Postnatal CCR disruption in MeCP2-defective mice

描述（由申请人提供）：Rett综合征（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个活产的女性中就有1个受到影响。RTT患者表现为呼吸异常，如间歇性呼吸不规律、屏气、呼吸暂停、呼吸急促、呼吸暂停、Valsalva呼吸、空气吞咽等。呼吸障碍在不明原因猝死中起着重要作用，并导致大脑发育异常。大多数呼吸障碍在Mecp2基因敲除小鼠中重现，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作用。呼吸障碍的另一个潜在机制是中枢二氧化碳化学接收（CCR），它对呼吸活动起反馈调节作用，因为CCR的破坏会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，并伴有几种二氧化碳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，在4周龄时未见。我们认为这些是重要的发现，因为在RTT小鼠模型中提出了一种新的呼吸功能障碍病因。由于CCR中断和呼吸性心律失常发生在出生后的一定年龄，对CCR中断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，我们提出了以下具体的实验目的：1)证明Mecp2-/Y小鼠CCR破坏及其发育过程，2)确定与Mecp2-/Y小鼠CCR破坏发展相关的细胞和分子异常。这些研究的结果将促进对RTT的理解和设计有效的治疗方式，以减轻RTT患者的症状和防止意外死亡。

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.