CAROTID BODY CHEMORECEPTION--MECHANISMS AND DEVELOPMENT

描述（改编自申请人摘要）：原发性缺氧 心肺系统的传感器是颈动脉体， 出生时相对不敏感，在出生后的前1-2周内成熟 生活 虽然化学转导的机制仍然不清楚， 血管球细胞、与传入神经末梢并列的分泌细胞， 因为神经末梢本身似乎形成了关键的化学感受性， 单位 电流转导模型提出，缺氧引起的释放， 兴奋性递质从血管球细胞，也许是由于抑制了一个 氧敏钾电流 在最初的资助期间，PI测试了 这一假设与一个新的实验模型，允许同时 记录神经活动，膜片钳记录血管球细胞电流 和微伏安法检测儿茶酚胺释放。 实验 结果不支持K+通道在氧感受中的中心作用 由于TEA和4-AP不能刺激分泌或神经活动， 推测传入神经化学敏感性的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 表明化学感受器的索马中具有固有的化学敏感性 神经元 拟议的工作重点是发育和缺氧诱导的 岩神经元膜电流的变化。 具体来说，PI 将：1）比较化学感受器和非化学感受器岩骨电流 神经元在发育过程中 2)确定缺氧引起的这些变化 水流 3)检查Na+和Ca+2通道在锋电位产生中的作用。 这些实验利用细胞外和细胞内（膜片钳） 岩骨化学感受器和非化学感受器神经元的记录， 来自传入轴突的峰电位间隔序列的分析。 预期 研究结果将有助于更好地了解血管球的机制。 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作用， 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.