PERINATAL HYPEROXIA AND ADULT ARTERIAL CHEMORECEPTION

描述(申请人摘要)：这项提案的根本目的是 研究与颈动脉小体可塑性相关的细胞机制 (CB)化学感受器。具体地说，我们建议研究细胞 低氧诱导心肌细胞功能恢复的机制 围产期高氧处理大鼠的CBS受损。大鼠，围产期 高氧(产后第一个月60%的氧气)会损害 对低氧的换气反应，这种反应会持续到成年。这 是由于CB功能受损，包括CB大小和数量减少 岩神经节(Pg)的化学传入轴突。据推测， 围产期高氧抑制CB和PG化学传入的正常成熟 关键发育窗口内的神经元。一旦这个发展窗口 已经结束，正常的发育可塑性机制就不能继续进行。近期 研究表明，1周的持续低氧(SH)引起显著的 缺氧呼吸反应的恢复，初步数据表明 这种恢复可能是由CB介导的。我们的中心假设是SH诱导的 呼吸功能的恢复源于CB及其周围组织的可塑性 化学传入神经元。为了验证这一假设，成年大鼠受到 围产期高氧症，将暴露在SH中长达4周。可预测的 结果应该确定SH诱导的CB功能恢复是否是永久性的。 SH处理组和对照组的测量将包括CB评估 通过颈动脉窦神经记录、免疫细胞化学分析和/或 功能蛋白的信使核糖核酸分析(磷酸化的环-AMP反应 元素结合蛋白、酪氨酸羟基酶、脑源性神经营养 因子，胶质细胞源性神经营养因子，血管内皮细胞 生长因子)以及CB和PG中形态恢复的证据。这 项目应提供有关SH诱导的CB神经可塑性的新信息 和PG在围产期高氧治疗和正常动物中的表达，并可能提示 儿童动脉化疗敏感性减退的治疗方法 围产期高氧症。

DESCRIPTION (Applicant's abstract): The fundamental goal of this proposal is to investigate cellular mechanisms associated with plasticity in the carotid body (CB) chemoreceptors. Specifically, we propose to investigate cellular mechanisms which underlie putative hypoxia-induced functional recovery of impaired CBs in rats treated with perinatal hyperoxia. In rats, perinatal hyperoxia (60 percent O2 for the first month post-partum) impairs the ventilatory response to hypoxia, an effect that persists into adulthood. This is due to impaired CB function and includes a reduction in CB size and number of chemoafferent axons from the petrosal ganglion (PG). It is postulated that perinatal hyperoxia suppresses normal maturation of the CB and PG chemoafferent neurons within a critical developmental window. Once this developmental window has ended, normal mechanisms of developmental plasticity cannot proceed. Recent studies indicate that 1 week of sustained hypoxia (SH) induces significant recovery of the hypoxic ventilatory response, and preliminary data suggest that this recovery may be CB-mediated. Our central hypothesis is that SH-induced recovery of ventilatory function arises from plasticity in the CB and its chemoafferent neurons. To test this hypothesis, adult rats subjected to perinatal hyperoxia, will be exposed to SH for up to 4 weeks. Predictable outcomes should determine if SH-induced recovery of CB function is permanent. Measurements in SH-treated and control groups will include assessment of CB function by carotid sinus nerve recording, immunocytochemical analysis and/or mRNA analysis of functional proteins (phosphorylated cyclic-AMP response element-binding protein, tyrosine hydroxylase, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, vascular endothelial growth factor) and evidence of morphological recovery in the CB and PG. This project should provide new information on SH-induced neuroplasticity of the CB and PG in both perinatal hyperoxia treated and normal animals and may suggest methods to treat children with impaired arterial chemosensitivity due to perinatal hyperoxia.