性低氧血症有关。低氧是通过颈动脉小体感觉到的，随之而来的反射对维持内环境平衡至关重要。然而，在新生儿中，颈动脉小体和化学反射途径还不成熟。这项拟议研究的总体目标是了解新生儿低氧血症对颈动脉小体和对低氧的呼吸系统反应的影响。根据我们的初步数据，我们假设：a)新生儿间歇性低氧促进颈动脉小体的发育成熟，进而改善对低氧的呼吸反应，b)IH诱导的颈动脉小体成熟变化涉及活性氧物种(ROS)的产生增加，导致球体细胞兴奋性和/或[Ca2+]i动态平衡和/或递质机制的改变。我们建议在新生大鼠幼鼠身上测试这些假说，因为它们在神经元成熟方面类似于未成熟的婴儿。将采用一系列技术，从完整动物的呼吸测量到从颈动脉小体到离子通道的感觉活动测量，以及分离的球体细胞中的递质测量，将采用一种综合方法。目标1中提出的实验确定了导致IH诱导的颈动脉小体对低氧敏感的成熟的因素。目标2中的方案确定了IH条件下大鼠幼鼠的呼吸模式，并评估了颈动脉小体的潜在贡献。目标3的实验旨在评估IH诱导颈动脉体部功能发育成熟的细胞机制(S)，并确定ROS的潜在作用。了解新生儿IH的后果有助于深入了解反复呼吸暂停引起的新生儿间歇性低氧如何影响早产儿的呼吸。实验动物模型：幼鼠。

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.