Glial chemosensitivity: molecular mechanisms of pH sensing and interactions with

胶质细胞化学敏感性：pH 传感及其相互作用的分子机制

• 批准号: 8113330
• 负责人: DANIEL K MULKEY
• 金额: $ 36.85万
• 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 2015-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113330
• 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）：中央化学感受是位于脑干中的专门CO2/pH传感器（即化学感受器）的机制，可调节呼吸，以应对组织pH的变化。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有助于几种病理状态，包括中枢睡眠呼吸暂停，周期性呼吸和中央中央次数不足综合征。尽管进行了深入的研究，但中央化学感受的基础的细胞和分子机制仍然鲜为人知。最近的证据表明，位于逆转肌核（RTN）中的pH敏感神经元是重要的化学感受器。证据还表明，RTN中的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驱动器的来源。我们建议，通过抑制异构体Kir4.1-KIR5.1通道，RTN GliA感应H+的谨慎群体，并释放ATP来通过激活P2受体激活pH敏感的神经元。我们还建议将RTN中释放的H+诱发的ATP的一部分水解为腺苷，并通过将血管舒张启动到缓冲组织pH值来限制化学感受器的活性。拟议的研究将结合电生理，免疫组织化学和遗传学方法来确定pH敏感的RTN胶质细胞的细胞认同，它们感知pH的分子机制以及它们与pH敏感的神经元和局部脉管系统的相互作用。该项目的四个具体目的是：1）确定对pH敏感的RTN神经胶质的细胞身份，2）确定RTN GliA含量在pH中的变化，3）确定pH敏感性神经元和pH敏感神经元之间的相互作用，4）确定RTTN pH敏感性是否在RTTN局部局部局部微验证中确定pH敏感性。我们希望确定这些机制将导致新的治疗途径，以管理抑制呼吸道驱动而导致的疾病。 公共卫生相关性：这些研究的结果将识别两种新型机制，通过这些机制通过化学感受促进该机制。具体而言，我们将通过抑制Kir4.1-KIR5.1通道来确定胶质细胞的群体感知H+，并可以向神经网络提供兴奋性的嘌呤能驱动器，以控制呼吸的深度和频率。我们还确定这些pH敏感性的神经胶质调节血管张力以帮助缓冲组织pH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新的药理学方法来治疗呼吸控制障碍。