Mechanism of Bilirubin-induced Apnea in Preterm Infants

早产儿游离胆红素(Bf)升高是全球长期致病的主要原因 神经发育障碍，但损伤机制仍不清楚。早产儿的BF 与间歇性呼吸停止有关，如果超过15秒，称为呼吸暂停 早产儿的。总的来说，这些呼吸暂停发作会导致间歇性低氧血症，最终导致 神经发育不良的后果。孤束核的神经元是 控制呼吸驱动的神经回路的重要部分，包括二氧化碳化学敏感性 神经元、外周化学感受器和对外周缺氧的中介反应。在 早产儿，大脑的NTS正在快速发育：神经元 分化和延伸神经突起，形成突触和经历髓鞘形成。这些 过程依赖于被称为脂筏的质膜的动态微域。脂类 木筏调节离子通道的活动、信号转导和蛋白质的运输。我们假设 Bf破坏脂筏导致NTS紊乱，而胆碱，一种已知的 神经保护剂，减少Bf对脂筏和呼吸暂停的影响。带着我们之前的 资助R21，我们使用Gunn建立了早产儿高胆红素血症的动物模型 缺乏将胆红素结合到葡萄糖醛酸脂从而将其排泄的能力的大鼠。我们发现 1)升高的Bf在体外和体外都破坏了脂筏相关蛋白的功能， 并改变小脑调节的行为，并且胆碱提供了对 BF对脂筏相关蛋白和行为的影响。这些结果使我们处于一个有利的地位 为了实现以下新的和临床相关的目标：1)探讨Bf对血脂的影响 参与呼吸的NTS和相关核团中的木筏及其对胆碱的反应，2) 确定Bf升高加或不加胆碱对NTS神经元兴奋性的影响 3)测量呼吸动力以及Bf和胆碱对呼吸动力的影响。我们预测脂筏 功能障碍会先于神经元兴奋性和呼吸驱动的变化，而所有的变化 胆碱会降低治疗效果。这些目标的实现将导致临床试验使用 胆碱，试图降低与人类早产儿Bf升高相关的发病率。

Elevated free bilirubin (Bf) in preterm newborns is a major global cause of long term neurodevelopmental disability but the mechanisms of injury are still unclear. Bf in preterm infants has been associated with episodic cessation of breathing, which if exceeds 15 sec is called apnea of prematurity. Collectively, these apneic spells lead to intermittent hypoxemia, ultimately resulting in poor neurodevelopmental outcomes. The neurons of the nucleus tractus solitarius (nTS) are an essential part of the neural circuitry governing respiratory drive including CO2 chemosensitive neurons, peripheral chemoreceptors and mediating responses to peripheral hypoxia. In the preterm newborn, the nTS of the brain is undergoing rapid development: Neurons are differentiating and extending neurites, forming synapses and undergoing myelination. These processes depend on dynamic microdomains of the plasma membrane called lipid rafts. Lipid rafts regulate activity of ion channels, signal transduction and protein trafficking. We hypothesize that Bf disrupts lipid rafts leading to perturbations in the nTS, and that choline, a known neuroprotectant, reduces the impact of Bf on both lipid rafts and apnea. With our previously funded R21, we developed an animal model of hyperbilirubinemia of prematurity using the Gunn rat which lacks the ability to conjugate bilirubin to glucuronide and thus excrete it. We discovered that 1) elevated Bf disrupts the function of a lipid raft associated protein both in vitro and ex vivo, and alters cerebellar mediated behaviors, and that 2) choline confers resistance to the effects of Bf on both the lipid raft associated protein and behaviors. These results have put us in a position to accomplish the following novel and clinically relevant goals: 1) explore the effects of Bf on lipid rafts in the nTS and associated nuclei involved in respiration, and their response to choline, 2) determine the impact of elevated Bf with or without choline on neuron excitability in the nTS and 3) measure respiratory drive and how it is impacted by Bf and choline. We predict that lipid raft dysfunction will precede changes in neuronal excitability and respiratory drive, and all changes in outcomes will be lessened by choline. The attainment of these goals will lead to clinical trials using choline to try to reduce the morbidity associated with elevated Bf in human preterm infants.