CAROTID BODY CHEMORECEPTION--MECHANISMS AND DEVELOPMENT

描述(改编自申请人的摘要)：原发缺氧 心肺系统的感应器是颈动脉小体，它是 出生时相对不敏感，在出生后1-2周内成熟 生活。尽管化学转导的机制仍然不清楚，但 与传入神经末梢相对的球状细胞、分泌细胞也是如此 因为神经末梢本身似乎形成了关键的化学感受器 单位。目前的信号转导模型认为，低氧可导致神经细胞释放 球体细胞的兴奋性递质，可能是由于抑制了一种 氧敏感钾电流。在最初的资助期，PI测试了 这一假设与一种新的实验模型相结合，它允许同时 神经活动记录，膜片钳记录球体细胞电流 微伏安法检测儿茶酚胺释放量。实验 结果并不支持K+通道在氧感应中的中心作用 由于茶和4-AP未能刺激分泌或神经活动，导致 推测传入神经对化疗药物敏感性的PI有助于 在器官功能中的重要作用。这得到了新的初步数据的支持 化学感受器胞体对化疗药物的固有敏感性 神经元。拟议的工作重点是发育和低氧诱导 岩神经元膜电流的变化。具体地说，PI 将：1)比较化学感受器和非化学感受器岩层电流 发育过程中的神经元。2)确定低氧引起的这些变化 洋流。3)研究Na+和Ca+2通道在穗电发生中的作用。 这些实验利用细胞外和细胞内(膜片钳) 岩石化学感受器和非化学感受器神经元的记录和 传入轴突的棘波间期序列分析。预期中的 结果将有助于更好地理解血管球蛋白的机制 细胞/神经末梢转导和成熟。这应该会导致 这些过程的药理学靶向，以改进治疗 呼吸暂停和/或呼吸困难。

DESCRIPTION (Adapted from the applicant's abstract): The primary hypoxia sensor of the cardio-respiratory system is the carotid body which is relatively insensitive at birth and matures over the first 1-2 weeks of life. Although the mechanisms of chemotransduction remains obscure, the glomus cells, secretory cells apposed to the afferent nerve endings, as well as the nerve endings themselves appear to form the critical chemoreceptive unit. Current transduction models propose that hypoxia causes release of an excitatory transmitter from glomus cells, perhaps due to inhibition of an oxygen sensitive K+ current. In the initial funding period the PI tested this hypothesis with a new experimental model which allowed for simultaneous recording of nerve activity, patch clamp recording of glomus cell currents and microvoltammetric detection of catecholamine release. Experimental results did not support the central role of K+ channels in oxygen sensing since TEA and 4-AP failed to stimulate secretion or nerve activity, leading the PI to speculate that chemosensitivity of the afferent nerve subserves an essential role in organ function. This is supported by new preliminary data demonstrating inherent chemosensitivity in the soma of chemoreceptor neurons. The proposed work focuses on developmental and hypoxia-induced changes in membrane currents of petrosal neurons. Specifically, the PI will: 1) Compare currents of chemoreceptor and non-chemoreceptor petrosal neurons during development. 2) Determine hypoxia-induced changes in these currents. 3) Examine the role of Na+ and Ca+2 channels in spike generation. These experiments utilize extracellular and intracellular (patch clamp) recordings of petrosal chemoreceptor and non-chemoreceptor neurons and analysis of spike interval trains from afferent axons. The anticipated results will allow for a better understanding of the mechanism of glomus cell/nerve ending transduction and maturation. This should lead to a pharmacologic targeting of these processes for the improved treatment of apnea and/or dyspnea.