Glial chemosensitivity: pH sensing and interactions with neuronal chemoreceptors

胶质细胞化学敏感性：pH 传感及其与神经元化学感受器的相互作用

• 批准号: 8268399
• 负责人: DANIEL K MULKEY
• 金额: $ 36.46万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268399
• 关键词: Address; Adenosine; Animals; Biological Neural Networks; Blood; Blood Circulation; Blood Vessels; Blood flow; Brain; Brain Stem; Breathing; Buffers; Caliber; Carbon Dioxide; Cell Nucleus; Cells; Central Sleep Apnea; Chemoreceptors; Electrophysiology (science); Frequencies; Genetic; Hypercapnic respiratory failure; Immunohistochemistry; In Vitro; Individual; Investigation; Knockout Mice; Lead; Measures; Mediating; Membrane Potentials; Messenger RNA; Microcirculation; Microscopy; Modeling; Molecular; Molecular Genetics; Neuroglia; Neurons; Output; Plethysmography; Population; Preparation; Proteins; Protocols documentation; Protoplasmic Astrocyte; Qualifying; Research; Respiratory Center; Signal Transduction; Site; Sleep; Slice; Source; Syndrome; Testing; Therapeutic; Tissues; Vasodilation; Video Microscopy; Voltage-Clamp Technics; Whole-Cell Recordings; base; cell type; defined contribution; disorder control; electrical property; in vivo; knockout animal; novel; novel therapeutics; public health relevance; receptor; respiratory; response; sensor; tool; voltage clamp

DESCRIPTION (provided by applicant): Central chemoreception is the mechanism by which specialized CO2/pH sensors (i.e., chemoreceptors) located in the brainstem regulates breathing in response to changes in tissue pH. This mechanism is important for normal breathing, especially during sleep, and disruption of chemoreception is thought to contribute to several pathological states including central sleep apnea, periodic breathing and central hypoventilation syndrome. Despite intensive investigation, cellular and molecular mechanisms underlying central chemoreception remain poorly understood. Recent evidence indicates that pH-sensitive neurons located in the retrotrapezoid nucleus (RTN) are important chemoreceptors. Evidence also indicates that CO2/H+-evoked ATP release in the RTN contributes to integrated output of the RTN and respiratory drive. We hypothesize that pH-sensitive RTN glial cells are the source of this purinergic drive to breathe. We propose that a discreet population of RTN glia sense H+ by inhibition of heteromeric Kir4.1-Kir5.1 channels, and release ATP to activate pH-sensitive neurons by activation of P2 receptors. We also propose that a portion of H+-evoked ATP released in the RTN will be hydrolyzed to adenosine and serve to limit chemoreceptor activity by initiating vasodilation to buffer tissue pH. The proposed research will use a combination of electrophysiological, immunohistochemical and genetic approaches to determine the cellular identity of pH-sensitive RTN glia, the molecular mechanism by which they sense pH, and their interactions with pH-sensitive neurons and local vasculature. The four specific aims of this project are: 1) determine the cellular identity of pH-sensitive RTN glia, 2) determine the molecular mechanism by which RTN glia sense changes in pH, 3) identify interactions between pH-sensitive glia and pH-sensitive neurons, 4) determine if pH-sensitive glia in the RTN modulate local microcirculation. It is our hope that determining these mechanisms will lead to new therapeutic avenues for the management of conditions resulting from suppressed respiratory drive. PUBLIC HEALTH RELEVANCE: The results of these studies will identity two novel mechanisms by which glial cells contribute to the mechanism by of chemoreception. Specifically, we will establish that a population of glial cells sense H+ by inhibition of Kir4.1-Kir5.1 channels and can provide an excitatory purinergic drive to the neural network that controls depth and frequency of breathing. We also determine that these pH-sensitive glia regulate vascular tone to help buffer tissue pH and limit chemoreceptor activity. Determining these basic cellular mechanisms will help guide new pharmacological approaches for the treatment of respiratory control disorders.

描述（由申请人提供）：中枢化学感受是位于脑干的专门 CO2/pH 传感器（即化学感受器）根据组织 pH 值变化调节呼吸的机制。这种机制对于正常呼吸很重要，尤其是在睡眠期间，化学感受的破坏被认为会导致多种病理状态，包括中枢性睡眠呼吸暂停、周期性呼吸和中枢性通气不足综合征。尽管进行了深入的研究，但中枢化学感受背后的细胞和分子机制仍然知之甚少。最近的证据表明，位于后梯形核 (RTN) 的 pH 敏感神经元是重要的化学感受器。证据还表明，RTN 中 CO2/H+ 诱发的 ATP 释放有助于 RTN 和呼吸驱动的综合输出。我们假设 pH 敏感的 RTN 神经胶质细胞是这种嘌呤能呼吸驱动力的来源。我们提出，RTN 神经胶质细胞的谨慎群体通过抑制异聚 Kir4.1-Kir5.1 通道来感知 H+，并通过激活 P2 受体释放 ATP 来激活 pH 敏感神经元。我们还提出，RTN 中释放的 H+ 诱发的 ATP 的一部分将被水解为腺苷，并通过启动血管舒张来缓冲组织 pH 来限制化学感受器活性。拟议的研究将结合电生理学、免疫组织化学和遗传学方法来确定 pH 敏感 RTN 神经胶质细胞的细胞身份、它们感知 pH 的分子机制以及它们与 pH 敏感神经元和局部脉管系统的相互作用。该项目的四个具体目标是：1）确定 pH 敏感的 RTN 神经胶质细胞的细胞身份，2）确定 RTN 神经胶质细胞感知 pH 变化的分子机制，3）识别 pH 敏感神经胶质细胞和 pH 敏感神经元之间的相互作用，4）确定 RTN 中的 pH 敏感神经胶质细胞是否调节局部微循环。我们希望确定这些机制将为治疗呼吸驱动抑制引起的病症带来新的治疗途径。 公共健康相关性：这些研究的结果将确定神经胶质细胞通过化学感受机制发挥作用的两种新机制。具体来说，我们将确定一群神经胶质细胞通过抑制 Kir4.1-Kir5.1 通道来感知 H+，并为控制呼吸深度和频率的神经网络提供兴奋性嘌呤能驱动。我们还确定这些 pH 敏感神经胶质细胞调节血管张力，以帮助缓冲组织 pH 值并限制化学感受器活性。确定这些基本的细胞机制将有助于指导治疗呼吸控制疾病的新药理学方法。