Breathing disorders in a mouse model of Rett syndrome

雷特综合征小鼠模型的呼吸障碍

• 批准号: 8488505
• 负责人: CHUN JIANG
• 金额: $ 30.5万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488505
• 关键词: Abbreviations; Accounting; Acute; Address; Aerophagy; Affect; Air; Animals; Apnea; Blood gas; Brain; Brain Stem; Brain-Derived Neurotrophic Factor; Breathing; Carbon Dioxide; Cell Line; Cell Nucleus; Cessation of life; Complex; Defect; Denervation; Desipramine; Development; Disease; Dissociation; Electrophysiology (science); Environmental air flow; Etiology; Financial compensation; Frequencies; Genes; Hypercapnia; Hypercapnic respiratory failure; Hyperpnea; Hyperventilation; In Situ Hybridization; Incidence; Intervention; Ion Channel; Knock-out; Lead; Link; Mammals; Mediating; Membrane Potentials; Methyl-CpG-Binding Protein 2; Molecular; Molecular Biology; Molecular Target; Mus; Neurons; Neurotransmitters; Norepinephrine; Nucleus solitarius; Patients; Periodicals; Periodicity; Peripheral; Physiological; Play; Potassium Channel; Preparation; Probability; RNA Interference; Resistance; Rett Syndrome; Role; Serotonin; Slice; Small Interfering RNA; Structure of phrenic nerve; Substance P; Symptoms; System; TRP channel; Techniques; Testing; Therapeutic Intervention; Tidal Volume; Time; Valsalva sinus; Whole Body Plethysmography; autism spectrum disorder; base; design; extracellular; immunocytochemistry; innovation; inward rectifier potassium channel; locus ceruleus structure; mouse model; receptor; research study; respiratory; response; uptake

DESCRIPTION (provided by applicant): Rett Syndrome (RS) is a neurodevelopmental disease caused by the disruption of the X- linked gene encoding methyl-CpG-binding protein 2 (MeCP2). People with RS show breathing instability in addition to autistic symptoms, such as hyperpnea, apnea, apneusis, Valsalva breathing, breath-holding, air swallowing, etc., which are recapitulated in the Mecp2-/Y mice. The breathing disturbances play a role in the high incidence rate of sudden unexplained death and the abnormal brain development. The involvement of brain-derived neurotrophic factor (BDNF), neurotransmitter systems, abnormal neuronal activity and remodeling of respiratory neuronal networks have been suggested. Another potentially important mechanism for the breathing disorders that we have recently found is the defect in central CO2 chemosensitivity (CCS). Our preliminary studies indicated that the Mecp2-/Y mice lost their sensitivity to moderate hypercapnia, while their sensitivity to severe hypercapnia appeared normal, which seems to be due, at least in part, to the defective expression of pH-sensitive ion channels. As a result, CO2 was detected in the mice only when hypercapnia became severe, and the accumulated CO2 caused hyperventilation. After the excessive CO2 was removed from the body, hypoventilation was resumed. The defective response to moderate PCO2 thus can lead to periodical hyper- and hypoventilation. However, the cellular and molecular mechanisms underlying the abnormal CO2 sensitivity are still unclear. Recent studies suggest that the physiologic and pathophysiologic PCO2 spectrum is detected by different pH-sensitive ion channels in wild-type (WT) mammals. The CCS can be disrupted when one of the sensing molecules, that normally covers a part of the PCO2 spectrum, is defective without adequate compensation by other sensing molecules, resulting in sporadic CO2 chemoreception and instable breathing activity, which we believe occurs in RS. We have therefore designed experiments to test this hypothesis that is innovative in the understanding of the breathing disorders in RS and has not been tested before. The central theme of the studies is that the MeCP2 deficiency causes abnormal expression of the pH-sensitive ion channels in the brainstem, leading to defective CO2 chemosensitivity of brainstem neurons and breathing instability. Our specific aims are to address the following questions: 1) How does the Mecp2 knockout affect systemic CO2 sensitivity and breathing rhythmicity? 2) Does the impaired CO2 sensitivity of Mecp2-/Y mice attribute to the central CO2 chemoreception, the peripheral CO2 chemoreception or both? 3) What ionic basis is responsible for the CCS defects in locus coeruleus (LC) neurons of Mecp2-/Y mice, and what ion channels are involved? 4) What mechanisms underlie the defects of the pH-sensitive ion channels in Mecp2-/Y mice? The information to be generated should have impacts on the etiology of the breathing disturbances in RS, the identification of molecular target(s) for therapeutic intervention to the breathing disturbances and the brainstem mechanisms for the CCS mediated by the pH-sensitive ion channels.

描述（由申请人提供）：RETT综合征（RS）是一种神经发育疾病，是由编码甲基-CPG结合蛋白2（MECP2）的X连锁基因的中断引起的。除自闭症症状外，患有RS的人还显示出呼吸不稳定，例如呼吸暂停，呼吸暂停，呼吸暂停，Valsalva呼吸，呼吸呼吸，空气吞咽等，它们在MECP2-/y小鼠中概括。呼吸障碍在突然无法解释的死亡和异常大脑发育的高发病率中起作用。已经提出了脑衍生的神经营养因子（BDNF），神经递质系统，异常神经元活性和呼吸神经元网络的重塑。我们最近发现的呼吸障碍的另一个潜在的重要机制是中央二氧化碳化学敏度（CCS）的缺陷。我们的初步研究表明，MECP2-/Y小鼠失去了对中度高脑膜的敏感性，而它们对严重高脑膜的敏感性似乎正常，这似乎至少部分归因于pH敏感性离子通道的缺陷表达。结果，只有在高碳酸血症变得严重时才在小鼠中检测到二氧化碳，并且累积的二氧化碳引起过度换气。从体内去除过多的二氧化碳后，恢复了不足的剂量。因此，对中度PCO2的有缺陷反应可能导致周期性的过度和不足衰减。然而，二氧化碳敏感性异常的细胞和分子机制尚不清楚。最近的研究表明，野生型（WT）哺乳动物中不同的pH敏感离子通道检测到生理和病理生理PCO2光谱。当通常覆盖PCO2光谱的一部分的感应分子之一时，CC可能会被破坏，而其他感应分子没有足够的补偿，从而导致零星的CO2化学感受和稳固的呼吸活性，我们相信这在RS中。因此，我们设计了实验来检验这一假设，该假设在理解Rs中的呼吸障碍时具有创新性，并且以前尚未进行过测试。研究的中心主题是，MECP2缺乏会导致脑干中pH敏感的离子通道异常表达，从而导致脑干神经元和呼吸不稳定的二氧化碳化学敏感性缺陷。我们的具体目的是解决以下问题：1）MECP2敲除如何影响全身性二氧化碳的灵敏度和呼吸节奏？ 2）MECP2-/Y小鼠的二氧化碳敏感性受损归因于中央二氧化碳化学感受，外围二氧化碳化学感受还是两者兼而有之？ 3）哪些离子基础负责MECP2-/Y小鼠基因座（LC）神经元中的CCS缺陷以及涉及哪些离子通道？ 4）哪些机制是MECP2-/Y小鼠中pH敏感离子通道缺陷的基础？要生成的信息应对Rs中呼吸障碍的病因，识别分子靶标的识别用于呼吸障碍的治疗干预以及由pH敏感离子介导的CCS的脑干机制。