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）：雷特综合征（RS）是一种由编码甲基CpG结合蛋白2（MeCP2）的X连锁基因破坏引起的神经发育疾病。 RS患者除了自闭症症状外还表现出呼吸不稳定，例如呼吸过度、呼吸暂停、呼吸暂停、Valsalva呼吸、屏气、吞气等，这些在Mecp2-/Y小鼠中都有重现。呼吸障碍是导致不明原因猝死率高和大脑发育异常的原因之一。有人提出脑源性神经营养因子（BDNF）、神经递质系统、异常神经元活动和呼吸神经元网络重塑的参与。我们最近发现的呼吸障碍的另一个潜在重要机制是中枢二氧化碳化学敏感性（CCS）的缺陷。我们的初步研究表明，Mecp2-/Y 小鼠失去了对中度高碳酸血症的敏感性，而对重度高碳酸血症的敏感性似乎正常，这似乎至少部分是由于 pH 敏感离子通道的表达缺陷所致。结果，只有当高碳酸血症变得严重时，小鼠体内才能检测到CO2，并且累积的CO2导致过度换气。当过量的CO2被排出体外后，通气不足又恢复了。因此，对中度 PCO2 的反应缺陷可能导致周期性过度通气和通气不足。然而，CO2敏感性异常的细胞和分子机制仍不清楚。最近的研究表明，野生型 (WT) 哺乳动物的生理和病理生理 PCO2 谱是通过不同 pH 敏感离子通道检测到的。当通常覆盖部分 PCO2 光谱的传感分子之一出现缺陷而没有其他传感分子充分补偿时，CCS 可能会受到干扰，导致零星的 CO2 化学感受和不稳定的呼吸活动，我们认为这发生在 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 呼吸障碍方面具有创新性，并且以前从未被测试过。研究的中心主题是MeCP2缺乏导致脑干中pH敏感离子通道的异常表达，导致脑干神经元的CO2化学敏感性缺陷和呼吸不稳定。我们的具体目标是解决以下问题：1）Mecp2 敲除如何影响全身 CO2 敏感性和呼吸节律？ 2) Mecp2-/Y 小鼠 CO2 敏感性受损是否归因于中枢 CO2 化学感受、外周 CO2 化学感受或两者？ 3）Mecp2-/Y小鼠蓝斑（LC）神经元的CCS缺陷是由什么离子基础造成的，以及涉及哪些离子通道？ 4) Mecp2-/Y 小鼠 pH 敏感离子通道缺陷的机制是什么？生成的信息应该对 RS 呼吸障碍的病因学、呼吸障碍治疗干预的分子靶标的识别以及 pH 敏感离子通道介导的 CCS 的脑干机制产生影响。