DIAPHRAGM NEUROMUSCULAR TRANSMISSION: HYPOXIA & MATURITY

隔膜神经肌肉传输：缺氧

• 批准号: 6389285
• 负责人: Alia R Bazzy-Asaad
• 金额: $ 19.59万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389285
• 关键词: action potentials; age difference; calcium channel; calcium channel blockers; developmental neurobiology; diaphragm; hypoxia; immunocytochemistry; laboratory rat; mature animal; motor neurons; neuromuscular transmission; newborn animals; phrenic nerve; synapses

Respiratory failure is a major cause of morbidity in the newborn period. Evidence from our work and that of others suggests that in this age group diaphragmatic fatigue contributes to this failure, and that neuromuscular transmission (NMT) is an important site of failure. Based on recent data from our laboratory the probable mechanism underlying NMT failure is inadequate neurotransmitter. Although calcium is known to play a pivotal in transmitter release, little is known regarding the maturation of this process with development. Also, little is known regarding how the hypoxia that is associated with respiratory failure modulates NMT in this age group. Hence we hypothesize that: 1) NMT failure is secondary to presynaptic mechanisms at the motor nerve terminal. Ca2+ plays an important role in the development of NMT failure because of structural and/or functional immaturity of specific subtypes of Ca2+ channels in the presynaptic nerve terminal. This will be tested in the isolated rat diaphragm a) using electrophysiological techniques to assess transmitter release in the presence of blockers of Ca2+ channel subtypes; and b) morphologically assessing Ca2+ channel subtypes using immunocytochemistry and molecular techniques. 2) Chronic hypoxia delays the maturation of the NM junction. This is associated with delayed functional maturity of the synapse and decreased synaptic efficacy. This will be tested by comparing the: a) morphology; b) force response; c) action potentials failures; d) quantal content and safety factor; and e) Ca2+ channels of diaphragms of rats raised in chronic hypoxia to control littermates at several time points during the first postnatal month. We believe that these studies will provide a better understanding of the mechanisms underlying diaphragmatic fatigue and respiratory failure in the newborn.

呼吸衰竭是新生儿发病的主要原因。我们和其他研究的证据表明，在这个年龄组中，膈肌疲劳导致了这种衰竭，神经肌肉传递（NMT）是一个重要的衰竭部位。根据我们实验室最近的数据，NMT失败的可能机制是神经递质不足。虽然已知钙在递质释放中起关键作用，但关于这一过程随着发育的成熟却知之甚少。此外，关于与呼吸衰竭相关的缺氧如何调节该年龄组的NMT，我们知之甚少。因此，我们假设：1)NMT故障继发于运动神经末梢的突触前机制。由于突触前神经末梢Ca2+通道的特定亚型的结构和/或功能不成熟，Ca2+在NMT失败的发展中起重要作用。这将在分离的大鼠隔膜中进行测试a)使用电生理技术来评估Ca2+通道亚型阻滞剂存在时的递质释放；b)利用免疫细胞化学和分子技术从形态学上评估Ca2+通道亚型。2)慢性缺氧延迟了NM连接处的成熟。这与突触功能成熟的延迟和突触效能的降低有关。这将通过比较：a)形态学；B)力响应；C)动作电位失效；D)定量含量及安全系数；e)出生后第一个月的几个时间点，在慢性缺氧条件下饲养的大鼠以控制窝仔鼠的膈肌Ca2+通道。我们相信这些研究将为新生儿膈肌疲劳和呼吸衰竭的机制提供更好的理解。