Mechanism of Bilirubin-induced Apnea in Preterm Infants

胆红素诱发早产儿呼吸暂停的机制

• 批准号: 10373330
• 负责人: CYNTHIA FRANCES BEARER
• 金额: $ 24.15万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373330
• 关键词: Acute; Address; Albumins; Animal Model; Apnea; Behavior; Bilirubin; Biochemical; Blood; Brain; Brain Stem; Brain region; Breathing; Calcium; Calcium-Activated Potassium Channel; Carbon Dioxide; Cell Nucleus; Cell membrane; Cells; Cerebellum; Chemoreceptors; Choline; Chronic; Clinical; Clinical Trials; Confocal Microscopy; Data; Development; Dietary Intervention; Event; Experimental Models; Exposure to; Foundations; Functional disorder; Funding; Globus Pallidus; Glucuronides; Glucuronosyltransferase; Goals; Gunn Rats; Hippocampus (Brain); Human; Hyperbilirubinemia; Hypoxemia; Hypoxia; Immunohistochemistry; Impairment; In Vitro; Infant; Injury; Intervention; Ion Channel; Laboratories; Lead; Lecithin; Length of Stay; Literature; Measures; Mediating; Membrane Microdomains; Modeling; Morbidity - disease rate; Mutation; Neural Cell Adhesion Molecule L1; Neurites; Neurodevelopmental Disability; Neurons; Neuroprotective Agents; Nutrient; Outcome; Oxygen; Peripheral; Phospholipids; Phosphorylation; Physiological; Plethysmography; Positioning Attribute; Potassium Channel; Premature Infant; Process; Proteins; Publishing; Rattus; Receptor Signaling; Reporting; Research; Resistance; Respiration; Respiratory Center; Serine; Signal Pathway; Signal Transduction; Signaling Protein; Slice; Sphingomyelins; Synapses; Testing; Therapeutic; Tyrosine; Uridine Diphosphate; Weight; alcohol effect; alcohol exposure; animal data; auditory nuclei; brain cell; cell type; choline supplementation; clinically relevant; high reward; high risk; improved; in vivo; intervention effect; myelination; neural circuit; neuron development; neuronal excitability; neurotoxicity; novel; patch clamp; postnatal; premature; preterm newborn; protein transport; pup; ranpirnase; respiratory; response; spelling; trafficking; voltage

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.

早产新生儿游离胆红素（Bf）升高是导致长期高胆红素血症的主要全球性原因。 神经发育障碍，但损伤的机制仍不清楚。早产儿BF 与阵发性呼吸停止有关，如果超过15秒，则称为呼吸暂停 早产儿总的来说，这些呼吸暂停会导致间歇性低氧血症，最终导致 神经发育不良孤束核（nTS）的神经元是 控制呼吸驱动的神经回路的重要部分，包括CO2化学敏感的 神经元、外周化学感受器和介导对外周缺氧的反应。在 在早产新生儿中，大脑的nTS正在快速发育：神经元 分化和延伸神经突，形成突触并经历髓鞘形成。这些 这些过程依赖于被称为脂筏的质膜的动态微区。脂质 筏调节离子通道、信号转导和蛋白质运输的活性。我们假设 Bf破坏脂筏，导致NTS的扰动，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。与我们之前 本研究利用古恩法建立了早产儿高胆红素血症动物模型， 大鼠缺乏将胆红素结合到葡萄糖醛酸苷的能力，因此无法将其排出体外。 1）升高的Bf在体外和离体都破坏了脂筏相关蛋白的功能， 并改变小脑介导的行为，2）胆碱赋予抵抗的影响， Bf对脂筏相关蛋白和行为的影响。这些结果让我们 为了实现以下新的和临床相关的目标：1）探索Bf对脂质的影响， nTS中的筏和参与呼吸的相关核团，以及它们对胆碱的反应，2） 确定有或没有胆碱的Bf升高对nTS中神经元兴奋性的影响， 3)测量呼吸驱动以及它如何受到Bf和胆碱的影响。我们预测脂筏 功能障碍将先于神经元兴奋性和呼吸驱动的变化，而神经元兴奋性和呼吸驱动的所有变化 结果会被胆碱削弱。这些目标的实现将导致临床试验， 胆碱，试图降低与人类早产儿Bf升高相关的发病率。