Intracellular pH Responses of Central Chemoreceptors

中枢化学感受器的细胞内 pH 响应

• 批准号: 7143793
• 负责人: Robert W Putnam
• 金额: $ 28.17万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143793
• 关键词: acid base balance; acidity /alkalinity; biological signal transduction; brain mapping; brain stem; calcium flux; chemoreceptors; hypercapnia; immunocytochemistry; intracellular; laboratory rat; mathematical model; membrane channels; model design /development; neurochemistry; neurons; newborn animals; respiration regulatory center; sleep apnea; sudden infant death syndrome; voltage /patch clamp

DESCRIPTION (provided by applicant): Hypercapnia (increased CO2) is a major stimulus for breathing and is sensed by specialized neurons, called chemosensitive neurons, from several brainstem regions. We have been studying the ionic pathways by which these neurons sense CO2. Based on our findings, we have proposed a new model of chemosensitive signaling, the multiple factors model. The main tenet of this model is that the response of chemosensitive neurons to hypercapnia involves multiple signaling pathways that target multiple ion channels. The work in this revised application is divided into 4 aims: 1) test directly that there are multiple signals involved in chemosensitive signaling, by measuring the intrinsic chemosensitivity of neurons from one brainstem region, focusing especially on neuronal responses to acidic stimuli with pHi held constant and on the role of Cai; 2) determine which ion channels act as targets of chemosensitive signaling and measure their properties, using a combination of immunocytochemistry and voltage clamp techniques to describe which channels are present in chemosensitive neurons and which are affected by hypercapnia; 3) compare the signaling pathways studied in Aim 1 in neurons from three different brainstem regions, the locus coeruleus (low chemosensitivity), the nucleus tractus solitarius (intermediate chemosensitivity) and the retrotrapezoid nucleus (high chemosensitivity) and develop a mathematical model to describe the response of mammalian chemosensitive neurons which combines the multiple signals and ion channel targets described for the neurons from each region; and 4) determine the efferent projections of CO2-chemosensitive neurons combining retrograde labeling with intracellular recordings. These studies will be the first to employ identical techniques in neurons from several brainstem regions which have widely different intrinsic chemosensitivitv, and should yield valuable new insights into the cellular properties that determine chemosensitivity. Further, our results should define the cellular signaling pathways and ion channel targets of chemosensitivitv in neurons and serve to test the multiple factors model. Many diseases, including sleep apnea and Sudden Infant Death Syndrome (SIDS) are believed to involve, in part, disordered central respiratory control, and yet no current drug treatments are available to modify this control pathway. Our studies should suggest new potential targets for drug treatment and may well indicate that a combination of drugs is most effective in modifying central respiratory drive. Lay Summary: Increased CO2, sensed by brainstem neurons, is a major stimulus that drives breathing. Alterations of this response are thought to be involved, in part, in diseases like sleep apnea, but no drugs are now available to affect this response. We are studying the ways in which neurons respond to CO2 to identify novel drug targets and to test a new theory that this pathway involves several different signals.

描述（由申请人提供）：高碳酸盐（增加的CO2）是呼吸的主要刺激，并由来自几个脑干区域的专门神经元（称为化学敏感神经元）感测。我们一直在研究这些神经元感应二氧化碳的离子途径。根据我们的发现，我们提出了一种新的化学信号传导模型，即多个因素模型。该模型的主要原则是化学敏感性神经元对高碳酸氢菌的反应涉及靶向多个离子通道的多个信号通路。该修订后的应用中的工作分为4个目标：1）直接测试化学敏感信号传导中涉及多个信号，通过测量一个脑干区域的神经元的固有化学敏感性，尤其集中于对酸性刺激的神经元响应，其对PHI的酸性刺激持续持续和CAI的作用； 2）使用免疫细胞化学和电压夹技术的组合来描述哪些离子信号传导的靶标并测量其性能，以描述哪些通道在化学敏感性神经元中存在，哪些通道受到高碳酸酯的影响； 3) compare the signaling pathways studied in Aim 1 in neurons from three different brainstem regions, the locus coeruleus (low chemosensitivity), the nucleus tractus solitarius (intermediate chemosensitivity) and the retrotrapezoid nucleus (high chemosensitivity) and develop a mathematical model to describe the response of mammalian chemosensitive neurons which combines the multiple signals and ion channel targets described对于每个区域的神经元； 4）确定将逆行标记与细胞内记录相结合的CO2化学神经元的传出投影。这些研究将是第一个在几个脑干地区采用相同技术的技术，这些神经元具有广泛不同的固有化学感应性，并应对确定化学敏感性的细胞特性产生有价值的新见解。此外，我们的结果应定义神经元中化学上含量的细胞信号通路和离子通道靶标，并用于测试多个因素模型。据信，许多疾病，包括睡眠呼吸暂停和猝死综合征（SIDS），部分涉及中央呼吸道控制无序，但目前尚无目前的药物治疗来修改该控制途径。我们的研究应提示药物治疗的新潜在靶标，并且很可能表明药物组合在修饰中央呼吸道驱动方面最有效。 Lay摘要：通过脑干神经元感知的CO2增加是驱动呼吸的主要刺激。这种反应的改变被认为部分涉及睡眠呼吸暂停之类的疾病，但现在没有药物可以影响这种反应。我们正在研究神经元对二氧化碳的反应方式以识别新的药物靶标，并测试该途径涉及几种不同信号的新理论。