Postnatal CCR disruption in MeCP2-defective mice

描述（申请人提供）：雷特综合症（RTT）是自闭症谱系障碍家族中的一种神经发育疾病，是由编码甲基 CpG 结合蛋白 2（MeCP2）的 X 连锁基因缺陷引起的，每 10,000 个活产女性中就有一个受到影响。 RTT患者表现出呼吸异常，如阵发性呼吸不规则、屏气、呼吸暂停、呼吸过度、呼吸暂停、Valsalva呼吸、吞气等。呼吸障碍在不明原因猝死中发挥作用，并导致大脑发育异常。大多数呼吸障碍在 Mecp2 敲除小鼠中重现，其中脑干呼吸神经元活动、神经递质系统、蛋白质表达和脑源性神经营养因子的缺陷已被证明发挥了作用。呼吸障碍的另一个潜在机制是中枢二氧化碳化学感受（CCR），用于呼吸活动的反馈调节，因为 CCR 的破坏可能导致严重的呼吸后果。我们的初步研究表明，雄性半合子 Mecp2 敲除 (Mecp2-/Y) 小鼠对特定水平高碳酸血症的呼吸反应受损，并伴有几种 CO2 化学敏感性和儿茶酚胺生物合成候选蛋白的缺陷。 CCR 缺陷发生在成熟期间，在 4 周龄时未见。我们相信这些都是重要的发现，因为 RTT 小鼠模型提出了呼吸功能障碍的新病因。由于 CCR 破坏和呼吸心律失常发生在出生后的特定年龄，因此对 CCR 破坏的发展及其分子和细胞基础的详细研究可能有助于深入了解该疾病，并有助于制定有效的治疗方式来控制 RTT 患者的呼吸障碍。因此，我们提出了实验来解决以下具体目标：1）证明 Mecp2-/Y 小鼠中的 CCR 破坏及其发育过程，2）确定与 Mecp2-/Y 小鼠中 CCR 破坏的发展相关的细胞和分子异常。研究结果将促进对 RTT 的理解以及有效治疗方式的设计，以减轻 RTT 患者的症状并防止意外死亡。 公共卫生相关性：雷特综合症是自闭症谱系障碍中的一种神经发育疾病。 Rett 患者因某些未知原因而表现出呼吸障碍，我们推测这与脑干 CO2 化学感受破坏有关。对呼吸障碍发展的研究将带来缓解呼吸障碍并减少疾病突然和意外死亡的信息。

DESCRIPTION (provided by applicant): Rett Syndrome (RTT), a neurodevelopmental disease in the family of Autism Spectrum Disorders, is caused by defects in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2), affecting one in every 10,000 live births of females. RTT patients show breathing abnormalities such as episodic respiratory irregularity, breath-holding, apnea, hyperpnea, apneusis, Valsalva breathing, air swallowing, etc. The breathing disorders play a role in the sudden unexplained death and contribute to the abnormal development of the brain. Most of the breathing disturbances are recapitulated in Mecp2- knockout mice in which defects in brainstem respiratory neuronal activity, neurotransmitter systems, protein expression and brain-derived neurotrophic factor have been shown to play a role. Another potential mechanism for the breathing disorders is central CO2 chemoreception (CCR) serving for the feedback regulation of respiratory activity, as disruption of the CCR can lead to severe breathing consequences. Our preliminary studies indicated that the breathing response to a particular level of hypercapnia was impaired in male hemizygous Mecp2-knockout (Mecp2-/Y) mice, accompanying with defects in the several candidate proteins for CO2 chemosensitivity and catecholamine biosynthesis. The CCR defect occurred during maturation and was not seen at age of 4 weeks. We believe that these are important findings, as a novel etiology for the respiratory dysfunction is suggested in the mouse model of RTT. Since the CCR disruption and breathing arrhythmias occur at certain age after birth, detailed studies of the development of the CCR disruption and its molecular and cellular basis may shed insight into the disease and help to formulate effective therapeutic modalities to control breathing disorders in RTT patients. Therefore, we have proposed experiments to address following specific aims: 1) to demonstrate the CCR disruption and its developmental course in Mecp2-/Y mice, and 2) to determine the cellular and molecular abnormalities associated with the development of CCR disruption in Mecp2-/Y mice. Outcome of the studies will advance the understanding of RTT and the design of effective therapeutic modalities to alleviate symptoms and prevent unexpected death of RTT patients. PUBLIC HEALTH RELEVANCE: Rett Syndrome is a neurodevelopmental disease in the Autism Spectrum Disorders. Rett patients show breathing disorders for some unknown reasons, which we hypothesize to be related to the disruption of brainstem CO2 chemoreception. Studies on the development of breathing disorders will lead to information to alleviate breathing disorders and reduce the sudden and unexpected death of the disease.