Retrotrapezoid nucleus and central chemoreception

梯形后核和中枢化学感受

• 批准号: 7463713
• 负责人: Patrice G. Guyenet
• 金额: $ 38.45万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463713
• 关键词: Abbreviations; Acids; Adrenergic Agents; Attenuated; BAC (bacterial artificial chromosome); Blood Pressure; Brain; Breathing; Cell Nucleus; Cells; Chemoreceptors; Complement component C1s; Complex; Economic Inflation; Gene Transfer Techniques; Glutamates; Hereditary Disease; Homeobox; Hormones; Hypercapnia; Hypercapnic respiratory failure; In Situ Hybridization; In Vitro; Lesion; Lung; Mechanoreceptors; Mediating; Medulla Oblongata; Messenger RNA; Molecular; Motor; Motor Neurons; Mus; Mutate; Mutation; NBPhox protein; Neural Pathways; Neurons; Obstructive Sleep Apnea; Pattern; Physiological; Polymerase Chain Reaction; Process; Property; Qualifying; Regulation; Research; Respiration; Role; Serotonin; Sleep; Sleep Apnea Syndromes; Slice; Source; Substance P; Surface; Symptoms; Synapses; Syndrome; System; Temperature; Testing; Thyrotropin-Releasing Hormone; Work; adrenergic; base; central pattern generator; design; glucose sensor; in vivo; man; pH Homeostasis; respiratory; response; selective expression; theories; transcription factor

DESCRIPTION (provided by applicant): Central respiratory chemoreception is the process by which CNS pCO2 activates respiration. This process is essential to maintain breathing automaticity during sleep. Its dysregulation probably contributes to common forms of sleep-disordered breathing (e.g. obstructive sleep apnea, Cheyne-Stokes breathing) and is the most probable cause of the central congenital hypoventilation syndrome (CCHS), a rare genetic disease due to a mutation of the homeobox transcription factor Phox2b. The cellular and molecular underpinning of central respiratory chemoreception is still poorly understood although some of the most important neurons are assumed to reside somewhere close to the ventral surface of the medulla oblongata (VMS). In the past three years, we have identified within a region of the VMS called retrotrapezoid nucleus (RTN) a cluster of glutamatergic neurons that have properties consistent with central chemoreceptors. The potential importance of these neurons was highlighted by our recent finding that they express Phox2b, the transcription factor that is mutated in CCHS. The present project is designed to explore the role of these Phox2b-expressing neurons in breathing in general and in respiratory chemoreception in particular. The research is organized around three Aims. In Aim 1 we seek further evidence that these RTN neurons regulate the respiratory rhythm and pattern generator. More specifically, we propose to determine whether selective lesions of the Phox2b-expressing neurons produce the expected reduction in central chemoreflexes and we also seek to identify which respiratory neurons are synaptic targets of these cells. In Aim 2 we ask whether these Phox2b- expressing neurons are activated by acidification in vitro, a property required for such cells to qualify as central chemoreceptors. Finally, in Aim 3 we propose to study some of the brain inputs that regulate the activity and pH-sensitivity of the Phox2b-expressing neurons of the RTN with a focus on lung mechanoreceptors and on inputs from the serotonergic system. In short, this research has two objectives: first to increase current understanding of the cellular mechanisms responsible for central respiratory chemoreception and second, to help understand the causes of CCHS.

描述（由申请人提供）：中央呼吸系统化学感受是CNS PCO2激活呼吸的过程。此过程对于在睡眠期间保持呼吸自动性至关重要。它的失调可能有助于呼吸呼吸的常见形式（例如阻塞性睡眠呼吸暂停，cheyne-stokes呼吸），并且是中央先天性先天性降解综合征（CCHS）的最可能原因，这是由于同源性转录因子Phox2b的突变而引起的罕见遗传疾病。尽管假定一些最重要的神经元驻留在髓质长石（VMS）的腹表面附近，但中枢呼吸性化学感受的细胞和分子基础仍然很少了解。在过去的三年中，我们在称为逆转录核核（RTN）的VM的区域中鉴定了一个与中央化学感受器一致的特性的谷氨酸能神经元簇。这些神经元的潜在重要性是通过我们最近的发现表达PHOX2B的潜在重要性，即CCH中突变的转录因子。本项目旨在探讨这些表达PHOX2B神经元在呼吸中尤其是呼吸性化学感受中的作用。这项研究是围绕三个目标进行的。在目标1中，我们寻求进一步的证据，表明这些RTN神经元调节呼吸节奏和模式发生器。更具体地说，我们建议确定表达PHOX2B的神经元的选择性病变是否会产生中央化学反射中心的预期减少，我们还试图确定哪些呼吸神经元是这些细胞的突触靶标。在AIM 2中，我们询问这些PHOX2B表达神经元是否通过体外酸化激活，这是该细胞符合中央化学感受器所需的特性。最后，在AIM 3中，我们建议研究一些大脑输入，以调节RTN表达PHOX2B的神经元的活性和pH值，重点是肺部机械感受器和血清素能系统的输入。简而言之，这项研究有两个目标：首先要增加对负责中央呼吸系统化学感受的细胞机制的当前理解，其次是有助于了解CCH的原因。