Postnatal CCR disruption in MeCP2-defective mice

描述(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，由编码甲基CpG结合蛋白2(MeCP2)的X连锁基因缺陷引起，每10,000名女性活产中就有一名受到影响。RTT患者表现为阵发性呼吸紊乱、屏气、呼吸暂停、Valsalva呼吸、吞气等呼吸异常，这些呼吸障碍在不明原因猝死中起一定作用，并导致脑发育异常。大多数呼吸障碍都是在MeCP2基因敲除小鼠中出现的，在这些小鼠中，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接收(CCR)，用于反馈调节呼吸活动，因为CCR的干扰可导致严重的呼吸后果。我们的初步研究表明，男性MeCP2基因敲除(MeCP2-/Y)小鼠对特定水平的高碳酸血症的呼吸反应受到损害，并伴有二氧化碳化学敏感性和儿茶酚胺生物合成的几个候选蛋白质的缺陷。CCR缺陷发生在成熟期，4周龄时未见。我们认为这些是重要的发现，因为在RTT的小鼠模型中提出了呼吸功能障碍的新病因学。由于CCR中断和呼吸心律失常发生在出生后的特定年龄，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这种疾病，并有助于制定有效的治疗方案来控制RTT患者的呼吸障碍。因此，我们提出的实验旨在解决以下特定目标：1)证明MeCP2-/Y小鼠Ccr中断及其发育过程；2)确定与MeCP2-/Y小鼠Ccr中断发展相关的细胞和分子异常。研究结果将促进对RTT的了解，并设计有效的治疗方法来缓解RTT患者的症状和防止意外死亡。 公共卫生相关性：Rett综合征是自闭症谱系障碍中的一种神经发育疾病。RETT患者表现出一些未知原因的呼吸障碍，我们推测这与脑干CO2化学接收中断有关。对呼吸障碍发展的研究将带来缓解呼吸障碍的信息，减少疾病的突然和意外死亡。

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.